Validating Medical Packaging

Validating Medical Packaging Validating Medical Packaging Ronald Pilchik CRC PR E S S Boca Raton London New York Was...

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Validating Medical Packaging

Validating Medical Packaging Ronald Pilchik

CRC PR E S S Boca Raton London New York Washington, D.C.

Library of Congress Cataloging-in-Publication Data Pilchik, Ronald. Validating medical packaging / Ronald Pilchik. p. cm. Includes index. ISBN 1-56676-807-1 (alk. paper) 1. Medical instruments and apparatus—Packaging—Standards—United States. I Title. R857.P33 P54 2002 681′.761—dc21

2002073339 CIP

This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage or retrieval system, without prior permission in writing from the publisher. The consent of CRC Press LLC does not extend to copying for general distribution, for promotion, for creating new works, or for resale. Specific permission must be obtained in writing from CRC Press LLC for such copying. Direct all inquiries to CRC Press LLC, 2000 N.W. Corporate Blvd., Boca Raton, Florida 33431. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation, without intent to infringe.

Visit the CRC Press Web site at www.crcpress.com © 2003 by CRC Press LLC No claim to original U.S. Government works International Standard Book Number 1-56676-807-1 Library of Congress Card Number 2002073339 Printed in the United States of America 1 2 3 4 5 6 7 8 9 0 Printed on acid-free paper

Table of Contents Introduction ...................................................................................................................... 1 What is Validation?....................................................................................... 2 Package Design Validation ..........................................................................2 Medical Packages.......................................................................................... 3 Package Process Validation .........................................................................4 Additional Reading ......................................................................................5 Chapter one Package Design Validation ........................................................... 7 Elements of Package Design ....................................................................... 7 Package Design Validation................................................................ 8 Function of the Package ....................................................................8 Properties of the Effective Package .................................................8 Shelf Life Considerations ..................................................................9 Package Design Issues ...............................................................................10 Package Testing Protocols ............................................................... 11 Test Sequences ..................................................................... 11 Validation Flowchart ..................................................................................13 Validation Needs ..............................................................................13 Simulation Criteria .....................................................................................13 Package Materials .......................................................................................13 Porous Packaging Materials ...........................................................14 Nonporous Packaging Materials ...................................................14 Qualified Suppliers .....................................................................................15 Additional Reading ....................................................................................15 Chapter two Package Process Validation .......................................................17 Process Validation: What is it? .................................................................17 The Sealing Process ..........................................................................18 Process Capability Studies ..............................................................19 Other Variables Associated with Packaging Sealing Processes .................................................................19 Ability to Control Critical Parameters .............................19 Ability of Critical Parameter Measuring Devices to Read Accurately and Consistently ...............20

Seal Plates Uniform, Level .................................................20 Support Gaskets ..................................................................20 Contamination ..................................................................... 20 Changes in Environmental Conditions ...........................20 Summary and Conclusions ....................................................................... 21 Additional Reading ....................................................................................21 Chapter three Putting It All Together — The Validation Protocol ........ 51 Example 1 .....................................................................................................57 FDA Form 483 .............................................................................................58 Table of Contents ........................................................................................59 Technical bulletin ........................................................................................ 60 Production Information Sheet................................................................... 61 Product Data Sheet A4220 ......................................................................... 62 Quality Audit Report ................................................................................. 64 General Information ...................................................................................65 Ratings Summary .......................................................................................65 Packaging Validation Protocol...................................................................66 Validation Protocol: Process Capability Study....................................... 70 Validation Protocol: Process Capability Study....................................... 71 Validation Protocol: Process Capability Study ......................................72 Subject: Cleanroom "Low Particulate" Cleaning/Maintenance Procedure ...........................................................................................73 Chapter four Regulatory Activities ...................................................................75 Selected Cases .............................................................................................75 Packaging Noncompliances ...................................................................... 76 Industry-Generated Support Documents ...............................................76 CASE STUDY # 1 ........................................................................................79 CASE STUDY # 2 ........................................................................................82 CASE STUDY # 3 ........................................................................................87 IN THE UNITED STATES DISTRICT COURT FOR THE WESTERN DISTRICT OF NORTH CAROLINA CHARLOTTE DIVISION..................................................................90 Appendix 1 .......................................................................................................................93 Appendix 2 .................................................................................................................... 103 Index ................................................................................................................................ 145

Introduction “Each manufacturer shall ensure that device packaging and shipping containers are designed and constructed to protect the device from alteration or damage during the customary conditions of processing, storage, handling, and distribution.” Food and Drug Administration Quality System Regulation 820.160 In this simple paragraph, the Food and Drug Administration (FDA) establishes the manufacturer’s responsibility for medical device packaging, but provides no directions on how to achieve compliance. This paragraph began with the initial Good Manufacturing Practices for Medical Devices published in 1978, and was retained without revision in the FDA QSR of 1997. It has withstood the test of time. We can analyze the requirements carefully: Ensure = guarantee without reservations Designed = package design must be proven Constructed = package processing must be proven Alteration or damage = what conditions represent alteration vs. damage? Customary conditions = “routine” handling — not dropping off a 10story roof or slamming the package against a brick wall or running a forklift through a skid Processing = usually includes sterilization, if the device is to be sterile Storage = when and how and for how long? Handling = throwing off the back of a truck? Distribution = box cars through Alaska in winter and through Arizona in July? Medical device packagers developed an instruction book called ISO 11607 Packaging for Terminally Sterilized Medical Devices. ISO 11607 provides a framework for implementing the Quality System Regulations (QSR) pack-

1

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Validating Medical Packaging

aging requirements if the final product or package is to be sterilized. If the product or package is not sterile, or packaged aseptically, there is no further reference. The key elements of ISO 11607 are package design and package process validation.

What is Validation? Validation is defined as: “establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes.” FDA Process Development Guideline, 1987 We can analyze the definition: Establishing = design + implement + validate + document. These are activities that will prove a package’s ability to meet goals. Documented = if it is not written down when it happened, it did not happen. Evidence = includes the testimony of witnesses, introduction of records, documents, exhibits, objects, or other means introduced for the purpose of inducing belief in the party’s contention by a fact-finder. High-degree of assurance = not absolute. The U.S. citizenry had a high degree (almost absolute) of confidence in the electoral counting system until the election of 2000. Consistently produce = not 100%, but how consistently? Produce a product = read as produce a package. Meeting = evaluated to prove compliance. Predetermined specifications = whose specifications: the manufacturer’s, the user’s, or the government’s? Quality attributes = attributes that are different from measured properties (specifications) that also provide a means of assuring confidence. Label clarity, peeled seal appearance (seal transfer), and others as developed by convention, tradition, or custom. Sections 5 and 6 of ISO 11607 define means for validating package design and package process. Coupled with Section 4 (Material Evaluation), this document is an industry-generated implementation guideline for compliance to FDA QSR 810.160. Validation is simple and additive to the QSR, not separate. It is not new, but is based on concepts first proposed formally by the FDA in 1987. It is not a religion, mythology, or branch of metaphysics, but a program that can be developed and implemented routinely in package design and package processing.

Introduction

3

Package Design Validation Does the design of the package result in the protection sought after time? Will the sterile barrier created initially hold up during the rigors of processing, storage, handling, and distribution? We must rely on simulation to provide the means to answer these questions. Some simulations, such as compatibility to sterilization processes, are easily designed because the sterilization process must be rigorously maintained and not altered. Thus, once established by direct testing, the simulation serves as reality, with no steps having to be “guessed.” Storage, handling, and distribution are entirely different matters. The manufacturer cannot, and should not, be concerned with every possible means of distribution, but instead focus on “standard” simulations, as defined in ASTM 4169 or ISTA-1A. These are annexed in ISO 11607 as alternatives to complex and extensive “guessing” (a high degree of confidence versus absolute assurance). For example, a device is packaged in Minnesota in February (average temperature is 10°F). It is then shipped to New Mexico for distribution. The shipping could be via railroad (3 days), via land vehicle (1 week), or via air (8 hours). Storage in New Mexico can be up to 1 year at ambient warehouse conditions (90°F) and then shipped to Europe for transfer to the Middle East for sale via a combination of ship, rail, air, and over land to the final destination. Transport might include a van (or bicycle) to the hospital receiving area, where the shipment can linger for hours, baking in the sun. How is this all simulated and evaluated? It is not; therefore, a reason for a “high degree of confidence” under “customary conditions.” To add to the level of confidence, the manufacturer should monitor all real-time shipping to look for anomalies that could quickly become trends with these stressful, often undefined, distribution systems.

Medical Packages There are thousands of medical devices and hundreds of manufacturers. With the array of available products, the packaging can often be categorized into groups, depending on several factors. 1. Size, weight, and shape of the device will determine the requirements of rigidity and durability of the package, its materials and design. 2. The sterilization process. There are several sterilization processes. The majority of medical products are sterilized either by gaseous processes (steam, ethylene oxide, hydrogen peroxide) or nongaseous processes (gamma radiation, electron beam). The package materials can differ in each method. Gaseous processes require porous packaging materials, such as paper or Tyvek®; radiation processes do not. 3. The packaging process is often mandated by the volume of products produced. High-volume, common products are usually packaged on high-speed automated equipment (thermoform/fill/seal; TFFS).

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Validating Medical Packaging Table I.1

Popular Packaging Formats in Use Today for Specific Applications

Application

Sterilization Method

Materials

Catheter

EtO Radiation

Porous Nonporous

Drapes

Radiation

Nonporous

Electro-device

EtO

Porous

Gloves

EtO Radiation EtO Radiation EtO

Porous Nonporous Porous Nonporous Porous

Radiation

Nonporous

Non-invasive

EtO

Porous

Orthopedic

Radiation EtO Radiation

Nonporous Porous Nonporous

Sutures

EtO

Porous

Radiation

Nonporous

EtO Radiation

Porous Nonporous

Injection Systems Kits

Wound Dressing

Packaging Process

Package Type

Manual Automated Manual Automated Manual Automated Manual Automated Automated Automated Automated Automated Manual Automated Manual Automated Manual Automated Manual Manual Manual Automated Manual Automated Manual Automated Automated Automated

Pouch Pouch on roll Pouch TFFS Bag Bag on roll Pouch TFFS Pouch on roll Pouch on roll TFFS TFFS Tray/lid TFFS Lid/tray TFFS Tray/lid TFFS Tray/lid Tray/lid Tray/lid TFFS Pouch Pouch on roll Pouch TFFS Pouch on roll Pouch on roll

Note: EtO = Ethylene oxide; TFFS = Thermoform/fill/seal. Source: Industry Source. As cited in Medical Device Packaging: Market Prospects and Technologies, published by Packaging Strategies, Westchester, PA, 2000.

Specialty products, such as kits unique to a particular surgical procedure, catheters, and orthopedic implants, are usually packaged individually (manually). Table I.1 describes ten common classes of devices and the types of package and packaging that are used. In every instance, the requirement for validation is identical and the techniques common. The only variation is in the complexity of the studies leading to validated packages and package processes.

Package Process Validation Package process validation is the sum total of qualifications, certifications, and verifications. First, materials and equipment must be qualified; that is,

Introduction

5

proven to be effective for producing a usable package. Material qualification requires assessment and adherence to mutually agreeable properties between the manufacturer and the producer of materials. Physical measurements, such as material thickness, resistance to tear or puncture, and sealing and forming properties are required; the manufacturer must ensure that these properties are appropriate for the packaging and sterilization process. Equipment is qualified with three levels of appraisal. Initially, installation qualification (IQ) is accomplished by the installers of the equipment based on the equipment manufacturer’s instructions; or, if these instructions cannot be implemented without modification, the modification is recommended by the equipment manufacturer. After IQ is accomplished, the process evolves into operational qualification (OQ). Operational qualification answers questions about the equipment operating properly. Examples of proper operation include the thermostatic heaters reaching and maintaining temperatures as indicated on the monitoring gauges, timers timing sequences accurately, and alarms indicating malfunction properly. IQ and OQ lead to performance qualifications (PQ). Here the equipment is tested to ensure production of proper packaging when set at predetermined parameters. Process capability studies, discussed later, provide the appropriate settings for the equipment. After the qualification of equipment via the IQ, OQ, and PQ routes and certification of the data, the review and approval of the qualification activities results in “certificates.” These documents serve as a permanent record that the proper studies have been conducted and reviewed by responsible parties. These documents become a substantial part of the QSR implementation file. Qualified and certified materials and equipment are placed into production, and the results of several runs are reviewed in depth. This review is verified on a continuing basis. The number of runs necessary for final verification varies as to the extent of the complexity of the process and historical data. Usually, convention calls for three successful, consecutive runs. Bear in mind that every run, which begins with a start-up routine (testing packages and equipment settings) and continues with a degree of inspect-andtest throughout, is a verification run. The effective packaging operation should show little or no significant difference between runs identified as “verification trials” and routine processing. The total of all the qualifications, certifications, and verifications is the validation of the packaging process. The remainder of the volume addresses the specific needs for validation of packaging of medical devices.

Additional Reading DeSain, C.V., and Sutton, C.V., Validation for Device and Diagnostic Manufacturers – Part 1, Basic Principles, Interpharm Press, Inc., Buffalo Grove, IL, 1994. Mogensen, S. and Pilchik, R., Medical Device Packaging: Market Prospects and Technologies, Packaging Strategies, Westchester, PA.

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N.J. Rules of Evidence, Rule 401, Definition of Relevant Evidence. Sharp, J., Validation — how much is required, PDA J. Pharm. Sci. Technol., May/June 1995. Stovak, J., Process Validation, presented at the Medical Device Process Validation Course (FDA), Dallas, TX, 1994.

chapter one

Package Design Validation Package design is a key element of validation. The package must be designed to withstand the rigors of sterilization, transportation, and storage. Therefore, these conditions must be tested for each package design, emphasizing various packaging material combinations. In this way one can be sure that the final package will meet all requirements. Design testing (validation) combined with package process validation (see Chapter 2) provide the basis for a fully validated, effective package.

Elements of Package Design Package design involves three components: 1. The primary package contains the device. The primary package may contain additional components to protect the device. These may include foam inserts for shock and vibration protection and platforms to prevent movement and shifting from potentially damaging the device or package. The primary package may also contain an outer element, or “overwrap” to provide additional sterility assurance. Overwraps are used when the entire inner package must enter the sterile field, rather than the device contained within. A typical primary package can be a multicomponent system, such as a tray/lid combination with various inserts to fill the tray and an outer vented bag to ensure that both the internal contents of the tray are sterile, as well as the outside surfaces of the tray/lid package. 2. The secondary package is usually a folded carton “shelf-pack” containing one primary package system. The shelf-pack often contains labeling information including barcodes for patient and device traceability. The secondary package is designed to remain with the primary package through most of the life cycle of the package system. 3. The tertiary package is a shipping carton containing multiple packages of the device. It is used for safe, efficient, and economical shipping to customers. The shipping carton is usually discarded on receipt while the secondary packages are stored in holding areas before use. 7

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Validating Medical Packaging

Package Design Validation To properly validate the design of the packaging for medical devices, one must test the entire packaging system. The packaging system interacts with the device at all levels. The addition of secondary and tertiary packaging may affect sterilization efficiencies and certainly impacts shock and vibration diffusion. This approach takes the entire system through a testing protocol that is standardized and rigorous. Two testing systems usually used for medical devices are ISTA-1 or ASTM 4169. An important aspect of package design validation that is not incorporated in standardized testing systems involves the transport of the device in the secondary packages after removal of the shipping carton. There are times when less than case quantities are transported between hospitals, when purchasing and storage is centralized for a multi-hospital network, or shipped again in multi-product shippers from a central distribution organization, such as a surgical supply company. These situations need to be addressed when designing package systems, if such activities are common for the device product.

Function of the Package What does the package do? Table 1.1 lists the functions of the package for medical devices. These packages differ from others as they undergo sterilization and must maintain the sterile barrier. These special needs distinguish sterile medical device packaging from all others and lead to specific testing and evaluation needs.

Properties of the Effective Package There are three basic elements of package design that must be measured to ensure proper evaluation of a medical device package. They are: 1. Seal strength 2. Seal integrity 3. Package integrity Seal strength is the property that holds the sealed members of the package together. A lid sealed onto a formed polymeric tray is a basic package design. The seal strength is the measurement of the force required to separate the lid from the tray. The two primary tests for seal strength are the ASTM burst test F1140 and the ASTM tensile test F88. Each test has been published and the data ensure validation. Seal integrity is the property associated with the seal being of sufficient quality to prevent microorganisms from penetrating through the seal. These areas for potential ingress are called “channels.” Channels result from partially activated adhesives, movement of the package before adhesive curing, poor or insufficiently maintained sealing equipment, or many other random

Chapter one:

Package Design Validation

9

TABLE 1.1 What Does the Package Do? • Protects/cushions product inside • Forms a sterile barrier • Maintains the barrier over time • Allows the sterilization process to proceed • Allows space for labeling: ID product size Instructions for use Manufacturer’s ID • Allows for easy entry • Allows for safe and sterile handling

occurrences during sealing. While a series of tests are available to evaluate seal integrity, they often require the destruction of the package, thus rendering the operation costly and inefficient. Some of the common tests for seal integrity include: Visual tests, destructive and nondestructive (ASTM F1886) Dye penetration (ASTM F1929) Bubble immersion Gas sensing Vacuum decay Package integrity is the property that ensures that the entire package is free from defects that can allow penetration of microorganisms. Channels in seals and pinholes in trays are primary problems. A test exposing the package to an atmosphere of concentrated microorganisms over time is the usual method for evaluation. Trace gas recognition after exposure of the package shows promise as an alternative method for evaluation without destructive testing.

Shelf Life Considerations Seal or package integrity, coupled with seal strength tests, provide the basis for sterile barrier evaluation. The stability of a sterility barrier is evolving. For many classes of devices, the expiration date is a direct function of the stability date available for the seal, rather than the device. Devices made of inert polymeric materials last a long time. The only limiting factor in the system is the information contained for the package seal and the most reliable approach to obtaining that data is “real time.” While many protocols exist

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Validating Medical Packaging

for accelerated aging of package materials, little is available on material or activated adhesive systems. The chemistry of adhesion is not well characterized; thus, the stability of the activated compounds is less defined. While not entirely valid, accelerated aging protocols are used for medical device packages.

Package Design Issues Table 1.2 lists design problems associated with medical device packages. This list has been developed by user (opener) input and has been consistent over many years. These “consumer aspects” are often at odds with the device marketer and package designer. For example, corporations attempt to establish a company identity with use of consistent graphics or colors. Consumers want less graphics and color differentiation. Package designers need to restrain the device from moving within the package. “Locking-in” the device often makes it difficult to remove it. Package design testing in the laboratory and “real-time” testing of prototypes allow for several designs and material combinations to be tested efficiently. Once design options have proven successful, real-time sterilization, shipping, and storage (stability) testing must follow to ensure complete validation. Table 1.3 lists the key aspects of laboratory simulation testing. The concept of worst-case or, more precisely, most challenging presents the package designer with validation issues. There are cases in which the package design TABLE 1.2 Design Problems • Hard to ID Look-alike packages • Difficult to open Strange shapes/peel tabs • Hard to open Strong bonds • Hard to open properly Sterile transfer • Device access Device "jumps" out Does not come out at all Package has sharp components/edges • Package hard to hold Slippery materials Poor balance

Chapter one:

Package Design Validation

11

TABLE 1.3 Laboratory Simulations • Require accurate models/prototypes or devices Multiple design options • Require controlled set of conditions Alternate practical combinations • Provide early warning signals • Have lower cost than unanticipated problems in scale-up • Must precede field trials as final package must be used for late-term clinical studies

is geared to a specific device, and other cases in which the design will be used for a variety of sizes or modifications of a device system. For example, a collection of intravenous delivery sets are to be contained in the same package configuration. Slight modifications in the number of components make each set unique and provide for a specific function. Do all combinations need to be tested for appropriate package design? The answer is usually “no,” with the design validation evaluator selecting the device combinations that will be the “most challenging” to the package system. “Head space” is a major condition to evaluate. The emptiest and fullest packages will provide the greatest risks for transportation testing; movement within the package and straining the package dimensions increase the potential for shipping damage. By identifying the risks associated with each of the devices within the “family,” package design validation can be reduced to manageable proportions.

Package Testing Protocols Table 1.4 lists the requirements of a testing protocol for package design validation. This list provides the necessary documentation to bring the program forward. While each of the elements is important, the key categories are sampling plans and test sequences.

Test Sequences Table 1.5 presents an acceptable test sequence for a medical device package and identifies test methods that have been published and thus accepted by the industry. Sampling plans are not quite as well defined. Note that simulation testing requires actual devices or accurate models. These are not often available, due to cost, difficulty of manufacture, etc. The package design validation must make some judgmental compromises in these instances. These compromises will affect the sampling plans and force reliance on more intensive real-time testing. Chapter 3 will outline the steps required to validate multiple runs to verify the packaging process. It is also possible to verify the design and packaging process simultaneously, but doing so is not

12

Validating Medical Packaging TABLE 1.4 Testing Protocols • Drawings of packages • Objectives of tests • All material specs and ranges • Processing specs Equipment to be used Projected machine settings Preconditioning • Test systems Specs/methods Equipment needs Sampling plans Controls • Test sequences • Evaluation methods TABLE 1.5 Flowchart for Prototype Qualification Materials at extremes of process capabilities + Products in their final form or accurate models = Test packages Sterilization and shipping studies Packages inspected for damage Packages opened and evaluated for: Device damage Product/packaging interactions Ease of opening Identification/ink interactions

as desirable as having a great deal of the effort completed in a laboratory or prototype environment.

Chapter one:

Package Design Validation

13

TABLE 1.6 Requirements for Simulations • Components and materials from suppliers at process limits • Product in final form or accurate models • Packaging equipment close to or actual production • Sterilization facilities • Package testing equipment • Environmental chambers for stability assessment

Validation Flowchart Table 1.5 provides a flowchart of the steps necessary for complete package prototype qualification.

Validation Needs Table 1.6 lists the requirements for simulation samples. Leading the list of needs is for packaging components and materials produced at the supplier’s process limits. This is ideal but not always available or practical. Multiple lots of packaging can reasonably be substituted because they will incorporate the range of output by the supplier and reflect the extremes of process limits. It is important to establish a procedure whereby the supplier becomes qualified to provide packaging. One of the key requirements of such qualification is an assessment of the supplier to recognize the limits of his processing and to have the necessary controls to ensure continuous operation within the limits.

Simulation Criteria Table 1.7 lists the criteria to evaluate when performing simulation studies. It is strongly recommended that several packaging options be carried through the simulation protocol. Examples of options are: Varying Varying Varying Varying

weights of paper adhesive formulations thickness of tray stock suppliers of similar materials

Package Materials There are two types of packaging materials for medical devices: porous and nonporous.

14

Validating Medical Packaging TABLE 1.7 Simulation Criteria Device damage Discoloration Must be fully functional Seal integrity Visual inspection plus strength testing Sterility maintenance Visual inspection for cracks, tears, holes, slits Dye penetration/water immersion or other physical tests Microbial challenge test/trace gas analysis Ease of opening/identification Packages are opened to look for material deterioration Print must not be discolored/smeared

Porous Packaging Materials There are two porous packaging materials commonly used for medical device packages: Tyvek and paper. Both are used in several grades (weights) based on the varying requirements for strengh and durability. Tyvek, produced by the Dupont company, is a polymeric fiber strand distributed in multiple layers to produce a flat sheet stock. Paper is a specialty produced “medical grade” that is designed to withstand sterilization processes. Both these materials are indicated for sterilized medical device packages requiring porous components to allow for gas sterilization processes.

Nonporous Packaging Materials Nonporous packaging materials are used extensively in medical device packaging. The most common are: polymeric films and foils. Polymeric films are used individually or in combinations. They can be combined by several processes including lamination, co-extrusion, and coating. Combinations are formulated to enhance the properties of any single component. Foils are used in combinations with polymeric components to increase the oxygen and water vapor resistance for those products requiring a high barrier, either to retain moisture or to prevent moisture and oxygen from entering the package. ISO 11607 contains a section (4) concerning the qualification of materials for medical packaging. Each producer of materials must conform to general delineated requirements and each device manufacturer must ensure compatibility of the packaging materials to the manufacturer’s specific device and sterilization and packaging processes.

Chapter one:

Package Design Validation

15

TABLE 1.8 A qualified supplier Reduces or eliminates inspection Commits to TQM/zero defects/GMPS Has broad array of materials Has qualified staff Is quick to supply samples/prototypes Qualifies suppliers Is customer-driven Is innovative Demonstrates continuous improvement Commits to reducing total cost of ownership Commits to long-term relationships Note: GMPS = good manufacturing practices; TQM = total quality management.

Qualified Suppliers Table 1.8 provides a list of requirements for suppliers to the medical device packaging industry. This list is critical to the producer of devices because it ensures that the supplier is a “partner” who will provide assistance in package design, provide timely samples and prototypes, has processes and suppliers under strict control, and has the proper respect for the special needs of the device manufacturer. The supplier is a key player in package design and validation. The expertise provided by qualified suppliers can render the design validation program simpler and more accurate.

Additional Reading AAMI TIR No. 22, Guidance for ANSI/AAMI/ISO 11607. ANSI/AAMI/ISO 11607, Packaging for Terminally Sterilized Medical Devices. Brown, D. L., The current approach to material selection, Proc. Healthpack 2000, CRC Press, Boca Raton, FL. Hergert, B., New developments in barrier films technology, Proc. Healthpack 2000, CRC Press, Boca Raton, FL. Nolan, P. J., An overview of validation of sterile package integrity for medical devices, J. Validation Technology, vol. 1, no. 4, 1996. Shantz, S., Medical device packaging validation: improving results, Package Technology and Engineering, Sept. 1998.

chapter two

Package Process Validation Package process validation is the heart and soul of the validation activity. Its goal is to ensure that packages produced on equipment that has been installed properly (IQ), inspected properly (OQ), maintained adequately, and recently calibrated will produce packages meeting specifications and predetermined quality attributes when operated by properly trained operators.

Process Validation: What is it? Process validation is defined in the 1999 Food and Drug Administration (FDA) guidance document as establishing by objective evidence that a process consistently produces a result or a product meeting its predetermined requirements. If the definition is altered somewhat to include “packaging” in front of “process,” then we have a statement specific for packaging processes. The guideline then devotes its content to the suggested method to attain the appropriate “objective evidence.” To begin, we should distinguish between a law, a regulation, and a guideline. A law is a definitive statement, legally binding, that defines the limits of an activity that are acceptable to society. For example, the Food, Drug and Cosmetic Act of 1938, amended in 1976, providing for the executive branch of the U.S. government to adequately control the activities of the medical device industry to protect the general welfare is a law. The law authorizes the FDA, as a part of the executive branch, to regulate this industry to uniform, consensus rules controlling its activities in the interest of the general public. Such regulations are proposed, discussed, and promulgated after a significant period. For example, the good manufacturing practice (GMP) requirements, initially drafted in 1978, were proposed to be updated in 1993. The resulting amendments were not instituted until 1998. As an alternative to the binding rules and regulations affecting the controlled industry, the FDA developed guidelines. Guidelines are nonbinding suggestions on how to implement appropriate mechanisms within the industry to comply with rules and regulations. 17

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Validating Medical Packaging

Such guidelines, because they are suggestions, can be adapted or altered by the members of the industry. When altered, the company needs to have a documented rationale for the alteration, including a statement that the results of the change still provide the same degree of effectiveness as the suggested approach. The FDA is able, in this manner, to assign regulations that are difficult to initiate or amend, with mechanisms that ensure compliance with the requirements. The process validation guidelines, originally issued in 1987 and amended in 1999, are examples. The primary differences between the 1987 and 1999 versions are primarily in the area of the statistical approach to validation. The document is reproduced as Appendix 2. A general discussion of IQ, OQ, and PQ was included in the introductory section. This chapter contains the elements of process validation that relate specifically to packaging. The FDA/GHTF (Global Harmonization Task Force) guideline illustrates the process for validating a heat sealer. This document should be referred to as the activity unfolds. Exhibits 1 and 2 represent a consistent, rigorous, and documented approach to qualifications of a heat sealer, for installation and operation. The protocols are enhanced representations of the installation and operation instructions in the manufacturer’s booklet. Although safety features are qualified in the protocol, this need not be accomplished as part of validation IQ and OQ, but certainly needs to be qualified early in the installation process.

The Sealing Process The sealing process is universal to package fabrication. The quality of the seal ensures that the package will hold together during sterilization, shipping, and extended storage. The quality of the seal is a combination of two distinct properties: seal strength and seal integrity. Seal strength is the force required to separate the components of the package to allow for removal of the device. Seal integrity is the effectiveness of the seal to prevent the possible introduction of microorganisms. Seal integrity is defined as the absence of channels, voids, creases, or other defects in the seal area. Seal strength is a quantitative measurement using a device that pulls the package members apart in a controlled manner (tensile strength) or bursts the package apart at a measured air pressure (burst strength). Seal integrity is a qualitative or semiqualitative value usually measured by: 1. Visual inspection: pressurizing the package 2. Bubble tests: pressurizing the package underwater and observing bubbles through the seal 3. Introducing a dye atop the seal and observing penetration through the seal 4. Introducing a marker gas, usually helium or carbon dioxide, and detecting any gas leaking outside the package under vacuum

Chapter two:

Package Process Validation

19

Sealing is accomplished by fusing the package components together to form a bond that is strong enough to hold together, yet weak enough to be separated with reasonable force. Sealing is most often accomplished with one member of the package containing an adhesive layer. The adhesive may be a complex mixture of polymers, plasticizers, tackifiers, and other additives that melt together upon heating and fuse to the other member of the package with time and increased pressure. Some adhesives may be simple polymers that are marginally compatible with the other package components, that melt on heating, weakly fuse with the second member with time and under pressure, and can be opened with force. In either instance the parameters of temperature, pressure, and dwell (time) are the critical parameters in creating a seal. The sealing process depends on these three parameters to ensure seals that are strong enough and are of the required integrity. The establishment and control of these three parameters are critical to process validation activities.

Process Capability Studies Exhibit 3 represents an actual process capability study to determine the optimum parameters for seal strength. In each instance, the temperature and time increase at a set pressure value. When the matrix is completed successfully for three different pressures, then the optimum settings are obtained from the varying charts. In every instance, seal integrity is assessed with visual inspection accompanied by the strength measurement. Two different supplier materials were evaluated. The goal of this exercise was to qualify two suppliers and establish appropriate critical parameters for each. They are not interchangeable. The requirement to revalidate the process when changing suppliers is always an issue. Process capability studies will rarely prove that different supplier products will react similarly. Different settings are the general rule.

Other Variables Associated with Packaging Sealing Processes We always consider temperature, pressure, and dwell as the critical parameters needing to be identified and controlled to ensure a “good” seal. Although this is always the case, another group of variables needs to be identified and controlled as well.

Ability to Control Critical Parameters There is a need to ensure the stability of the parameters during extended processing, to recognize any surge or decrease in electricity during the run, and to ensure that pressure changes can be recognized and reacted to. Operational qualification is the appropriate activity to develop this information, but one needs to consider the cost and decrease in efficiency when placing the equipment “on test” for extended periods and consuming large quantities of packaging materials, and perhaps devices as well.

20

Validating Medical Packaging

Ability of Critical Parameter Measuring Devices to Read Accurately and Consistently Operational qualification is the place to begin assessing the accuracy of meters. However, extended runs may indicate that measuring devices can vary with electrical charges during the course of the run.

Seal Plates Uniform, Level There is concern that sealing tools are installed properly and are level. Some change over time may occur and needs to be considered.

Support Gaskets Gaskets are used to absorb the shock of the platen pressing on the sealing tool. This gasket changes over time, that is, the material hardens and becomes brittle over time, and cycles of heat and pressure.

Contamination Packaging materials, the product, the operators, and the environment can introduce particulate contamination to the sealing process. Sealing requires a clean set of tools properly maintained and cleaned. Build-up of contaminants on the sealing surfaces results in hot or cold spots and may be sharp and pierce the seal flange or lid material.

Changes in Environmental Conditions The environment surrounding the sealing equipment can have an adverse effect on the quality of the seal. For example, if the temperature of the room changes, extra heating or cooling can occur on the sealing surface; a change in air velocity (an open door) can cool the heated platen; and a change in humidity can adversely affect the packaging materials (especially paper). All of the above emphasizes the requirement that, to be completely validated, packaging processes need to be studied over time, usually the time required to complete a typical run. These routine production runs are designated as verification trials. Verification trials are a necessary and significant element of the validation process. Verification trials need to be: 1. Multiple: trials should try to use separate packaging material lots. Common practice designates three as the usual number of trials. 2. Complete: each trial will be of sufficient duration to establish equipment stability, up to but not exceeding an expected production run. 3. Typical: each run should begin with approved packaging material, approved devices, and set up with parameters developed in the process capability study. 4. Overtested: extensive samples exceeding the number anticipated for routine production should be tested in depth, often using test methods not suitable for routine production. For example, a designated number

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21

of samples should be obtained during the course of the run and tested for seal integrity, using a method that may not be suitable for routine testing, such as the dye penetration test. In addition, a number of samples should be obtained to test similarly to proposed routine testing. An in-depth analysis of the results of the tests is then undertaken to ensure: 1. No unexpected indications of failure of seal strength, integrity, or both occurred during the entire run. 2. The proposed reduced sample size and test protocol proved sufficient to adequately evaluate the entire run. 3. The assigned process parameters were correct and did not vary sufficiently during the run to produce any unexpected defects. The results are plotted on a statistical control chart (qualifications results) and a complementary table of qualifications or semiquantitative results (seal integrity) should be included.

Summary and Conclusions In summary, process validation activities are undertaken to ensure a successful outcome for packaging — a seal of proper strength and integrity. The elements of packaging process validation are: 1. Acceptable starting materials approved in joint discussion with suppliers and design validation activities. 2. Optimum operating conditions developed by process capability studies. 3. Multiple verification runs, of maximum duration to ensure stability of the process, compensate for noncritical but potentially significant process drifts. 4. Oversampled and overtested to ensure an accurate profile of the entire output. 5. Analyzed to ensure that routine production can be adequately evaluated by process monitors, sampling plans, and test protocols.

Additional Reading Bernier, C., The new process validation guidelines, Proc. Healthpack, CRC Press, Boca Raton, FL, 2000. Jones, L. et al., Medical Device and Diagnostics, MDDI, September 1995. Torbeck, L. et al., Banning, Designed experiments — A vital role in validation, Pharm. Technol., June 1996. Wolniewicz, J., Defining a process during the operational qualification (OQ), paper presented at MDM Conference, New York, 1999, Session 211.

22

Validating Medical Packaging Rev. No. A Date: June 1, 2000

Exhibit 1: Validation Protocol Installation Qualification Heat Sealer 1) Protocol Approval Approved: Name

Title

Date

Title

Date

Title

Date

Approved: Name Approved: Name

Installation Qualification Protocol Index 1. PROTOCOL APPROVAL .............................................................................................. 2. OBJECTIVE ...................................................................................................................... 3. IDENTIFICATION.......................................................................................................... 4. SYSTEM DESCRIPTION ............................................................................................... 5. RESPONSIBILITIES........................................................................................................ 6. PROCEDURE .................................................................................................................. 7. ACCEPTANCE CRITERIA............................................................................................ 8. REFERENCES.................................................................................................................. 9. SYSTEM COMPONENT INSTALLATION INSPECTION ...................................... 10. UTILITIES ........................................................................................................................ 11. INSTRUMENT LIST....................................................................................................... 12. MANUALS ...................................................................................................................... 13. DIAGRAMS AND SCHEMATICS ............................................................................... 14. DOCUMENTATION ...................................................................................................... 15. SUPPLEMENTAL DATA SHEET ...................................... ........................................... 16. DEVIATIONS/ EXCEPTIONAL CONDITIONS.......................................................

2) Objective The objective of this Installation Qualification (IQ) is to verify that the Heat Sealer and its services have been installed in accordance with design criteria, manufacturers' recommendations and user requirements, and that the system documentation is accurate and complete. 3) Identification 3.1 System / Equipment: Heat Sealer

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3.2 System Number: Medical H400 3.3 Location: Cherry Hill, New Jersey

4) System Description The Heat Sealer is used to close the end of Tyvek® / Poly / PET Pouches. This system supports the manufacturing and packaging of blades and handles. The system consists of a temperature controller, sealing module, heat band, and control foot switches. 5) Responsibilities 5.1 Execution and testing (manufacturing) 5.2 Data review and analysis (quality assurance) 5.3 Final report preparation (quality assurance) 5.4 Protocol / final report review and approval (regulatory affairs)

6) Procedure Document the installation of the equipment by completing the data entry sections of this protocol according to the following guidelines: 6.1 All data collection spaces in this protocol will be filled in. 6.2 For each entry in the applicable sections of this protocol, record the observed attribute directly to the right of the appropriate specification. 6.3 Ensure that the system characteristics are as specified in the "Specified" column by visual verification. Indicate the actual observance in the appropriate column. 6.4 Ensure that the specified installation requirements have been met, and indicate how the attribute was verified in the "Verification Procedure" section. Indicate whether the situation is acceptable (Yes / No). 6.5 If an exception is observed, explain the circumstances in the "Deviations / Exceptional Conditions" section. 6.6 Record test results on the associated data collection spaces / forms. Sign each test when completed. 6.7 Prepare the Installation Qualification Final Report.

7) Acceptance Criteria 7.1 The system conforms with the specifications listed in this protocol.

24

Validating Medical Packaging 7.2 The system has no unauthorized modifications. 7.3 Any deviations or exceptional conditions have been investigated and an appropriate course of action for each (justification or correction) has been determined and documented as part of this protocol.

8) References The following documents were used to assist in establishing specifications for the protocol. 8.1 The Medical H 400 Operation Manual, no date.

9) System Component Installation Inspection Mechanical Sealer Manufacturer Model Serial Number Equipment Number Specified Controls • • Installation Requirements • • Comments:

Specified XYZ Corporation Medical H400 Not Specified Verification Procedure On-Off Switch Installed Electronic Foot Switch Included Verification Procedure Unit Installed on Level Surface Heatseal Band Installed

Actual

Acceptable [ ]Yes [ ] No [ ]Yes [ ] No Acceptable [ ]Yes [ ] No [ ]Yes [ ] No

Acceptance Criteria Met and System Installation Acceptable [ ]Yes [ ] No

10) Utilities Verify that the system's utility requirements are met and are acceptable. Record the information below. Mechanical Sealer Electrical Comments:

Specified 110 Vac / 50–60 Hz

Actual

Acceptance Criteria Met and System Installation Acceptable [ ]Yes [ ] No

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11) Instrument List Identify and list instruments in the spaces below. Indicate whether the instrument is classified as "Calibrated" or "Not Calibrated." Use additional sheets as necessary. Instrument List Type: Range: Instrument Number: Manufacturer / Model: Use: Type: Range: Instrument Number: Manufacturer / Model: Use: Type: Range: Instrument Number: Manufacturer / Model: Use:

[ ] Calibrated

[ ] Not Calibrated

[ ] Calibrated

[ ] Not Calibrated

[ ] Calibrated

[ ] Not Calibrated

12) Manuals List all applicable manufacturers' manuals. Manuals Title:

Location: Title:

Location: Title:

Location:

13) Diagrams and Schematics Identify and list all applicable system diagrams and schematics below.

26

Validating Medical Packaging Drawings Drawing Number: Revision / Date: Title:

Location: Drawing Number: Revision / Date: Title:

Location: Drawing Number: Revision / Date: Title:

Location:

14) Documentation Standard Operating Procedures Identify and review all applicable Standard Operating Procedures (SOPs) for the equipment. List all SOPs below and identify any deficiencies that may require submittal of a document change. Indicate the listed SOPs as “Interim” or “Approved.” Use additional sheets as necessary. Standard Operating Procedures Document No.: Revision / Date: Title:

Location: Document No.: Revision / Date: Title:

Location: Document No.: Revision / Date: Title:

Location:

[ ] Interim

[ ] Approved

[ ] Interim

[ ] Approved

[ ] Interim

[ ] Approved

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Preventative Maintenance Procedures Identify and list all applicable Preventative Maintenance Procedures (PMs) for the equipment. Indicate the listed PMs as “Interim” or “Approved.” Use additional sheets as necessary. Preventative Maintenance Procedures Document No.: Revision / Date: Title:

Location: Document No.: Revision / Date: Title:

Location: Document No.: Revision / Date: Title:

[ ] Interim

[ ] Approved

[ ] Interim

[ ] Approved

[ ] Interim

[ ] Approved

Location:

Support Documentation Identify and locate any applicable supporting system documentation. This would include any purchase orders, vendor installation certificates, spare parts lists, or vendor test reports. Use additional reports. Use additional sheets as necessary. Support Documentation Date of Document: Title / Description:

Location: Date of Document: Title / Description:

Location: Date of Document: Title / Description:

Location:

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Validating Medical Packaging

15) Supplemental Data Sheet Use the space provided below to document any additional observations or comments. Duplicate this sheet as necessary. Supplemental Data Sheet Protocol Section / Page:

/

Comment No.:

Completed By: Reviewed By:

Date: Date:

16) Deviations / Exceptional Conditions Document each deviation or exceptional condition encountered during the execution of the protocol in the space provided below. The "Justification" section must be approved by the protocol director or designee. Use additional sheets as necessary. Deviations / Exceptional Conditions Protocol Section / Page: / Deviation / Exceptional Condition:

Deviation No.:

Completed By: Justification / Corrective Action Plan:

Date:

Completed By: Reviewed By:

Date: Date:

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29 Rev. No. A Date: June 1, 2000

Exhibit 2: Validation Protocol Operational Qualification Heat Sealer 1) Protocol Approval Approved: Name

Title

Date

Title

Date

Title

Date

Approved: Name Approved: Name

Operational Qualification Protocol Index 1. PROTOCOL APPROVAL .............................................................................................. 2. OBJECTIVE ...................................................................................................................... 3. IDENTIFICATION.......................................................................................................... 4. SYSTEM DESCRIPTION ............................................................................................... 5. RESPONSIBILITIES........................................................................................................ 6. PROCEDURE .................................................................................................................. 7. ACCEPTANCE CRITERIA............................................................................................ 8. REFERENCES.................................................................................................................. 9. INSTALLATION QUALIFICATION REVIEW .......................................................... 10. STANDARD OPERATING PROCEDURES REVIEW .............................................. 11. INSTRUMENT CALIBRATION VERIFICATION ..................................................... 12. OPERATIONAL QUALIFICATION TESTS ............................................................... 13. SUPPLEMENTAL DATA SHEET ................................................................................. 14. DEVIATIONS / EXCEPTIONAL CONDITIONS..................................................... .

2) Objective The objective of this Operational Qualification (OQ) is to verify that the Heat Sealer operates according to manufacturers' specifications, applicable industry standards, and any specific company requirements.

3) Identification 3.1 System / Equipment: Heat Sealer 3.2 System Number: Medical H400 3.3 Location: Cherry Hill, New Jersey

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Validating Medical Packaging

4) System Description The Heat Sealer is used to close the end of Tyvek® / Poly / PET Pouches. This system supports the manufacturing and packaging of blades and handles. The system consists of a temperature controller, sealing module, heat band, and control foot switches. 5) Responsibilities 5.1 Execution and testing (maufacturing) 5.2 Data review and analysis (quality assurance) 5.3 Final report preparation (quality assurance) 5.4 Protocol / final report review and approval (regulatory affairs)

6) Procedure Document the operation of the equipment by completing the data entry sections of this protocol according to the following guidelines: 6.1 All data collection spaces in this protocol will be filled in. 6.2 Follow the procedure described in each Operational Qualification Test subsection in order to evaluate the system operation. Where applicable, ensure that each operational characteristic listed in the "Response" column is acceptable and indicate "Pass" or "Fail" in the appropriate column. A "Fail" must be explained in the Deviations / Exceptional Conditions section. 6.3 At the end of each Operational Qualification Test subsection, indicate whether the acceptance criteria have been met and system operation is acceptable. A "No" must be explained in the Deviations / Exceptional Conditions section. 6.4 If an exceptional condition is observed, explain the circumstances in the "Deviations / Exceptional Conditions" section. 6.5 Record test results on the associated data collection spaces / forms. Sign each test when completed. 6.6 Prepare the Operational Qualification Final Report.

7) Acceptance Criteria 7.1 The system conforms with the specifications listed in this protocol. 7.2 Acceptance criteria listed in each OQ test shall be met for acceptance of this system as operationally qualified. 7.3 Any deviations or exceptional conditions have been investigated and an appropriate course of action for each (justification or correction) has been determined and documented as part of this protocol.

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8) References The following documents were used to assist in establishing specifications for the protocol. 8.1 The Medical H 400 Operation Manual, no date.

9) Installation Qualification Review Review the IQ Package for the Heat Sealer and verify that the IQ Final Report has been approved. IQ Final Report Approval Date: Completed By:

Date:

Reviewed By:

Date:

10) Standard Operating Procedures Review Identify and list all applicable Standard Operating Procedures (SOPS). Verify that each SOP is available and acceptable. Use additional sheets if necessary. Standard Operating Procedures Document Number Title Operation of the Heat Sealer Preventative Maintenance of the Heat Sealer

Acceptable [ ]Yes

[ ] No

[ ]Yes

[ ] No

Completed By:

Date:

Reviewed By:

Date:

11) Instrument Calibration Verification 11.1 Purpose To verify that all instruments requiring calibration are documented and within their calibration date.

11.2 Acceptance Criteria A) System and validation test instruments are within their certified calibration dates. B) Applicable calibration documentation is complete.

11.3 Procedure A) List system and validation test requirements requiring calibration in the following tables and verify that all units are within their calibration due date.

32

Validating Medical Packaging B) Review all calibration records and certificates and ensure that results indicate satisfactory operation. C) Attach copies of the calibration certificates to this protocol or reference their location. Completed By:

Date:

Reviewed By:

Date:

11.4 System Instruments System Instruments Description: Heat Sealer Model: Cal Due Date:

Serial No.: NIST Traceable:

[ ] Yes [ ] No

Completed By:

Date:

Reviewed By:

Date:

11.5 Validation Test Instruments Validation Test Instruments Description: Stopwatch Model: Cal Due Date:

Serial No.: NIST Traceable:

[ ] Yes [ ] No

Completed By:

Date:

Reviewed By:

Date:

12) Operational Qualification Tests 12.1 Alarm / Safety Verification 12.1.1 Purpose To verify the manufacturer's specified alarm and safety features by: A) Initiating Alarm signal when calibration is performed incorrectly. B) Demonstrating that the heat cycle does not start when an obstructive device is placed between sealing bars.

12.1.2 Acceptance Criteria A) The alarm is indicated as specified in the following table. B) The safety features perform as specified in the following table.

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12.1.3 Equipment A) One plastic test package. B) Obstructive device (non-flammable) of width slightly greater than 1/4".

12.1.4 Procedure A) Follow the steps listed in the alarm / safety verification test table. B) Indicate whether the system performance is acceptable in the "Pass / Fail" column.

12.1.5 Alarm / Safety Verification Tests Step 1

2

3

4 5 6 7

Procedure Ensure that the heat seal band is at ambient temperature (approx. 20°C) (tactile verification or equivalent) Rotate the "ZERO CAL" potentiator until the temperature needle is between 0–5°C Place the test package between the jaws and attempt to start the cycle Turn the power supply off and then on again Rotate the "ZERO CAL" dial until the temperature needle is at the "Z" mark Place non-flammable obstruction device between the jaws of the sealer Attempt to start the sealing cycle

Response

Pass / Fail

Needle is set at approx. °C The "ALARM" LED illuminates and the cycle stops The "ALARM" LED is reset (not illuminated) Needle is at the "Z" mark

The heating cycle does not start and the sealing bars release

COMMENTS:

Acceptance Criteria Met and System Operation Acceptable [ ] Yes [ ] No Completed By:

Date:

Reviewed By:

Date:

34

Validating Medical Packaging 12.2 Cycle Temperature and Time Verification 12.2.1 Purpose To verify that the cycle time and temperature controls have the specified effect on system operation by verifying: A) Temperature range, 50–300°C. B) Sealing time, 0–6 seconds. C) Cooling cycle temperature at 50 and 75% of temperature set.

12.2.2 Acceptance Criteria A) The specified system responses listed in the following table are found acceptable.

12.2.3 Equipment A) Tyvek® / Poly / PET pouches. B) Calibrated stopwatch.

12.2.4 Procedure A) Follow the steps listed in the cycle time and temperature verification test table. NOTE: Steps 1 and 2 need only be completed if the system has not yet been zero calibrated on the day the test takes place. If the system has already been zero calibrated on that day, indicate "Pass" in the "Pass / Fail" column and continue. B) Indicate whether the system performance is acceptable in the "Pass / Fail" column.

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12.2.5 Cycle Temperature and Time Verification Step 1

2

3

4

Procedure Ensure that the heat seal band is an ambient temperature (approx. 20°C) tactile verification or equivalent Rotate the "ZERO CAL" dial until the temperature needle is at the "Z" mark Set the system control to: "SEALING TEMP" "SEALING TIME" "COOLING TIME" Place a test package between the jaws and start the sealing cycle After the temperature (as indicated on the controller) has been reached, the "SEALING TIME" LED illuminates When the "SEALING TIME" LED illuminates, start a stopwatch When the "HEATING TIME" and "SEALING TIME" LEDs turn off and the "COOLING TIME" LED turns on, stop the stopwatch and record the time When the preset cooling temperature is reached (approx. 50°C), the jaws open

Response

Pass / Fail

Needle is at the “Z” mark

The sealing jaws close and the "HEATING LED" illuminates Temperature Reading: °C The "SEALING TIME" LED illuminates Sealing Time:

Seconds

Temperature Reading: °C The "COOLING" LED turns off and the sealing jaws open.

Completed By:

Date:

Reviewed By:

Date:

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Validating Medical Packaging

13) Supplemental Data Sheet Use the space provided below to document any additional observations or comments. Duplicate this sheet as necessary. Supplemental Data Sheet Protocol Section / Page:

/

Comment No.:

Completed By:

Date:

Reviewed By:

Date:

14) Deviations / Exceptional Conditions Document each deviation or exceptional condition encountered during the execution of the protocol in the space provided below. The "Justification" section must be approved by the Protocol Director or designee. Use additional sheets as necessary. Deviations / Exceptional Conditions Protocol Section / Page: / Deviation / Exceptional Condition:

Completed By: Justification / Corrective Action Plan:

Deviation No.:

Date:

Completed By:

Date:

Reviewed By:

Date:

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Exhibit 3 X Y Z Medical Device Corporation

Subject: Process Capability Study

ISSUE DATE: ORIGINATOR:

REVISION original

Written by:

Procedure No. 61-0100-001 Supersedes: Effective Date:

Page 1 of 13 Revision No. 000 NEW

November 16, 1999

DATE

DESCRIPTION

11/16/99

Reviewed by:

Approved by:

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X Y Z Medical Device Corporation

Subject: Process Capability Study

Procedure No. 61-0100-001 Supersedes: Effective Date:

Page 2 of 13 Revision No. 000 NEW

1.0 PURPOSE 1.1

To establish a method for determining the optimum heat sealing parameters for a given combination of materials.

2.0 SCOPE 2.1

To determine the heat seal conditions of temperature, dwell, and pressure which will produce the optimum seal strength and adhesive transfer for any combination of materials. Since different suppliers use different films, this protocol and matrix is modified to follow each supplier's recommended conditions.

2.2

In order to bracket the optimum sealing conditions, combinations of temperature, dwell, and pressure have been selected to represent a range of conditions.

2.3

This protocol will not be undertaken until Calibration of the Heat Sealer and Burst Tester is satisfactorily completed.

3.0 EQUIPMENT 3.1

Hand held digital pyrometer with a miniature right angle surface probe.

3.2

Sentinel Heat Sealer

3.3

ARO Burst Tester

4.0 RESPONSIBILITIES 4.1

It shall be the responsibility of the Quality Assurance department to ensure the equipment is satisfactorily calibrated.

4.2

It shall be the responsibility of the Quality Assurance department to perform the following procedure and record the results herein.

4.3

It shall be the responsibility of the Quality Assurance department to recommend the optimal sealing parameters based on the results of the following procedure.

Written by:

Reviewed by:

Approved by:

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Subject: Process Capability Study

Procedure No. 61-0100-001 Supersedes: Effective Date:

39 Page 3 of 13 Revision No. 000 NEW

5.0 PROCEDURE 5.1

Using five samples from each supplier, measure the burst pressure on the ARO Burst Tester. (Note: The gage on the burst tester measures inches of water. There are 27.68 inches of water per 1 PSI.) Record the burst pressure data on Attachment I.

5.2

Set the heat sealer temperature controller so that the lowest temperature per the attached "Matrix for Sealing Conditions" (Attachment II) is reached on the face of the heat seal bar. Allow at least two hours for the temperature to reach stabilization, if the heat sealer was just turned on; otherwise, wait one hour.

5.3

Using the calibrated pyrometer, measure and record the temperature on the face of the heat seal bar at four equally spaced segments. Record this data on the "Temperature Data Sheet" Attachment III.

5.4

Set the pressure gage to the lowest effective jaw pressure on the matrix.

5.5

Set the dwell to the lowest value per the attached "Matrix."

5.6

Take one package and heat seal the open end. Mark the package using a permanent marker with the sealing jaw temperature, dwell, and pressure (ex. "300/1/30" which is 300°F, 1 second dwell, and 30 PSI jaw pressure).

5.7

Repeat 5.6 for a second sample.

5.8

Keeping the temperature the same, increase the dwell to the next setting per the "Matrix" and repeat steps 5.6 and 5.7. Do the same for all the dwell settings.

5.9

Keeping the temperature the same, repeat steps 5.6 through 5.8 for the remaining jaw pressures.

5.10

Raise the jaw temperature to the next level as shown on the "Matrix". Allow at least one hour for stabilization to occur. Reduce the dwell and pressure to the lowest values shown on the "Matrix." Repeat steps 5.1 through 5.9.

5.11

Repeat step 5.10 until all temperatures shown on the "Matrix" have been attained. Written by: Reviewed by: Approved by:

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Subject: Process Capability Study

Procedure No. 61-0100-001 Supersedes: Effective Date:

Page 4 of 13 Revision No. 000 NEW

6.0 TESTING 6.1

For each package, cut the seal off the opposite end of the package which has the supplier's seal. Using the ARO Burst Tester, measure and record the burst pressure on the attached "Matrix for Sealing Conditions” (Attachment II). If the package bursts at one of the side seals made by the manufacturer, make note of that as well as the pressure at which it burst.

7.0 ACCEPTANCE CRITERIA 7.1

Written by:

The optimal heat sealing parameters will be chosen based on the burst pressure data/results recorded on Attachment II.

Reviewed by:

Approved by:

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Page 5 of 13 Procedure No. Revision No. 61-0100-001 000 Supersedes: NEW Effective Date:

Attachment I

SUPPLIER’S BURST PRESSURE MEASURMENTS

Supplier:

SAMPLE NUMBER

BURST PRESSURE

1 2 3 4

Written by:

Reviewed by:

Approved by:

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Page 6 of 13 Procedure No. Revision No. 61-0100-001 000 Supersedes: NEW Effective Date:

Attachment II

SUPPLIER 1 "MATRIX FOR SEALING CONDITIONS" Sealing Jaw Pressures: 35, 45, and 55 PSI

Sealing Jaw Pressure 35 PSI Sample 1

Jaw Temp. °F 220 230 240 250 260 270 280

.4

Dwell, Seconds .8 1.2

1.6

Dwell, Seconds .8 1.2

1.6

Sealing Jaw Pressure 35 PSI Sample 2

Jaw Temp. °F 220 230 240 250 260 270 280 Written by:

.4

Reviewed by:

Approved by:

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Page 7 of 13 Procedure No. Revision No. 61-0100-001 000 Supersedes: NEW Effective Date:

Attachment II

SUPPLIER 1 "MATRIX FOR SEALING CONDITIONS" Sealing Jaw Pressures: 35, 45, and 55 PSI

Sealing Jaw Pressure 45 PSI Sample 1

Jaw Temp. °F 220 230 240 250 260 270 280

.4

Dwell, Seconds .8 1.2

1.6

.4

Dwell, Seconds .8 1.2

1.6

Sealing Jaw Pressure 45 PSI Sample 2

Jaw Temp. °F 220 230 240 250 260 270 280 Written by:

Reviewed by:

Approved by:

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Procedure No. 61-0100-001 Supersedes: Effective Date:

Page 8 of 13 Revision No. 000 NEW

Attachment II SUPPLIER 1 "MATRIX FOR SEALING CONDITIONS" Sealing Jaw Pressures: 35, 45, and 55 PSI

Sealing Jaw Pressure 55 PSI Sample 1

Jaw Temp. °F 220 230 240 250 260 270 280

.4

Dwell, Seconds .8 1.2

1.6

.4

Dwell, Seconds .8 1.2

1.6

Sealing Jaw Pressure 55 PSI Sample 2

Jaw Temp. °F 220 230 240 250 260 270 280 Written by:

Reviewed by:

Approved by:

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Page 9 of 13 Procedure No. Revision No. 61-0100-001 000 Supersedes: NEW Effective Date:

Attachment II SUPPLIER 2 "MATRIX FOR SEALING CONDITIONS" Sealing Jaw Pressures: 20, 30, and 40 PSI

Sealing Jaw Pressure 20 PSI Sample 1

Jaw Temp. °F 235 245 255 265 275 285 295

1

Dwell, Seconds 1-1/2 2

2-1/2

Dwell, Seconds 1-1/2 2

2-1/2

Sealing Jaw Pressure 20 PSI Sample 2

Jaw Temp. °F 235 245 255 265 275 285 295

Written by:

1

Reviewed by:

Approved by:

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Procedure No. 61-0100-001 Supersedes: Effective Date:

Page 10 of 13 Revision No. 000 NEW

Attachment II

SUPPLIER 2 "MATRIX FOR SEALING CONDITIONS" Sealing Jaw Pressures: 20, 30, and 40 PSI

Sealing Jaw Pressure 30 PSI Sample 1

Jaw Temp. °F 235 245 255 265 275 285 295

1

Dwell, Seconds 1-1/2 2

2-1/2

1

Dwell, Seconds 1-1/2 2

2-1/2

Sealing Jaw Pressure 30 PSI Sample 2

Jaw Temp. °F 235 245 255 265 275 285 295 Written by:

Reviewed by:

Approved by:

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47 Page 11 of 13 Revision No. 000 NEW

Attachment II

SUPPLIER 2 "MATRIX FOR SEALING CONDITIONS" Sealing Jaw Pressures: 20, 30, and 40 PSI

Sealing Jaw Pressure 40 PSI Sample 1

Jaw Temp. °F 235 245 255 265 275 285 295

1

Dwell, Seconds 1-1/2 2

2-1/2

1

Dwell, Seconds 1-1/2 2

2-1/2

Sealing Jaw Pressure 40 PSI Sample 2

Jaw Temp. °F 235 245 255 265 275 285 295 Written by:

Reviewed by:

Approved by:

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Validating Medical Packaging

X Y Z Medical Device Corporation

Subject: Process Capability Study

Page 12 of 13 Procedure No. Revision No. 61-0100-001 000 Supersedes: NEW Effective Date:

Attachment II

SUPPLIER 1 "TEMPERATURE DATA SHEET"

Desired Jaw Temp. °F

Controller Temp. °F

A

B

C

D

AVERAGE

220 230 240 250 260 270 280

Written by:

Reviewed by:

Approved by:

Chapter two:

Package Process Validation

X Y Z Medical Device Corporation

Subject: Process Capability Study

49

Page 13 of 13 Procedure No. Revision No. 61-0100-001 000 Supersedes: NEW Effective Date:

Attachment III

SUPPLIER 2 "TEMPERATURE DATA SHEET"

Desired Jaw Temp. °F

Controller Temp. °F

A

B

C

D

AVERAGE

235 245 255 265 275 285 295

Written by:

Reviewed by:

Approved by:

chapter three

Putting It All Together — The Validation Protocol This chapter provides guidance on the development of the package validation file. Examples will be used to illustrate the approach. Figure 3.1 represents the contents of a complete validation file for a tray/lid combination. Section I deals with the specifications of the materials for both the tray and lid and the specifications and design elements of the converted components (the formed tray and printed lid.) Typically the tray will be produced from a “medical grade” polymeric material. The specifications of the material are included in the file. Note that the polymeric material specification must be for the specific formulation of the plastic. Thus, Eastar PETE 6368 specification is incorporated, not “PETG.” If the material is available from different suppliers with different trade names and formulations, these may be incorporated as well, as long as equivalency has been proven in the design validation step. Similarly, the lid material specifications must also refer to a specific material. For example, Tyvek is commonly used as a lid material after it has been coated with an adhesive to assist in bonding. The specification included is the one relating to a specific formulation from a specific supplier, i.e., “DuPont 1073B Tyvek coated in CR-90 adhesive by Perfectseal/Bemis” is the appropriate specification. The elements of the converted components are included in Section I as well. The mutually agreed to specifications for the components, the location and specifications of the print (if printed) including location, print size, graphics, color, and specifics on the ink are to be adhered to. Note that for medical packaging applications, inks are components rather than suppliers; that is, traceability formulation aspects and inventory control must be provided in greater detail than that typically used by printing shops. Dimensional drawings of the lids and trays must also be incorporated into the file. Section II presents audits or other assurance that the supplier shows control of its operation and processes. This includes assessment reviews of

51

52

Validating Medical Packaging

Section I

Section II

Section III

Section IV

Section V

Section VI

Section VII Section VIII

Material specifications Lid material Tray material Converted components Supplier specifications—Tray/lid Print copy location Complete dimensional drawings Ink specifications Audit reports Lid supplier Tray supplier Typical supplier/Production/QC reports Packaging validation protocol Outline Machine installation certification Calibration procedures Process equipment Measurement equipment Maintenance procedures Process equipment Measurement equipment Cleaning procedures Process capability study Calibration record Maintenance records Procedure Results Packaging process description/flowchart Packaging procedures and specifications Production Quality assurance Verification lots Results Batch records Quality results Post-sterilization results Shipping test results Conclusion

Figure 3.1 Package validation file: Tray/Lid combination.

the procedure in place to ensure adherence to specifications, traceability of raw materials, review of supplier’s operations, change procedures, and personnel training records. Examples of the supplier’s production and quality control sheets are also provided in the file. In this way, any discrepant components can be compared to a specific set of records. These records may be required for routinely manufactured components, and may be included in the device history file.

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Section III contains the package validation protocol; that is, the description of the path to follow to ensure a high degree of confidence that the design and process to produce the package will provide a package that can withstand sterilization, shipping, and storage. Also included are the procedures in existence at the time for the calibration of process and monitoring equipment, maintenance of same, as well as all pertinent cleaning procedures. These procedures are not part of the information bank for the organization; that is, these procedures are not to be included in the revision scheme for standard operating procedures, but need to be reviewed when changes in the process occur to ensure that the changes have not been altered significantly to alter the outcomes of the protocol. The protocol also integrates the process capability study, the key element to develop the optimum parameters to initiate the activities lending to process verification — the multiple runs at normal operating conditions to ensure process consistency. The final major segment of the protocol describes the procedure for final verification of the process. The procedure calls for multiple runs at routine operating parameters (as developed in the process capability study). These runs are used to ensure consistency of routine production. The packages, although isolated initially while testing before and after sterilization is completed, are defined as commercial and can be released into distribution after acceptance. It is advised to retain a larger number of samples from those runs to ensure that evaluation can be conducted in the event of some unanticipated outcome during shipping and storage. Section IV contains the results of the process capability study. It often contains the process capability study procedure again, abstracted from the protocol, along with the records of calibration and maintenance performed immediately before initiation of the study. A statistical study of the data, as described in the FDA’s new guidelines for process validation, is contained in Appendix 2. Section V presents a description of the packaging process. Key to the section is the flowchart, a pictorial of the material, product, and process flow through the system, including control points. A control point is defined as a specific spot in the process where assessment of critical elements is evaluated, primarily because lack of control of the elements of the control points could lead to defects that may be undetectable further along the process. Package sealing is just such a point. Evaluation of the strength and integrity of the seal must be accomplished at the sealing station, even if further inspections are enacted later. This information forms the nucleus of a hazards analysis and reduction program discussed in Appendix 1. The procedures for both manufacturing and quality assurance of the packaging process are also included. Unlike the static procedures incorporated in Section III (Validation Protocols), these procedures must be monitored and revised as part of the document control system. The identification and evaluation of multiple lots to ensure consistency are incorporated into Section VI. Typically three lots are evaluated and are

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Validating Medical Packaging

appropriate for most instances. In the event of a process proving to be only marginally capable, statistically, then several more lots should be evaluated. In some cases, a marginally capable process may require continuous control over every lot. Obviously, it is wise to reconfigure the package, the materials, or the equipment to one providing greater consistency. In every instance, it is advisable to perform some degree of inspection and testing to ensure consistency on a daily basis. The production and quality records for all batches identified as verification trials are included in the validation file in Section VI. Any deviation from specification compiled in Section V must be carefully documented with a root cause identification and corrective action. These deviate runs cannot be considered among the multiple runs ensuring consistency; in fact, they show inconsistency and must be addressed. As above, if the deviations persist during attempts at verification, the process validation must be reconsidered. All batches, those that meet requirements and those that do not, must be permanently located in the file. Section VII presents the shipping tests used to ensure package design. The protocols used to validate the design are described in Chapter 1. A note on post-sterilization testing. If the criterion for valid packaging design is not using the protocols described in Chapter 1, than it is appropriate to not use a post-sterilization evaluation of the routine production runs. It is appropriate to check pre- and post-sterilization package samples for seal strength and integrity. After a predetermined time period or batches, an assessment of the value of continuing post-sterilization monitoring should be undertaken. If a decision is taken to discontinue testing, then the reasoning and data to support the decision should be documented and placed into the package validation file in this section. No file is complete without conclusions. The last section closes the validation file with statements documenting that: 1. Material and components specifications have been reviewed, approved, and accepted and that no changes can be made without notification. This is essential to ensure that all changes are reviewed to determine if revalidation will be necessary. 2. Suppliers have been audited and have shown that their processes are capable and controlled and that the appropriate information is collected for each batch produced. 3. A formal package validation protocol has been developed and implemented, using approved procedures. 4. A process capability study was conducted and proved that the process was capable and consistent, as long as the stated limits for the critical process parameters were not exceeded. 5. A package process has been defined, identifying critical control points, specifications, and procedures to use on an on-going routine basis.

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6. Multiple runs have been produced, sampled, and tested, and are proven to be consistent. Any deviation with lack of consistency has been evaluated as to the cause and additional batches produced to compensate. A statistical model has been used. 7. Shipping tests have been performed that indicate that the package has been properly designed to ensure that the device is protected during the processes of sterilization, transportation, and storage. The file is then closed. Revalidation may be considered when significant changes in materials or processing may alter prior validation and verification. In that case, the file is reopened and repeated, in total, to allow for the change and resulting outcome. While much of the information is contained in this file, it may also be in other locations such as: Material/component specifications in purchasing Audit reports in quality assurance/regulatory affairs Packaging process descriptions and flowcharts in production Verification lots in the device history record It is important to consider this file as a core technology file for the organization, where all the necessary information pertaining to packaging of the device, or family of devices is located in one place for easy reference by any designated corporate entity. In this way, in the event of problems, regulatory activity, either internal or external, or marketplace issues can be handled efficiently. Example 1 illustrates the processes in action. The example differs somewhat from the prior description of a preformed tray/lid combination sealed at the manufacturer to a prefabricated pouch filled and sealed by a contract packager. Note that the major change is the incorporation of data on the packaging contractor, specifically an audit report, included in Section V. All other sections are virtually the same. Page 1 of the example is the validation file. Page 2 is a portion of an inspector’s summation of adverse findings of an FDA quality audit of the manufacturer, outlining the deficiency relating to lack of seal validation along with some advising material and a request for a formal validation protocol. This audit led to the development of additional information included in the example. Page 3 is the contents page for the validation file. Note that no section was included for shipping because shipping concerns were not part of the adverse finding. The company had a long history of shipping products worldwide. Page 4 represents the specification for the paper used for the pouch. Page 5 represents the specification for the film used for the pouch. Page 6 is the pouch specification and acceptance criterion. Page 7 is a drawing

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Validating Medical Packaging

of the finished pouch dimensions copy and print location. Pages 1 through 7 are the elements contained in Section 1 of this file. Pages 8 and 9 are abstracts from an audit of the pouch supplier using a typical format-checklist well established for the industry. Page 10 through 11 is the package validation protocol, a description of the activities undertaken to validate the package process. Page 12 is an example of a correspondence from the supplier to the manufacturer stating baseline criteria process parameters. This information is contained in Section IV. Page 13 is information received from the supplier on the consistency of the sealing process. Note that the packager seals only the open side of the prefabricated pouch and the parameters and strength of that seal should correspond directly to the others sealed by the supplier. Page 14 through 16 represents the process capability study used and included in Section IV. Pages 17 and 18 are contract packager procedures and checklists incorporated into Section V. The above documents, along with others as stated in the Package Validation File Table of Contents, completed the file.

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Example 1 Package Validation File: Prefabricated Pouches/Contract Packager Section I

Material Specifications Surgical Paper PE Coated Polyester Film Prefabricated Pouch Specifications Supplier Specifications Print Copy/Location Complete Dimensional Drawing Supplier Correspondence

Section II Supplier Audit Report Typical Supplier Production/QC Reports Section III Packaging Validation Protocol Section IV Process Capability Study Procedure Results Section V Packaging Process/Flowchart Contract Packager Audit Report Low Particulate Room Procedures/Monitoring Calibration/Cleaning/Maintenance Procedures Contract Packager Process Procedures Contract Packager Quality Procedures Process/Quality Documentation Section VI Validation Trial Procedures Validation Lot Results Post-Sterilization Results Section VII

Validation Trial Procedures Validation Lot Results Post-Sterilization Results

Section VII Shipping Test Protocols/Results Section VIII Conclusions

Page 1

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FDA Form 483 1. Failure to establish specification control measures to assure that the design basis for the device, components and packaging is correctly translated into approved specifications [21 CFR §820.100(a) (1)]. For example: The sealer used by your contract packager has not been validated. No specification parameters for sealing pressure, temperature and dwell time have been established to assure seal integrity, and post sterilization package integrity testing is limited to testing of empty pouches. Package seal integrity testing conducted in 2/93 revealed that DCS packages did not meet the baseline specifications for seal tac and burst pressure. 2. Process validation requires the development of a protocol, process parameters, verification that the parameters are stable and that acceptable product can be consistently produced operating within the process parameters. Your response states that you will conduct package seal integrity testing "utilizing one of the next two disposable collection system lots to be sterilized." Validation of the sealer is not complete until pouches, containing a product, have been subjected to the stress of sterilization. Furthermore, since validation is intended to assure that a process will consistently produce an acceptable product, validation data should be developed based on a minimum of three lots. The device master record should identify the packaging materials as well as the sealer used and established setting for temperature, pressure, and dwell time. Please submit your validation protocol, including plans for installation qualification, and performance qualification of the sealing equipment.

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Table of Contents Section I

Material Specifications Surgical Paper PE Coated Polyester Film Prefabricated Pouch Specifications 4511140 Supplier Specifications Print Copy/Location Complete Dimensional Drawing Supplier Correspondence

Section II

Supplier Audit Report Typical Supplier Production/QC Reports

Section III

Packaging Validation Protocol Procedure QSP 10~5

Section IV

Process Capability Procedure Results

Section V

Packaging Process Quality Audit Low Particulate Room Cleaning Maintenance Procedures DCS Process Sheet DCS Production Area Monitoring DCS Job Rate Sheet Process Control

Section VI

Validation Lots Results

Section VII

Conclusions

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Technical Bulletin STERILE GUARD 12 LOW POROSITY HIGH VAC STERILIZABLE SURGICAL PAPER Sterile guard 12 low porosity is primarily designed for the manufacture of a heat sealable paper to film pouch for the packaging of medical and surgical devices that are sterilized by the use of High Vacuum Auto Clave. This grade is fabricated from 100% soft wood kraft for strength and durability. It contains a high percentage of wet strength resins to provide the necessary wet strength during the sterilization cycle of less than five (5) minutes. The lower Gurley densometer readings allow a high and rapid vacuum to remove air from the sealed pouch prior to the injection of the live steam. The surface of the paper is chemically treated to produce a minimum of fiber tear when sealed pouches are opened. Type "G" paper has less surface chemical treatment allowing easier sealing parameters. The inherent fiber structure and surface treatment has proven to be an effective barrier for bacteria and particulate matter. This grade has passed the half micron carbon chamber test. TYPICAL PHYSICAL PROPERTIES ARE LISTED BELOW: Basis weight, 24 × 36/500 Caliper (mils) Smoothness, Sheffield, Felt Density, Gurley (Secs/ 100cc) Tear MD,CD Tensile Dry MD Tensile Wet MD Mullen (psi)

Type G 45±5% 3.5–4.0 100–200 15–35 48–60 40–50 15–20 55–80

3.8–4.2 200–280 15–35 48–60 40–50 15–20 55–80

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Production Information Sheet PET 20 6C-4 PRODUCTION DESCRIPTION:

48 gauge Polyester/2.0 mil Polyethylene heat seal coated/polyester film.

PHYSICAL CHARACTERISTICS: Basis Weight Coating Weight Yield Caliper Seal Strength Tear Burst Haze Tensile Strength Elongation MVTR or Porosity

39 lbs./ream ± 10% 28 lbs./ream ± 10% 11,000 SI/lb. ± 10% 2.5 mil ± 10% at 300, .5 Sec, 40 psi 500 grams/ inch minimum .70 lbs MD/CD (Graves) 50 psi (Mullen) 10% (Gardner) 15 lbs./inch MD, 17 lbs./inch CD (ASTMD-882) 80% MD, 70% CD .5 gm H20/100 square inches/24 hours (MVTR)

Materials used in this structure are compliant under FDA regulation 21 CFR 175,300 (resin ous and polymeric coating). The above is believed to be correct on the basis of information and testing provided to us, however its accuracy cannot be guaranteed. The data provided herein, whether tentative or established represents a typical condition for this product. It is not intended to be used for specification limits or other finite acceptance criteria. Nothing contained herein shall be construed as a recommendation to use any product in conflict with existing patents. The information above describes this product as it leaves our facility. Qualification and/or validation of the final seal(s) of the package, and package appropriateness for specific devices and/or sterilization processes is the responsibility of the Device Manufacturer.

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Product Data Sheet A4220 1. Description: A42 (White surgical grade kraft) to 20 (48 gauge polyester/2ml polyethylene) pouch generally used for radiation or gas sterilization. Acceptance Level (AQL) 2. Manufacturing attributes to be checked at production. A. Pouch shall be constructed with materials specified on our order acknowledgement and customer approved drawing. B. Pouch shall be cosmetically clean; the outer and inner surfaces shall be free from dirt, foreign marks and materials. Employing the dirt estimation chart for Tappi standards T213 and T437, particles of .40 mm2 or larger are cause for reject. C. Seal strength (all seals) shall have minimum value of 0.75 pounds per linear inch of seal as determined by ARO test method. Maximum value shall be considered exceeded if, upon peeling, either web tears or the paper delaminates causing encapsulation of the product. There will be fiber tear in the seal area with this product combination. D. All seals must be uninterrupted and show evidence of sealing all around. Pouches without tabs can have an unsealed area of up to 1/4" at the open end of the pouch. E. Finished package is free of holes, openings, tears, etc. (visual). 3. Dimensions and tolerances shall be as indicated on customer accepted Beacon drawing or customer specification as accepted by Beacon. 4. Printing must match customer approved stat. A. Printing shall be generally clean and legible. B. Color to color register tolerance + 1/16". C. Print position on pouch ± 1/8". Nothing contained herein shall be construed as a recommendation to use any product in conflict with existing patents. The information above describes this product as it leaves our facility. Validation of the final seal(s) of the package and package appropriateness for specific devices and/or sterilization processes is the responsibility of the Device Manufacturer.

Reviewed: July 7, 1994 Rev:A Page 6

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Quality Audit Report Company Surveyed: Faser Medical Packaging Address: Saddle Brook, NJ Parent Company: Beacon Converters Personnel Contacted: Jackie Daly Johnson, Robert Cohen Auditor: Ron Pilchik, The Techmark Group Audit Date: November 10, 1994 Date of Last Audit: July 19, 1994 Nature of Audit:

Qualification: Routine: Problem Related:

Nature of Problem: Items Currently Purchased: DCS Paper/Film Pouch

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General Information 1. Facility Size: 19,000 sq. ft. and 5,000 off-site warehouse 2. Other Facilities Making Product: Of yes, where? 3.Number of Employees: Total: 55–58 Production: 16 Maintenance: 3 Engineering: 1 Quality Control: 24 (Inspector-Packers) Technician Services: 2 Sales/Marketing Admin.: 6 4. Number of Shifts: 1 5. Other Products Manufactured at this Facility:Medical Packaging and food bags.

Ratings Summary 1. Administrative/General:

Audit Total Score:

2. Materials Control: 3. Manufacturing: 4. Quality Control/Assurance: 5. Warehouse/Shipping: 6. Documentation: 7. Facilities: Rating Guide: For each item, a rating of 2 = Compliance; 1 = Partial Compliance; 0 = Non-Compliance. Use N/A where necessary. Score for each section is based on items rated and their score vs. the maximum possible.

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Packaging Validation Protocol 1.0

PURPOSE To validate the packaging of the sterile Disposable Collection Systems (DCSs).

2.0

SCOPE The materials and processes of the pouches used for the sterile DCSs.

3.0

4.0

REFERENCE DOCUMENTS 3.1

QSP 10-6 "Sterilization Validation and Audit."

3.2

ANSI/AAMI/ISO 11135-1994 "Medical devices — validation and routine control of ethylene oxide sterilization."

3.3

FDA COMP "21 CFR Part 820."

3.4

ISO 9001-1994 "Quality systems — Model for quality assurance in design, development, production, installation and servicing."

PRELIMINARY 4.1

Shall be audited by Quality Assurance to the applicable requirements of FDA GMP and ISO 9001, including a thorough review of employees training records. The audit report and applicable corrective actions shall be reviewed and approved by Quality Assurance, and be made part of the validation file.

4.2

The sealer used by our contract assembler/packager of the DCS, shall be calibrated prior to validation. The parameters to be calibrated are temperature, pressure and dwell. Certification of calibration and calibration report shall be reviewed and approved by Quality Assurance, and be made part of the validation file.

4.3

The seal dimensions and parameters for temperature, pressure, and dwell are as follows: 4.3.1 Seal dimensions = approx. 3/4" w × 9.60" 4.3.2 Temperature = 300°F 4.3.3 Pressure = 80 PSI 4.3.4 Dwell = 4 seconds

4.4

A process capability study shall be performed employing routinely manufactured pouches. Page 10

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4.5

All material specifications, pouch specifications and supplier records shall be reviewed and become part of the permanent record.

4.6

An audit of the pouch suppliers facility shall be conducted and become part of the permanent record.

4.7

Installation qualification of the sealer shall be performed upon return of the sealer from calibration. The installation instructions of the manufacturer shall be used. The qualification shall ensure that the proper electrical and air pressure connections have been accomplished.

4.8

Seal validation shall be performed on three consecutive lots of Disposable Collection Systems. All correspondence and reports shall reference their respective lot numbers.

5.0 PROCEDURE 5.1

The parameters for temperature, pressure, and dwell shall be periodically monitored and recorded during production of three lots designated for validation. These parameters shall be recorded a minimum of twice per day, for each day of production. These data shall be reviewed by Quality Assurance.

5.2

Record peel strength of the closure seal. These data shall be reviewed by Quality Assurance.

5.3

Sterilized samples, placed adjacent to the sterilizer thermocouples, from each of the three lots shall be tested for peel strength and burst pressure by Beacon Converters, Inc. Faser Medical Packaging division. The number of samples for each of the tests is as follows: 5.3.1 (10) Peel Strength per lot 5.3.2 (10) Burst Pressure per lot

5.4

All test reports shall be reviewed by Quality Assurance and compared to the following specifications: 5.4.1 Peel Strength: > 1 lb./inch 5.4.2 Burst Pressure: > 15 in. H2O

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BEACON CONVERTERS, INC. FASER MEDICAL PACKAGING GROUP Andrea Boulevard P.O. Box 8208 Saddle Brook, NJ 07663 Tel (201) 797-2600 Fax (201) 797-3015 October 4, 1994 I am writing to you regarding your request for our initial (paper pouch) scaling parameters, referencing your conversation with ——————————— on 10/4/94. For the materials used in your products, our initial settings would be: Temperature: 280 Pressure: 120 PSI Dwell: 2 sec. Please note that these are initial settings used to create peelable seals. I'm sure that you will want to make adjustments for your final seal. If you have further questions, please don't hesitate to contact me.

Sincerely,

Quality Assistant

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X-bar Chart for Burst 24

UCL = 23.247 Centerline = 21.5333 LCL = 19.8197

X-bar

23 22 21 20 19 0

4

8

12

Subgroup

16

20

24

S Chart for Burst 2.4

UCL = 2.25177 Centerline = 0.876801 LCL = 0.0

2

S

1.6 1.2 0.8 0.4 0 0

4

8

12

Subgroup

16

20

24

Process Capability for Burst

Frequency

16

Cpk = 3.41409 Cpk (lower) = 3.41409

12 8 4 0 17

20

23

26

Burst

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Validation Protocol: Process Capability Study 1.0

PURPOSE 1.1

2.0

3.0

4.0

To establish a method for determining the optimum heat sealing parameters for a given combination of materials.

SCOPE 2.1

To determine the heat seal conditions of temperature, dwell, and pressure which will produce the optimum seal strength.

2.2

In order to bracket the optimum sealing conditions, combinations of temperature, dwell, and pressure have been selected to represent a range of conditions.

2.3

This protocol cannot be undertaken until Calibration of the Heat Sealer and Force gauge is satisfactorily completed.

EQUIPMENT 3.1

Sentinel Heat Sealer.

3.2

Accu Force Cadet Force gauge manufactured by Ametek.

RESPONSIBILITIES 4.1

It shall be the responsibility of the Quality Assurance department to ensure the equipment is satisfactorily calibrated.

4.2

It shall be the responsibility of the Quality Assurance department to perform the following procedure and record the results herein.

4.3

It shall be the responsibility of the Quality Assurance department to recommend the optimal sealing parameters based on the results of the following procedure.

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Validation Protocol: Process Capability Study 5.0

PROCEDURE 5.1

Using five pouch samples, measure peel force on the force gauge tester at various places around the seal.

5.2

Set the heat sealer temperature controller so that the lowest temperature per the attached "Matrix for Sealing Conditions" is reached on the face of the heat seal bar.

5.3

Record the temperature.

5.4

Set the pressure gauge to the lowest jaw pressure on the matrix.

5.5

Set the dwell to the lowest value per the attached "matrix."

5.6

Take one pouch and heat seal the open end. Mark the pouch using a permanent marker with the sealing jaw temperature, dwell, and pressure (ex. "260/3/50" which is 2600°F, 3 second dwell, and 50 PSI jaw pressure).

5.7

Repeat 5.6 for a second sample.

5.8

Keeping the temperature the same, increase the dwell to the next setting per the "matrix" and repeat steps 5.6 and 5.7. Do the same for all the dwell settings.

5.9

Keeping the temperature the same, repeat steps 5.6 through 5.8 for the remaining jaw pressures.

5.10 Raise the law temperature to the next level as shown on the "matrix." Reduce the dwell and pressure to the lowest values shown on the "matrix." Repeat steps 5.2 through 5.9. 5.11 Repeat step 5.10 until all temperatures shown on the "matrix" have been attained.

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Validation Protocol: Process Capability Study “MATRIX FOR SEALING CONDITIONS” Sealing Jaw Pressures: 50, 60, and 80 PSI Sealing Jaw Pressure 80 PSI Sample 1 Jaw Temp. °F 260 280 300 320

3 3.55 4.02 4.50

Dwell, Seconds 4 3.50 4.13 3.38 1.50

5 3.88 1.61 4.76

3 3.30 3.95 2.69

Dwell, Seconds 4 3.84 2.85 2.41 2.89

5 3.99 2.34 2.91

Sealing Jaw Pressure 80 PSI Sample 2 Jaw Temp. °F 260 280 300 320

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Subject: Cleanroom "Low Particulate" Cleaning/Maintenance Procedure 1.0

PURPOSE To prescribe the cleaning and maintenance practices that are necessary to assure that assembly and packaging and clean room areas are being controlled and cleaned as required.

2.0

APPLICATION Applies to clean "low particulate" rooms, people, workstations and equipment.

3.0

ASSOCIATED MATERIALS Form Number F-CLEAN, XLS PRODUCTION AREA MONITORING.

4.0

PROCEDURE 4.1

The clean room is to be regarded as a restricted area. AUTHORIZED EMPLOYEES only are to enter the clean room.

4.2

All authorized employees are to wear specified laboratory garments and a hair cover when in the room. The garments are to be put on when entering the area and removed when leaving the area.

4.3

All soiled, dirty garments are removed from the clean room area and sent out for cleaning on a weekly basis.

4.4

Smoking, eating, jewelry and cosmetics, except lipstick, are prohibited in the clean room area.

4.5

All employees authorized to work in the clean room area will be trained in personal health and hygiene.

4.6

Lead pencils, crayons and unclean tools are prohibited.

4.7

Doors or other wall openings are to remain open only while actually in use.

4.8

Production components are to be air-washed (De-Dusted) and carefully checked for contaminants before being brought into the clean room.

4.9

Production components are to be positioned for use at the beginning of each day as required, and put away or covered upon leaving for break, lunch or the end of the day.

Form 2.1.1-3

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Date

Dwell Timing Sealer Temperature Humidity Room Temperature Pressure-Gauge Reading

Date

Initials

Date

Initials

Date

Initials

Putting It All Together — The Validation Protocol

Dry Mop Floors (weekly) Wet Mop Floors (weekly) Wipe Down Tables Wipe Down Chairs Wipe Down Sealer Wipe Down Light Above Sealer Sweep Area Outside Cleanroom Wipe Down Tables Outside Cleanroom Wipe Down Tape Machine Clean Flaps Clean Windows

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Page 18

chapter four

Regulatory Activities Package design and validation have been a concern of the U.S. Food and Drug Administration (FDA) for the past 20 years. At the outset, the medical device amendments to the Food and Drug Act passed in 1976 and the ensuing implementation of a specific set of good manufacturing practice (GMP) requirements of 1978, spelled out the need for packagers of medical devices to design and produce packages that withstand the rigors of sterilization, transportation, and storage. Two events, the institution of the first guidelines for process validation of drugs and devices (1987) and the completion of a “problem recognition” study in 1988, highlighted serious issues in device packaging that led to intense agency activity. The 1988 study showed that more than 50% of medical device recalls over a 5-year period were the result of packaging failures. Validation became a driving force to GMP compliance, with numerous citations, seizures, and closures resulting. The following cases illustrate some of the FDA activities in Medical Device Packaging Validation between 1988 and 1993.

Selected Cases Case study 1 highlights deficiencies in evaluating sterilization effects on package seals via validation, installation, and operation of new packaging machines without appropriate process validation, and no routine set-up procedure recommending and qualifying operational parameters. The “summary of findings” reported by the investigator was followed by a warning letter dated May 8, 1992. Note the strong language and threat of severe action if violations are not corrected. Case study 2 addresses additional issues at the same time at a different company. Here testing practices are challenged, specifically testing for package integrity in a lot basis — after sterilization. Also in question is the sensitivity of test methods. Note that very little had been accomplished with regard to industry-wide published test methods at the time. It was the sole

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responsibility of the packager to design and validate the test methods. The company was also cited for not routinely testing for package integrity after sterilization. Note also that the investigator challenges the adequacy of documentation and that validation studies need to be completed on sterilized samples. The investigator confuses design validation (Chapter 1), which uses post-sterilization samples, and process validation (Chapter 2), which need not use post-sterilized samples. Included in the case is the management response, which tries to separate design and process validation testing by immersion testing on a lot basis. Standard practice, which has evolved since 1992, has shown that this practice is generally unwarranted, because sterilization compatibility can be accomplished efficiently during the design validation steps. Case study 3 takes regulatory action even further as it enjoins a manufacturer and establishes a consent decree requiring specific actions before a company can reenter interstate commerce. Note that many of the violations involve packaging validation activities, or, more properly, the lack of or inadequacy of such activities. The reader can review the sad story, but, in essence, this company did not choose to validate its packaging equipment and was packaging products improperly, allowing potentially inadequately sealed packages to reach the market.

Packaging Noncompliances Karen Coleman, at the FDA Atlanta research office and internal FDA device packaging expert, listed the most frequent GMP regulation non-compliances as related to packaging. They are listed in Table 4.1. Note in the table the emphasis on “most challenging” package configurations and the consideration for revalidation. As noted in the “Process Validation Guidelines,” revalidation should follow any significant change in materials or processes. It is the sole decision of the manufacturer to take that direction. Needless to say, most err on the side of revalidation in almost all but the most insignificant change. Table 4.2 lists the five most common package validation issues. All in all, some leeway exists in the company’s ability to implement and interpret GMP requirements as they relate to packaging, but in general, “If you perform validation activities incorrectly, you’re dumb, if you don’t perform validations at all … you’re guilty.”

Industry-Generated Support Documents Two important documents have been published in the past few years that help provide important information for validation activities. They are ISO 11607 and CEN 868.

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Table 4.1 Ms. Karen Coleman Atlanta Branch Office Office of Compliance, CDRH Food & Drug Administration June 28, 1995 Presentation Medical Packaging Symposium '95 Princeton, NJ 21 CFR 820 — Common GMP Regulation Noncompliances • QA auditors and inspectors are not sufficiently trained to identify material defects or training documentation is lacking. • Lack of calibration or inspection of equipment, particularly test equipment, according to written procedures. • No maximum and minimum tolerance verification of the packaging process. • Package qualification has not demonstrated the most difficult product/package size to sterilize. • No consideration to changes made to the process and their effect on previous validations. • No specifications for testing package integrity after the sterilization process. Note:

Visual examination only of package seal integrity after sterilization is acceptable provided the package and process have been properly validated.

• Different package size/configurations not included in aging studies.

ISO 11607 was developed by ISO as an international standard for terminally sterilized medical device packages. There are three primary sections in dealing with a specific validation activity. Section 4 relates all the requirements to ensure material compatibility to the device to be packaged, the packaging process, and sterilization. Section 5 presents a uniform approach to package process validation, and section 6 describes package design validation. ISO 11607 has been recognized by FDA as an industry generated consensus standard and needs to be considered when approaching packaging validation activities. The document is available in the U.S. from the Association for the Advancement of Medical Instrumentation (AAMI). AAMI also provides a technical supplement to augment validation activities. In addition to ISO 11607, European compliance groups have generated CEN 868, a listing of package material requirements that clarifies and expands section 4 of ISO 11607.

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Top Five Validation Problems 1. No process qualification work/data exist to show how the critical process parameters were developed. 2. Process parameters are not clearly identified/specified during process qualification capability runs prior to final performance qualification. 3. Package seal studies are conducted with empty packaging without the device and do not take into consideration the additional stresses from sterilization and shipping. Note: Package integrity testing for sterility maintenance requires both quantitative and qualitative methods (e.g., seal integrity and seal strength). 4. Sampling size for seal strength and seal integrity studies are not based on an acceptable statistical rationale. 5. Failure to use a minimum of three successful consecutive batches or lots for the final validation runs.

These two documents form the basis of international compliance activities for medical device packages.

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CASE STUDY # 1 Company:

Manufacturer and repacker of class I and class II plastic medical devices

Date of Audit: 4/8/1992 – 4/17/1992 Location: Georgia

SUMMARY OF FINDINGS

Previous inspection dated 3/22–24/1989 was a directed follow-up inspection to a regulatory letter which found that the firm still lacked packaging validation and associated written procedures, and some QA and manufacturing procedures, and did not have an adequate warehouse storage system. There is no written validation data showing that the current ETO sterilization process does not affect the integrity of the seals on packages sealed on the new XXX packaging machine. The last validation of the sterilization process was completed in March 1990. At that time, all products were packaged in preformed pouches with heat seals applied using the XXX sealers. The firm bought a XXX form fill packaging machine in January 1991, and has been packaging the majority of its sterile products on this machine since July 1991. The firm has no validation data showing that the current sterilization process does not affect the integrity of the packages and seals. There is no approved process validation using the XXX packaging machine relating to temperature, pressure, and seal dwell time. The firm has never validated the packaging process using the XXX machine. Ml products packaged and sealed on this machine are intended to be sterile. There are no written procedures for the set-up of the packaging machine describing the specific recommended operational parameters used for each type of package and material. See exhibit D2 for an example of the different types of parameters that need to be set on the machine. Each operation parameter may be different depending on the package type and material used. There are no procedures describing how to set up the machine and which specific parameter settings are needed for each type of product and material packaged.

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May 8, 1992

CERTIFIED MAIL RETURN RECEIPT REQUESTED Owner Marietta, GA 30062 WARNING LETTER Dear Sir/Madam: An inspection of your medical device manufacturing facility was conducted on April 8–17, 1992 by investigator Eric S. Weilage. Investigator Weilage documented serious deviations from the Good Manufacturing Practice For Medical Devices (GMPs), (Title 21, Code of Federal Regulations, Part 820). These deviations cause your medical devices, such as the XXX, to be adulterated as defined by Section 501 (h) of the Federal Food, Drug, and Cosmetic Act (the Act). You have failed to validate the manufacturing and sterilization processes currently in use. There was no documentation or other evidence available to conclude that the ETO sterilization process does not adversely affect the integrity of devices sealed on the XXX packaging machine. This machine has been utilized to package the majority of your sterile products since July 1991. No validation has been performed on the packaging process utilizing this new equipment. You have failed to establish formal written procedures describing the operation of and the parameters required for the XXX packaging machine. These procedures should be specific to each type of product packaged and material utilized. No written maintenance schedules have been established for several pieces of critical equipment, such as the XXX packaging machine, injection molding machines, and the insert molder. These schedules are required to help ensure that the equipment is working properly and consistently. Your firm has failed to maintain any written documentation of in-process quality assurance checks reportedly performed on your products at crucial steps during the manufacturing process to include dimension checks on components during injection molding, finished syringe assembly, and seal integrity checks after packaging. No calibration checks have ever been performed to determine the accuracy of the angiographic syringes' volume scale.

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The above discussion of deficiencies should not be construed as an all inclusive list of violations that may be in existence at your firm. At the close of the inspection, Investigator Weilage issued his Inspectional Observations (FDA-483) to and discussed his findings with XXXX, President. It is your responsibility to ensure that all requirements of the Act are being met. A copy of the FDA-483 is enclosed for your review. Many of the deviations are repeat violations which have been pointed out during previous FDA inspections. The recurring discrepancies include failure to validate critical processes, deficient procedures associated with the manufacturing process, deficient documentation of quality control checks reportedly performed, and inadequate warehouse controls. Your responsibilities have been clearly explained in previous FDA correspondence to you and your firm. A Regulatory Letter was issued to you on May 17, 1988 and a Notice of Adverse Findings was issued to XXX on April 28, 1989 in response to our documentation of similar violations during our inspections. XXX and yourself responded to each of these letters and included plans for extensive corrective action. You have failed to implement the corrective actions promised and to establish adequate quality controls for changes made in the manufacturing operations since the previous inspections. You should take immediate action to address and correct these deviations. Failure to correct these deviations may result in legal sanctions provided by the law, such as product seizure and/or injunction, without further notice to you. In addition, until adequate corrective action has been taken, the FDA will not approve any requests for evaluation by government procurement agencies which your firm may have pending involving device products that are affected by these violations. You are requested to notify this office in writing within fifteen (15) working days of receipt of this letter of all steps you have taken, or intended to take, to correct these violations. Your response should be addressed to Philip S. Campbell, Compliance Officer, at the above address. Sincerely,

John H. Turner, Director Atlanta District

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CASE STUDY # 2 Company:

Major division of major medical device corporation producing many disposable sterile medical devices

Date of Audit: 12/19/91–1/16/92 Location: Kansas

SUMMARY OF FINDINGS Deficiencies were noted in package testing practices. The firm sterilizes devices in five package types: form/fill/seal, poly pouches, paper pouches, PVC trays with Tyvek lids. and "header" bags. The firm does not routinely test package integrity, on a lot basis, after sterilization. Neither was sufficient documentation available to validate the ability of these various package types to maintain a sterile barrier through the ETO sterilization process. As an annual audit, the firm conducts visual examinations of sterilized packages at the rate of only eight lots per year; however, these are non-destructive visual exams only with no seal strength tests, leak tests, peel tests, etc. Package field examinations were performed during this inspection per CP 7382.830A on three sterilized lots in the firm's finished goods warehouse, but no visible seal voids were found. An "Attachment B" sterility checklist form CP 7382.830A was completed. Documentary samples DOC 92-597706/8 were collected. 11. The firm has not performed integrity testing of sterile device packages via methods which are capable of detecting minute package defects, e.g., leak testing, immersion testing, dye testing, etc. The firm performs in-process testing of package seals prior to sterilization on an hourly basis. This test consists of testing seal strength via an Instron test apparatus. Visual (non-destructive) seal examinations are also performed prior to sterilization. However, methods such as those listed in Item #11 which would detect minute seal defects are not performed. Copies of such pre-sterilization package exams appear in Samples DOC 92-597-706/8. 12. Package integrity is not routinely tested after sterilization. The firm has not adequately demonstrated their various forms of sterile device packaging (form/fill/ seal, trays, pouches, header bags) will withstand sterilization and maintain a sterile barrier. The only documented examinations of sterilized packages have been visual exams (i.e., no seal strength tests, peel tests, burst tests, leak tests, etc.).

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Management contends the firm has validated the ability of its device packages to withstand the ETO cycle; therefore, testing of packages after sterilization is not performed on a lot-by-lot basis. However, sufficient documentation was not presented to the investigators during this inspection to support this claim. The firm has conducted validation studies on their package sealing equipment. A copy of a typical example appears in Exhibit 35. As can be seen in this exhibit, the firm varies the temperature, dwell time, and air pressure on the sealer, and then checks seal strength via a pull test on their Instron test apparatus. However, these tests are all performed on packages that have not been sterilized. Deficiencies were noted in documentation of rework performed on 3628, Suction Connecting Tubing, due to package seal problems: a. Documentation of the "Voluntary Rework" performed on Pallets 5 and 6 by production personnel was inadequate (i.e., description of seal defects, pallets affected, and corrective actions.) b. The "Final Inspection of Blister Packaging" record reports two seal failures in eight packages from Pallet #9, but the QARN lists two failures in four packages. c. The final inspection record does not indicate previous pallets were reinspected (under a tightened sample plan as specified on the Inspection Record Form) following the discovery of "Critical" seal defects in Pallet #9.

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March 3, 1992 Mr. Clarence R. Pendleton Compliance Officer Food & Drug Administration Kansas City District 1009 Cherry Street Kansas City, MO 64106 RE: Lawrence, KS--Establishment Reg. #1950487 XXXX, Subsidiary of XXXX, Inc. Warning Letter Issued February 10, 1992 483 Issued January 16, 1992 Dear Mr. Pendleton, On January 16, 1992, investigators James Planchon and Cynthia Rashid issued an FDA 483 summarizing the observations made during their inspection of the Lawrence, Kansas manufacturing facility. Subsequently, on February 10, 1992, Chairman and Chief Executive Officer of XXX, Inc. received a Warning Letter concerning the documented deviations from Good Manufacturing Practices. This letter and attachments provide XXX response to the Warning Letter and to each of the observations documented in the FDA 483. We request that this document be made part of the official file. XXX and specifically, XXX, Inc., considers this Warning Letter and the FDA 483 as a serious matter. Corrective action for many of the observations has already been implemented. With respect to sterile package inspection, equipment maintenance and cleaning, environmental monitoring, finished device inspection, device history and master records, our procedures governing these elements of good manufacturing practices have been upgraded and our employees have been retrained to the new procedures. Specifics of the programs implemented can be found in the individual responses to the respective FDA 483 observations enclosed. In closing, XXX is working expeditiously to correct the deviations cited in the FDA 483 and the Warning Letter. We believe that the action taken thus far, and the programs which have been instituted, will prevent the recurrence of similar violations. If you should have any questions regarding the information provided in this letter or the attached FDA 483 responses, please do not hesitate to contact me. Yours very truly, XXX VP and General Manager enclosures cc:

XXX, VP of manufacturing XXX, Plant Manager, XXX, Inc., Lawrence, KS

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LAWRENCE FD-483 RESPONSE PACKAGING Observation: 11. The firm has not performed integrity testing of sterile device packages via methods which are capable of detecting minute package defects. e.g., leak testing, immersion testing, dye testing, etc. Response: Integrity testing of sterile device packages is a parameter included in our packaging validation practices. Packaging validation is a standard component of XXX overall product validation process during new product development. It is a multi-directional approach to package qualification performed prior to release to production and it is based on many years of using the same packaging materials and design on a variety of product types. Our packaging validation program includes: 1) ship testing of a representative sampling of sterilized product with methods which are based on the national Safe Transit Association standards and simulate free fall drops, repetitive drop test for analyzing the ability of the package to withstand loose load vibrations, and external ship testing where the packaged product is shipped common carrier cross country to two different destinations in order to obtain an accurate indicator of actual shipping conditions; and, 2) environmental testing which subjects the package and product to various levels of temperature and humidity to determine their effect during shipping and storage. After all tests, experienced quality technicians visually examine all packaging surfaces and seals for integrity. Additionally, packaging process validation practices include testing of product packaged and sealed under a variety of process parameters in order to create an acceptable process window for future production. Seals are checked both visually and mechanically for seal strength. Packaging validation practices will be upgraded to include immersion testing (reference Exhibit 16, Draft Procedure for Packaging Validation). Immersion testing has been included since this test evaluates both the seal and total package surface. Training of appropriate personnel will be conducted to ensure understanding of the new procedure. Observation: 12 . Package integrity is not routinely tested after sterilization. The firm has not adequately demonstrated its various forms of sterile device packaging (form/fill/ seal, trays, pouches, header bags) will withstand sterilization and maintain a sterile barrier. The only documented examinations of sterilized

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packages have been visual exams (i.e., no seal strength tests, peel tests, burst tests, leak tests, etc.). Response: Subsequent to the facility inspection, a procedure addressing Post Sterile Inspection has been written (Procedure #ST 014-reference Exhibit 17). The Lawrence facility will begin routine testing of post sterile packaging with immersion testing and with the Instron tensile tester or equivalent for seal strengths. Training of appropriate personnel has been conducted to ensure understanding of the new procedure. Documentation of that training also is provided in Exhibit #17. With the inclusion of immersion testing in our packaging validation program (see response to observation #11 above) and immersion and Instron testing as part of post-sterilization inspection XXX will demonstrate that the various forms of sterile device packaging will withstand sterilization and maintain a sterile barrier.

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CASE STUDY #3 Company:

Privately held manufacturer of sterile gauze and sterile scrub brushes

Date of Injunction: February 11, 1988 Location: North Carolina

Date:

May 13, 1987

From:

Atlanta District Compliance Branch (HFR-4140)

Subject:

Injunction Recommendation

To:

Case Management Branch, Division of Compliance Operations Office of Compliance Center for Devices and Radiological Health (HFZ-322)

A. BUSINESS AND INDIVIDUALS TO BE ENJOINED XXX, Inc., also d/b/a/ XXX, Inc., a solely owned subsidiary, Charlotte, North Carolina 28217. D. ALLEGED VIOLATION We propose to enjoin the firm from violating section 301(e) and (k) of the Act. We are charging that all devices (sterile gauze and sterile surgical scrub brushes) manufactured are adulterated within the meaning of Section 501(c) and 501(h). Field examination and laboratory analysis of samples of the firm's products, including lap sponges and surgical scrub brushes, reveal defective seals that compromise the sterility of the devices. The firm has failed to properly validate their packaging machines. One of the machines has had no validations studies and one has inadequate validation. There is a lack of sampling and quality control over the finished product. E. SUMMARY OF EVIDENCE The firm has a history of violations of the FD&C Act. The initial inspection was conducted on 11/21–27/1985. There were numerous GMP deviations, including lack of validation of the steam sterilizer and packaging machines.

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Master device records were incomplete and quality assurance audits were not performed. Field examination of lots of sterile gauze found two lots with defective package seams. Lab analysis confirmed the defective packaging. The firm initiated a recall of six lots of gauze sponges on 12/12/1985. (Recall No. Z-308-2). A regulatory letter was issued on March 5, 1986. The inspection conducted on 9/17–25/1986 revealed continuing GMP deficiencies. The firm had not validated their packaging machines. Field examination of one released lot of 4" x 4" 8-ply sterile gauze sponges revealed defective seals. Laboratory analysis confirmed the investigator's observations. Seizure was recommended (86-504-364) but later withdrawn when the firm decided to recall. Five additional samples of sterile gauze sponges were also found to contain defective seals. After a meeting with the District management on 11/6/1986, the firm decided to recall all lots of sterile gauze sponge in packets from consignees who received them in 1986. (Recall Z308-6) This recall included seven separate lots. The current inspection 3/19, 20 and 23/1987, focused on the packaging operation. None of the three packaging machines had been adequately validated. The three machines are as follows: Hayssen Model RT 113 This machine is used to package sterile scrub brushes as represented by sample number 87-505-225. There had been no validation work on this machine. There were no records of seal examination and no tests were performed on the package seals, except for a squeeze test. There were no records of operating parameters, calibration of the gauges, or maintenance of the machine. Alloyd Machine This machine is used for products in plastic trays with Tyvek lids such as lap sponges represented by 87-515-687. This machine had not been properly validated and the firm has established no written procedures for its operation. There are no operating parameters such as pressure, temperature and dwell time. There are no procedures for checking seal integrity. Three lots of sterile gauze had been processed using this machine. Rotowrap Machine Some effort has been made to validate this machine which is used to pack sterile gauze in paper pouches. However, validation was considered inadequate because the validation run did not represent a normal packaging run. There was no record or description of defects found and no record of packages examined or rejected. Records of the study did not indicate dates, signatures of persons doing the study or what product was utilized in the study.

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Sample Analysis 87-505-225: This sample consisted of sterile surgical scrub brushes. Field examination revealed defective seams. Laboratory examination revealed that 25 of 56 units had leaks or holes. All units but one had wrinkles in the seams. 87-515-687: Sterile Lap Sponges: Field and lab examination revealed defective seals. Laboratory examination of 24 trays revealed all had defective seals between the plastic tray and Tyvek top. Twenty trays had openings in the seal ranging from 1/2" to 6 1/2" in length. We have recommended seizure on the above lots. REASONS FOR SEEKING INJUNCTIVE RELIEF Two previous inspections, a warning letter, two recalls and a meeting with District management have failed to bring this firm into compliance with the law. The firm continues to ship adulterated products in interstate commerce. They have not validated their packaging machines, even though they promised to do so before packaging any more sterile products. The District believes that an injunction is the only way to ensure that the firm comes into compliance with the law. Samuel E. Atkins Compliance Officer Atlanta District

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IN THE UNITED STATES DISTRICT COURT FOR THE WESTERN DISTRICT OF NORTH CAROLINA CHARLOTTE DIVISION UNITED STATES OF AMERICA, Plaintiff,

Civil Action No. C-C-88-0068-M

v. XXXX, Inc. a corporation, also doing business as XXXX, X, Inc., and XXXX, an individual,

CONSENT DECREE OF PERMANENT INJUNCTION

Defendants will refrain from: A. Introducing or delivering for introduction into interstate commerce any medical device, or holding for sale any device after receiving one or more of its components in interstate commerce, or manufacturing, packing, or labeling any device at said defendants' facility, unless and until: 1. Methods, facilities, and controls for the manufacturing, processing, packing, and storing or medical devices at the defendants' plant are established, operated, and administered in conformity with good manufacturing practice regulations (21 CFR Part 820), which methods, facilities, and controls shall specifically include but not be limited to the following:. a. Inspecting the packaging machines to assure that the design basis for the medical device packaging is correctly translated into adequate operating parameters necessary to assure package integrity for sterile device. b. Developing and following written manufacturing specifications and processing parameters for the packaging operation to assure that the device conforms to its specifications. c. Performing adequate calibration testing of all instruments that measure critical factors in package sealing operations, and maintaining the records of calibration. d. Preparing adequate equipment maintenance procedures, implementing such procedures, and documenting results.

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e. Establishing and implementing adequate written finished device inspection procedures to assure that all product specifications are met and sterile medical devices with defective package seals will not be released for distribution. f. Establishing procedures for in-process and finished product sealintegrity testing which are appropriate and adequate for their purpose and are performed correctly. g. Establishing procedures and specifications for packaging material to assure that the adhesive coating on sterile product packaging material is acceptable for adequate sealing. 2. Defendants select and retain a person who, by reason of training and experience, is qualified to make inspections of device manufacturing plants to determine that the established methods, facilities, and controls are operated and administered in conformity with the regulations for good manufacturing practice set forth in 21 CFR Part 820. 4. Duly authorized FDA representatives make inspection of defendants' premises including, but not limited to, the buildings, pertinent equipment, finished and unfinished materials, containers, labeling, and all records relating to the methods used in, and the facilities and controls used for, the manufacture, packaging, and holding of each device, and said representatives determine that all the requirements set forth in Parts I.A.1. have been met, the costs of any such inspection and supervision to be borne by the defendants at the rate of $38.00 per hour and fraction thereof per representative for inspectional work, $46.00 per hour and fraction thereof per representative for laboratory and analytical work, 20.5 cents per mile for travel expenses, and $77.00 per day per diem for subsistence expenses. IV. The defendants shall give written notice of the provisions of the Decree to each and all of their directors, officers, agents, servants, employees, contract laboratories, successors and assign in active concert or participation with them or any of them who assist or participate in the manufacture, processing, and distribution of the aforesaid articles of devices. The defendants shall, within 30 days of the entry of this Decree, submit to the FDA an affidavit setting forth the fact and manner of their compliance with this paragraph, including the names and positions of each person provided notice pursuant to this paragraph. VI. The jurisdiction of this Court is retained for the purpose of enforcing or modifying this Decree and for the purpose of granting such additional relief as may hereafter appear necessary or appropriate. SO ORDERED. Dated: Feb. 11, 1988

United States District Judge

Appendix 1

HACCP and Its Implications for Sterile Medical Device Packaging Introduction Hazard Analysis and Critical Control Point (HACCP) is relatively new to medical device manufacturing. Packaging of devices that must remain sterile is a critical control point, and seal strength and seal integrity are the two attributes that must be monitored. Whereas, seal strength can effectively be monitored by operating equipment within the validated control limits, seal integrity failures are often random occurrences the trained operator must identify. Precise testing equipment is a more effective way to manage the critical control point. Improved technology can significantly decrease the criticality of defined hazards and should be considered for monitoring at each critical control point. HACCP is a preventative system of hazard control. Medical device manufacturers can use it to ensure safer medical devices for customers. To ensure safer medical devices, the HACCP system is designed to identify hazards, establish controls and monitor these controls. A hazard can be any condition that results in an adverse consequence detrimental to the medical device, patient or health care professional. A condition is any event or potential event that can result in device malfunction, quality failure or other hazard. The FDA recognized the benefits of such a system and first required HACCP controls for food processing in 1973 for canned foods to protect against Clostridium botulinum, which causes botulism. The FDA's Seafood HACCP Regulation became effective in 1996. The U.S. Department of Agriculture enacted an HACCP regulation for meat and poultry in 1998. In an assessment of the effectiveness of U.S. food regulations, the National Academy of Sciences (NAS) recommended in 1985 that the HACCP approach be adopted by all regulatory agencies and that it be mandatory for food processors. This recommendation led to the formation of the National Advisory Committee on Microbiological Criteria for Foods (NACMCF). This committee standardized the HACCP principles used by industry and regulatory authorities. The Center for Devices and Radiological Health (CDRH) embraced this program for medical devices with some adaptation to this industry.

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HACCP is a preventative system for ensuring medical device quality, but it is not a stand-alone system. HACCP is built upon the elements contained in the Quality System Regulation including design controls, current Good Manufacturing Practices, environmental controls and personal hygiene, as well as other safety related programs to make it work. The HACCP concept can be used by regulators during inspections of medical device manufacturers to focus their attention on the parts of the process that are most likely to affect the quality of the product.

Seven Principles of HACCP • • • • • • •

Conduct hazard analysis Determine the critical control points (CCPs) in the process Establish critical limits Monitor each critical control point (CCP) Establish corrective actions Establish verification procedures Establish record-keeping and documentation procedures

Hazard Analysis A hazard is a condition that results in an adverse consequence to user/patient health and safety, either actual or potential. Hazards can result for both normal use and/or fault conditions. The HACCP plan is designed to control all reasonably likely safety hazards. To perform a hazard analysis for the development of an HACCP plan, manufacturers must gain a working knowledge of known and potential hazards associated with the medical device in both normal and fault conditions. Both actual and potential hazards are addressed in an HACCP plan. To begin a hazard analysis, characteristics of the medical device must first be identified that could result in a hazard to the patient or user. The hazards may be in the form of a product failure resulting in nonperformance or erroneous performace that can result in physical, mental or latent injury to the patient or user.

Biological Hazards Biological hazards include biocompatibility hazards and nonsterility/microbial contamination, pyrogen, bioburden and tissue compatibility problems. Nonsterility can result in infection and patient illness. In implantable devices, microorganisms have the potential to become pathogenic, given certain circumstances in immune-compromised individuals. The manufacturer depends on the process of sterilization to destroy all microorganisms introduced by the process and the environment. The package is the only protection from the potential introduction of microorganisms

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after the sterilization occurs. This establishment and maintenance of a sterility barrier is one of the primary functions of the sterile package. The properties most often used to assess sterility barrier effectiveness of the package is seal strength and seal integrity. Seal and package integrity can be established by any validated visual and/or physical test that demonstrates the seals are impermeable and continuous. These tests, along with microbial barrier testing of porous packaging materials, can be used to establish the capability of a package to maintain package integrity. Seal strength is an entirely different attribute, requiring different tests and test protocols. They are mutually exclusive; that is, acceptable seal strength does not ensure seal integrity and vice versa. If seal integrity failure only occurs occasionally, as it will in a robust sealing operation employing well maintained equipment, regularly calibrated and operated by trained personnel, that, coupled with the critical effect on the patient, brings seal integrity failures near the "maximum tolerable risk" limit. This analysis forces the manufacturer to identify the risk as significant and establish appropriate monitoring steps for control.

Determining Critical Control Points The Essential Control Point or "ECP" — similar to traditional HACCP critical control point, "CCP" — is a specific point in the process flow where application of a control measure effectively prevents, eliminates or reduces the hazard or functional failure to an acceptable level. It is often the last step where control is possible. It may not be possible to fully eliminate or prevent a hazard. In some processes and with some hazards, minimization may be the only reasonable goal of the HACCP plan.

ECPs vs. Control Points Only points at which significant device safety or functionality can be controlled are considered to be ECPs. ECPs should be limited to that point or those points at which control of the hazards or product functionality can be best achieved. In the package sealing operation, there are no prior or following steps that can aid in the control of the sealing process. While proper selection of materials, a validated sealing process, and control of key sealing parameters may positively impact seal strengths, only a test or observation of sealed packages can effectively monitor the success of the sealing process. The sealing of the package used to contain a medical device that must maintain sterility before use is always defined as an essential control point.

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Establish Critical Limits Essential limits must be established for the package sealing process. An essential limit represents the boundaries (maximum and/or minimum values) that are used to ensure a process produces safe and effective products. Each ECP must have one or more essential limits to prevent, eliminate or reduce to an acceptable level the occurrence of a device safety hazard. When the process deviates from the essential limit, a corrective and preventative action must be taken to ensure device safety. For package sealing, the control limits are a validated range of temperature, pressure, and dwell required to produce acceptable seals.

Critical Control Point Monitoring Monitoring is the process an operator relies upon to maintain control at an ECP. Accurate monitoring also indicates when there is a loss of control at an ECP and a deviation from an essential limit. It is important to ensure the essential limits are consistently met. When an essential limit is compromised, a corrective action is needed. The extent of the problem needing adjustments/corrections can be assessed by reviewing the monitoring records and finding the last recorded value that meets the essential limit. Monitoring is the essence of the HACCP system and appropriate selection of monitoring systems can aid greatly in the reduction of hazards. Monitoring also facilitates the ready availability of written documentation for the process control and the products that are produced in compliance with the HACCP plan. This information is useful in the verification of the HACCP plan.

Monitoring System Design The control measures discussed in principle one and the essential limits discussed in principle three are intended to control the hazards at each ECP. Monitoring procedures are used to determine if the control measures are being enacted and the essential limits are being met. Monitoring procedures must identify: • What will be monitored? This is usually a measurement or observation to assess if the ECP is operating within the critical limit. • How the essential limits and control measures will be monitored. Usually physical or chemical measurements (for quantitative critical limits) or observations (for qualitative critical limits). Needs to be realtime and accurate. • How frequently will the monitoring be performed? This can be continuous or intermittent. • Who will perform the monitoring? Is someone trained to perform the specific monitoring activity?

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What Will Be Monitored? Monitoring may mean measuring a characteristic of the product or the process to determine compliance with an essential limit. In the packaging example, monitoring of the processing parameters (temperature, pressure and dwell) have been shown to be sufficient for monitoring the seal strength attribute. Visual inspection of the seals of the intact package has served as the monitoring tool for seal integrity.

Essential Limits and Control Measures Monitoring must be designed to provide rapid (real-time) results. There is no time for lengthy analytical testing. Essential limit failures must be detected quickly and an appropriate corrective action instituted before there is further processing and/or distribution. Generally, physical measurements of seal parameter are preferred monitoring methods. They are quick, save time, and produce realtime results. They are also nondestructive. The selection of the monitoring equipment is a major consideration during development of an HACCP plan. Equipment used for monitoring ECPs varies with the attribute being monitored. It is important that equipment chosen for monitoring at the ECP be accurate to ensure control of the hazard. The variability of the monitoring equipment should also be considered when setting the essential limit. Periodic calibration or standardization is necessary to ensure accuracy. The critical control point identified as package sealing requires the monitoring of the two basic attributes — strength and integrity. While it is appropriate to rely on monitoring devices to indicate operation within the validated seal parameters, it is difficult to rely on the visual test for seal integrity. The human eye is often an unreliable monitoring device. In an informally conducted study of the reliability of visual identification of known seal defects, primarily channels through the seal area, participants were able to recognize the failures in only 51 percent of the instances.

Monitoring Frequency Where possible, continuous monitoring should be used. Continuous monitoring is possible for control of sealing parameters to ensure seal strength. A monitoring instrument that produces a continuous record of the measured value will not control the hazard on its own. The continuous record needs to be observed periodically and action taken when needed. This, too, is a component of monitoring. The length of time between checks will directly affect the amount of rework or product loss when an essential limit deviation is found. In all cases, the checks must be performed in time to ensure that nonconforming product is isolated before shipment. When it is not possible to monitor an ECP on a continuous basis, it is necessary for the

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monitoring interval to be short to detect possible deviations from essential limits or operating limits. The frequency on noncontinuous monitoring should be determined from historical knowledge of the product or process.

Who Will Monitor? Assignment of the responsibility for monitoring is an important consideration when developing an HACCP plan. Monitoring by line personnel and equipment operators can be advantageous since they are continuously viewing the product and/or equipment and can readily observe changes from the norm.

Corrective Actions Corrective actions involve procedures followed when a deviation or a malfunction occurs. These procedures and actions should be predetermined when developing the HACCP plan. Corrective actions should state procedures to restore process control and determine the safe disposition of the affected product. When essential limits are violated at an ECP, the predetermined, documented corrective actions should be instituted as quickly as possible. Effective corrective actions depend heavily on an adequate monitoring program. The primary objective is to establish a process that permits rapid identification of deviations from an essential limit. The sooner the deviation is identified, the more easily the corrective actions can be taken and the greater the potential for minimizing the amount of nonconforming product. Corrective action options include: isolating and holding product for safety evaluation; diverting the affected product or component to another line where deviation would not be considered essential; reprocessing; or destroying the product. An individual who has thorough training and an understanding of the process, and has the authority to make decisions, needs to be assigned the responsibility of making corrective actions.

Verification Procedures Verification are those activities that determine the validity of the HACCP plan and that the system is operating according to the plan. The purpose of verification is to provide a level of confidence that the plan is based on solid scientific principles, and that adequate hazard controls are available for the product and process, and the controls are being followed. At the package sealing essential control point, verification involves the maintenance of the equipment, trained personnel, recorded calibration, and targeted sampling and testing of incoming materials and finished packages. This testing must be based on a sound statistical rationale and be conducted employing validated test methods.

Appendix 1

101

Record-Keeping Procedure It is essential to the effectiveness of an HACCP program that monitoring records at each critical control point be created and reviewed. Thus, the continuous monitoring of seal processing parameters must be captured, either automatically or by periodic observation and recorded by appropriate personnel. All test data must be recorded as well. Visual monitoring of seal integrity must be recorded and compared to a "library" of known defects. The visual method must be validated and performed in an appropriately lit area, by trained individuals with proper visual acumen.

Summary HACCP is not a new concept — it is only recent to medical device manufacturing. Packaging of devices that must remain sterile is always a critical control point, as there are no ensuing steps that can be employed to correct defects. Seal strength and seal integrity are the two attributes that must be monitored at the critical point. Seal strength can effectively be monitored by operating the sealing equipment within the validated control limits. Seal integrity is another matter entirely. Seal integrity failures are often random occurrences that must be visible to the trained operator. This is not true in every instance. The use of precise testing equipment, exceeding the capabilities of visual testing, is a more effective way to manage the critical control point. Improved technology is a significant way to decrease the criticality of defined hazards and should be considered for monitoring at each critical control point.

Appendix 2

GHTF.SG3.N99-10

GHTF

FINAL DOCUMENT Title: Process Validation Guidance Authoring Group: SG3 Endorsed by: The Global Harmonization Task Force Date: June 29, 1999 Elizabeth D. Jacobson, Ph.D., GHTF Chair

The document herein was produced by the Global Harmonization Task Force (GHTF), a voluntary group of representatives from medical device regulatory agencies and the regulated industry. The document is intended to provide nonbinding guidance to regulatory authorities for use in the regulation of medical devices, and has been subject to consultation throughout its development. There are no restrictions on the reproduction, distribution or use of this document; however, incorporation of this document, in part or in whole, into any other document, or its translation into languages other than English, does not convey or represent an endorsement of any kind by the Global Harmonization Task Force.

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Process Validation Guidance Contents 0

Introduction

1

Purpose and scope 1.1 Purpose 1.2 Scope

2

Definitions

3

Processes that should be validated 3.1 3.2 3.3 3.4

Special processes Process validation within the quality system Process validation decision Examples

4

Statistical methods and tools for process validation

5

Conduct of a validation 5.1 5.2 5.3 5.4 5.5

6

Getting started Protocol development Installation qualification (IQ) Operational qualification (OQ) Performance qualification (PQ)

Maintaining a state of validation 6.1 6.2 6.3 6.4

Monitor and control Changes in process and/or product Continued state of control Examples of reasons for revalidation

7

Use of historical data in process validation

8

Summary of activities

Annexes A

Statistical methods and tools for process validation

B

Example validation

Appendix 2

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0 Introduction Process validation is a term used in the medical device industry to indicate that a process has been subject to such scrutiny that the result of the process (a product, a service or other outcome) can be practically guaranteed. This is vitally important if the predetermined requirements of the product can only be assured by destructive testing. Processing deficiencies may only become apparent after an intermediate component is further processed or the finished product is in use. Validation of a process entails demonstrating that, when a process is operated within specified limits, it will consistently produce product complying with predetermined (design) requirements. The medical device industry encompasses a wide range of technologies and applications, ranging from simple hand tools to complex computercontrolled surgical machines, from implantable screws to artificial organs, from blood-glucose test strips to diagnostic imaging systems and laboratory test equipment. These devices are manufactured by companies of varied size, structure, volume of production, manufacturing processes and management methods. These factors, especially production volume and number of manufacturing steps per unit (e.g., soldering or welding steps) significantly influence how process validation is actually applied. Given this diversity, this guidance does not suggest particular methods of implementation, and therefore, must not be used to assess compliance with quality system requirements. Rather, the intent is to expand on quality system requirements with practical explanations and examples of process validation principles. Manufacturers can and should seek out/select technology-specific guidance on applying process validation to their particular situation. This guidance provides general suggestions on ways manufacturers may prepare for and carry out process validations. Other ways may be equally acceptable; some regulatory requirements place the responsibility on the manufacturer to specify those processes which require validation and the qualification of personnel who operate validated processes. Regardless of the method used to validate the process, records of all validations activities should be kept and the final outcome documented. While the completion of process validation is a regulatory requirement, a manufacturer may decide to validate a process to improve overall quality, eliminate scrap, reduce costs, improve customer satisfaction, or other reasons. Coupled with properly controlled design activities; a validated process may well result in a reduced time to market for new products. In general, the validation of a process is the mechanism or system used by the manufacturer to plan, obtain data, record data, and interpret data. These activities may be considered to fall into three phases: 1) an initial

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qualification of the equipment used and provision of necessary services — also know as installation qualification (IQ); 2) a demonstration that the process will produce acceptable results and establishment of limits (worst case) of the process parameters — also known as operational qualification (OQ); and 3) an establishment of long-term process stability — also known as performance qualification (PQ). Many processes are controlled by computers. While the computer software may be considered an integral part of the process, this guideline does not cover software validation. While the theory of process validation is reasonably straightforward, the decision of the manufacturer to evaluate every process for potential validation may lead to uncertainty. Some regulatory requirements state that every process that cannot be fully verified by subsequent inspection or test be validated. Deviation from this principle may be allowed by local regulation, but should be fully justified by the manufacturer on the basis of lack of risk to patient. Guidance is provided for reaching decisions on whether to validate or not. 1

Purpose and scope

1.1 Purpose This process validation guidance is intended to assist manufacturers in understanding quality system requirements concerning process validation. 1.2 Scope This document has general applicability to manufacturing (including servicing and installation) processes for medical devices. Specific recommendations for verification of design output and design validation is included in the GHTF document covering design control. 2

Definitions

For this document, the following definitions apply. Terms other than those defined herein may be found in the literature. 2.1 Installation qualification (IQ): establishing by objective evidence that all key aspects of the process equipment and ancillary system installation adhere to the manufacturer's approved specification and that the recommendations of the supplier of the equipment are suitably considered. 2.2 Operational qualification (OQ): establishing by objective evidence process control limits and action levels which result in product that meets all predetermined requirements.

Appendix 2

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2.3 Performance qualification (PQ): establishing by objective evidence that the process, under anticipated conditions, consistently produces a product which meets all predetermined requirements. 2.4 Process validation: establishing by objective evidence that a process consistently produces a result or product meeting its predetermined requirements. 2.5 Process validation protocol: a document stating how validation will be conducted, including test parameters, product characteristics, manufacturing equipment, and decision points on what constitutes acceptable test results. 2.6 Verification: confirmation by examination and provision of objective evidence that the specified requirements have been fulfilled. 3

Processes that should be validated

3.1

Special processes

Special processes (those processes for which the product cannot be fully verified) need special consideration. In the medical device industry these considerations often lead to process validation. National or regional regulations may require that process validation be performed for special processes. 3.2

Process validation within the quality system

Process validation is part of the integrated requirements of a quality system. It is conducted in the context of a system including design control, quality assurance, process control, and corrective and preventive action. The interrelationship of design control and process development may, for some technologies, be very closely related. For others the relationship may be remote. The product should be designed robustly enough to withstand variations in the manufacturing process and the manufacturing process should be capable and stable to assure continued safe products that perform adequately. Often this results in a very interactive product development and process development activity. Daily quality assurance activities are conducted as specified by the process control plan which is often largely developed during process validation. Corrective actions often identify inadequate processes/process validations. Each corrective action applied to a manufacturing process should include the consideration for conducting process validation/revalidation.

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3.3

Process validation decision

The following model may be useful in determining whether or not a process should be validated: A Is Process Output Fully Verifiable?

Yes

B Is Verification Sufficient and Cost Effective?

No

No

D What is Level of Risk to Patient?

Low

E Accept Risk; Verify and Control the Process

F Validate for Business Reasons

High

G Validate to Control Risk

Yes

C Verify and Control the Process

H Redesign Product and/or Process

Figure 1 Process validation decision tree.

Figure 1 describes a decision tree that a manufacturer can follow when deciding on whether a process needs to be validated. The process under consideration in this model is the simplest possible — many processes may be large and/or a complex set of sub-processes. Each process should have a specification describing both the process parameters and the output desired. The manufacturer should consider whether the output can be fully verified by inspection and/or test (A). If the answer is positive, then the consideration should be made as to whether or not verification alone is sufficient to eliminate unacceptable risk and is a cost effective solution (B). If yes, the output should be verified and the process should be appropriately controlled (C).

Appendix 2

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If the output of the process is not verifiable then the manufacturer should consider the risk to the patient of the process or the final product (D). If the risk is high, then the decision should be to validate the process (G); alternatively, it may become apparent that the product or process should be redesigned to reduce variation and improve the product or process (H). If the risk is low, then the manufacturer may consider justifying not validating the process and accept those risks (E). Also, if the risk is low, management may decide to validate a process even though the output of the process is verifiable (F). This may be because the cost of ensuring compliance with output requirements of a nonvalidated process is too high, or because the manufacturer may not be prepared to accept the risk-to-patient of verification only, or for other reasons. The risk or cost may also be reduced by redesigning the product or process to a point where simple verification is an acceptable decision (H). 3.4 Examples The following table is a list of examples of processes that normally: (1) should be validated, (2) may be satisfactorily covered by verification, and (3) processes for which the above model may be useful in determining the need for validation. (1)

Processes that should be validated • • • • • • • •

(2)

Sterilization processes Clean room ambient conditions Aseptic filling processes Sterile packaging sealing processes Lyophilization processes Heat treating processes Plating processes Plastic injection molding processes

Processes that may be satisfactorily covered by verification • • • •

Manual cutting processes Testing for color, turbidity, total pH for solutions Visual inspection of printed circuit boards Manufacturing and testing of wiring harnesses

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(3)

Processes for which the above model may be useful in determining the need for validation • • • •

Cleaning processes Certain human assembly processes Numerical control cutting processes Filling processes

To determine the level of risk to the patient in the context of this guidance, it is suggested that the failure modes of the device be analyzed relative to the manufacturing process. If a failure of the process could cause a failure of the device, that process failure should be evaluated for its severity and frequency and subsequent failure rate of the device. Guidance on risk management can be found in other standards and guidances. The output of a process may be fully verifiable and the overall process may not require validation. However, software used to automate such processes should be validated for its intended use. Manufacturers should document the rationale used for not validating processes, including risk analysis and the reasons as to why verification and/or process control are sufficient. 4

Statistical methods and tools for process validation

There are many methods and tools that can be used in process validation. A primer on statistics and process validation is provided in Annex A as a guide through the basic concepts. Control charts, capability studies, designed experiments, tolerance analysis, robust design methods, failure modes and effects analysis, sampling plans, and mistake proofing are some of the examples. 5

Conduct of a validation

5.1

Getting started

A consideration should be given to form a multi-functional team to plan and oversee the validation activities. A team approach will help ensure the validation processes are well thought out, the protocols are comprehensive and the final packages are well documented and easy to follow. The team should advise "what could go wrong." The team also provides an opportunity for key functional areas to communicate early about important new and changed products and processes and can foster cooperation. Members of the validation team could include representatives from or personnel with expertise in:

Appendix 2

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• • • •

Quality Assurance Engineering Manufacturing Others depending on company organization and product types: • Laboratory • Technical Services • Research and Development • Regulatory Affairs • Clinical Engineering • Purchasing/Planning

Once the validation team has been formed, the next step is to plan the approach and define the requirements. Many manufacturers develop what is referred to as a master validation plan which identifies those processes to be validated, the schedule for validations, interrelationships between processes requiring validation and timing for revalidations. Once these have been established, and the purpose and scope for validations are clearly stated and known, protocol development can commence. Following is a list of activities that may be used as a checklist to review validation activity: • • • • • • • • • • • 5.2

Form multi-functional team for validation Plan the approach and define the requirements Identify and describe the processes Specify process parameters and desired output Decide on verification and/or validation Create a master validation plan Select methods and tools for validation Create validation protocols Perform IQ, OQ, PQ and document results Determine continuous process controls Control the process continuously Protocol development

Detailed protocols for performing validations are essential to ensure that the process is adequately validated. Process validation protocols should include the following elements: • Identification of the process to be validated • Identification of device(s) to be manufactured using this process • Objective and measurable criteria for a successful validation

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• Length and duration of the validation • Shifts, operators, equipment to be used in the process • Identification of utilities for the process equipment and quality of the utilities • Identification of operators and required operator qualification • Complete description of the process • Relevant specifications that relate to the product, components, manufacturing materials, etc. • Any special controls or conditions to be placed on preceding processes during the validation • Process parameters to be monitored, and methods for controlling and monitoring • Product characteristics to be monitored and method for monitoring • Any subjective criteria used to evaluate the product • Definition of what constitutes nonconformance for both measurable and subjective criteria • Statistical methods for data collection and analysis • Consideration of maintenance and repairs of manufacturing equipment criteria for revalidation For all three phases, IQ, OQ, and PQ, based on product/process requirements: • • • • • •

Determine what to verify/measure Determine how to verify/measure Determine how many to verify/measure, i.e, statistical significance Determine when to verify/measure Define acceptance/rejection criteria Define required documentation

Knowing exactly what the product requirements are and what key parameters will be necessary to answer the questions of what to measure. Seal thickness, seal strength, pressure testing and visual defects of samples are examples of measurable parameters. Utilizing statistically valid techniques such as sampling, design experiments, Taguchi methods, response surface studies and component swapping are statistically valid techniques to answer the questions of how many to measure. Utilization of standard test methods such as those contained in international or national standards will provide guidance in how to measure specific parameters. Also, it is important to ensure test methods replicate actual use conditions.

Appendix 2

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During the conduct of various phases of validation, the protocol should address the resolution of discrepancies. Some deviations in established protocol may not negate the results. Each deviation should be addressed, evaluated and a conclusion drawn as to acceptance or rejection of the results. As a result, process control procedures may require modification and those modifications should be validated as part of the overall process. Addressing all product and process requirements and the establishment of specific criteria for each requirement, upper and lower limits based on product specifications and established standards will help define the acceptance/rejection criteria. 5.3

Installation qualification (IQ)

Simply stated, IQ means is it installed correctly? Important IQ considerations are: • Equipment design features (i.e., materials of construction cleanability, etc.) • Installation conditions (wiring, utilities, functionality, etc.) • Calibration, preventative maintenance, cleaning schedules • Safety features • Supplier documentation, prints, drawings and manuals • Software documentation • Spare parts list • Environmental conditions (such as clean room requirements, temperature, humidity) Sometimes activities are conducted at the equipment supplier's site location prior to equipment shipment. Equipment suppliers may perform test runs at their facilities and analyze the results to determine that the equipment is ready to be delivered. Copies of the suppliers' qualification studies should be used as guides to obtain basic data, and to supplement installation qualification. However, it is usually insufficient to rely solely upon the validation results of the equipment supplier. Each medical device manufacturer is ultimately responsible for evaluating, challenging, and testing the equipment and deciding whether the equipment is suitable for use in the manufacture of a specific device. The evaluations may result in changes to the equipment or process.

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5.4

Operational qualification (OQ)

In this phase the process parameters should be challenged to ensure that they will result in a product that meets all defined requirements under all anticipated conditions of manufacturing, i.e., worst case testing. During routine production and process control, it is desirable to measure process parameters and/or product characteristics to allow for the adjustment of the manufacturing process at various action level(s) and maintain a state of control. These action levels should be evaluated, established and documented during process validation to determine the robustness of the process and ability to avoid approaching "worst case conditions." OQ considerations include: • Process control limits (time, temperature, pressure, linespeed, setup conditions, etc.) • Software parameters • Raw material specifications • Process operating procedures • Material handling requirements • Process change control • Training • Short-term stability and capability of the process (latitude studies or control charts) • Potential failure modes, action levels and worst-case conditions (Failure Mode and Effects Analysis, Fault Tree Analysis) • The use of statistically valid techniques such as screening experiments to establish key process parameters and statistically designed experiments to optimize the process can be used during this phase. 5.5

Performance qualification (PQ)

In this phase the key objective is to demonstrate the process will consistently produce acceptable product under normal operating conditions. Please note the guidance for process stability in Annexes A and B "Methods and tools for process validation." PQ considerations include: • Actual product and process parameters and procedures established in OQ • Acceptability of the product • Assurance of process capability as established in OQ • Process repeatability, long-term process stability Challenges to the process should simulate conditions that will be encountered during actual manufacturing. Challenges should include the

Appendix 2

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range of conditions as defined by the various action levels allowed in written standard operating procedures as established in the OQ phase. The challenges should be repeated enough times to ensure that the results are meaningful and consistent. Process and product data should be analyzed to determine what the normal range of variation is for the process output. Knowing the normal variation of the output is crucial in determining whether a process is operating in a state of control and is capable of consistently producing the specified output. One of the outputs of OQ and PQ is the development of attributes for continuous monitoring and maintenance. Process and product data should also be analyzed to identify any variation due to controllable causes. Depending on the nature of the process and its sensitivity, controllable causes of variation may include: • • • • • • • • • •

Temperature Humidity Variations in electrical supply Vibration Environmental contaminants Purity of process water Light Human factors (training, ergonomic factors, stress, etc.) Variability of materials Wear and tear of equipment

Appropriate measures should be taken to eliminate controllable causes of variation. Eliminating controllable causes of variation will reduce variation in the process output and result in a higher degree of assurance that the output will consistently meet specifications. 5.6

Final report

At the conclusion of validation activities, a final report should be prepared. This report should summarize and reference all protocols and results. It should derive conclusions regarding the validation status of the process. The final report should be reviewed and approved by the validation team and appropriate management. 6

Maintaining a state of validation

6.1

Monitor and control

Trends in the process should be monitored to ensure the process remains within the established parameters. When monitoring data on quality characteristics demonstrates a negative trend, the cause should be investigated, corrective action may be taken and revalidation considered.

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6.2

Changes in processes and/or product

Any changes in the process and /or product including changes in procedures, equipment, personnel, etc. should be evaluated to determine the effects of those changes and the extent of revalidation considered. 6.3

Continued state of control

Various changes may occur in raw materials and/or processes, which are undetected, or considered at the time to be inconsequential. (An example of this type of process is sterilization.) These changes may cumulatively affect the validation status of the process. Periodic revalidation should be considered for these types of processes. 6.4

Examples of reasons for revalidation

Revalidation may be necessary under such conditions as: • Change(s) in the actual process that may affect quality or its validation status • Negative trend(s) in quality indicators • Change(s) in the product design which affects the process • Transfer of processes from one facility to another • Change of the application of the process The need for revalidation should be evaluated and documented. This evaluation should include historical results from quality indicators, product changes, process changes, changes in external requirements (regulations or standards) and other such circumstances. Revalidation may not be as extensive as the initial validation if the situation does not require that all aspects of the original validation be repeated. If a new piece of equipment is purchased for a validated process, obviously the IQ portion of the validation needs to be repeated. However, most of the OQ aspects are already established. Some elements of PQ may need to be repeated, depending on the impact of the new equipment. Another example might be if a raw material supplier is changed, the impact of that change on the process and resultant product should be considered. Parts of OQ and PQ might need to be redone, as the interaction between the new raw material and the process may not be fully understood. 7

Use of historical data for validation

Validation of a process can be partially based on accumulated historical manufacturing, testing, control, and other data related to a product or process. This historical data may be found in batch records, manufacturing log

Appendix 2

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books, lot records, control charts, test and inspection results, customer feedback, field failure reports, service reports, and audit reports. A complete validation based on historical data is not feasible if all the appropriate data was not collected, or appropriate data was not collected in a manner which allows adequate analysis. Historical manufacturing data of a pass/fail nature is usually not adequate. If historical data is determined to be adequate and representative, an analysis can be conducted per a written protocol to determine whether the process has been operating in a state of control and has consistently produced product which meets its predetermined requirements. The analysis should be documented. The terms "retrospective validation," "concurrent validation" and "prospective validation" are often used. Any validation can use historical data in the manner described above, regardless of the term used. 8

Summary of activities

Initial considerations include: • Identify and describe the processes • Decide on verification and/or validation • Create a master validation plan If the decision is to validate: • • • • • • • • • • •

Form multi-functional team for validation Plan the approach and define the requirements Identify and describe the processes Specify process parameters and desired output Create a master validation plan Select methods and tools for validation Create validation protocols Perform IQ, OQ, PQ and document results Determine continuous process controls Prepare final report and secure management approval Control the process continuously

Maintaining a state of validation: • Monitor and control the process continuously • Revalidate as appropriate

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Annex A: Statistical Methods and Tools for Process Validation A.1 Introduction Process validation requires that a process is established that can consistently conform to requirements and that studies are conducted demonstrating that this is the case. Process development and optimization may lead directly to the validation of the process. In other words, the methods for developing and optimizing a process may be used (and the data developed) to demonstrate process capability and stability. Thus often there is no clear distinction between process development and process validation. However, many processes are well established and subject to routine process validation. Many of the methods and tools described here may already be used for these processes. As validation methods and tools are reviewed for existing processes, some of these may be helpful to improve validation protocols and improve processes. This annex describes the many contributions that statistical methods and tools can make to validation. Each tool appearing in bold is further described in Annex A.3. Nonconformities often occur because of errors made and because of excessive variation. Obtaining a process that consistently conforms to requirements requires a balanced approach using both mistake proofing and variation reduction tools. When a nonconformance occurs because of an error, mistake proofing methods should be used. Mistake proofing attempts to make it impossible for the error to occur or at least to go undetected. However, many nonconformities are not the result of errors, instead they are the result of excessive variation and off-target processes. Reducing variation and proper targeting of a process require identifying the key input variables and establishing controls on these inputs to ensure that the outputs conform to requirements. One output of process validation is the development of a control plan. The final phase of validation requires demonstrating that this control plan works, i.e., that it results in a process that can consistently conform to requirements. One key tool here is a capability study. A capability study measures the ability of the process to consistently meet the specifications. It is appropriate for measurable characteristics where nonconformities are due to variation and off-target conditions. Testing should be performed not only at nominal, but also under worst-case conditions. In the event of potential errors, challenge tests should be performed to demonstrate that mistake proofing methods designed to detect or prevent such errors are working. Acceptance sampling plans can be useful in optimizing the number of samples to be tested and to demonstrate conformance to specification.

Appendix 2

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A.2 Primer on statistics and process validation Each unit of product differs to some small degree from all other units of product. These differences, no matter how small, are referred to as variation. Variation can be characterized by measuring a sample of the product and drawing a histogram. For example, one operation involves cutting wire into 100 cm lengths. The tolerance is 100 ± 5 cm. A sample of 12 wires is selected at random and the following results are obtained: 98.7 100.2

99.3 96.4

100.4 103.4

97.6 102.0

101.4 98.01

102.0 00.5

A histogram of this data is shown in Figure 2. The width of the histogram represents the variation.

Number

3

LSL

USL

2

1 0 95

100

105

Length (cm)

Figure 2 Histogram of data. Of special interest is whether the histogram is properly centered and whether it is narrow enough to easily fit within the specification limits. The center of the histogram is estimated by calculating the average of the 12 readings. The average is 99.99 cm. The width of the histogram is estimated by calculating either the range or standard deviation. The range of the above readings is 7.0 cm. The standard deviation is 2.06 cm. The standard deviation represents the typical distance a unit is from the average. Approximately half of the units are within ±1 standard deviation of the average and about half of the units are more than one standard deviation away from the average. On the other hand, the range represents an interval containing all the units. The range is typically 3 to 6 times the standard deviation.

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Frequently, histograms take on a bell-shaped appearance that is referred to as the normal curve as shown in Figure 3. For the normal curve, 99.73% of the units fall within ± 3 standard deviations of the average.

Average -3 Std. Dev.

Average +3 Std. Dev.

Average

99.73%

Figure 3 Normal curve applied to histogram. For measurable characteristics like wire length, fill volume, and seal strength, the goal is to optimize the average and reduce the variation. Optimization of the average may mean to center the process as in the case of fill volumes, to maximize the average as in the case with seal strengths, or to minimize the average as in the case with harmful emissions. In all cases, variation reduction is also required to ensure all units are within specifications. Reducing variation requires the achievement of stable and capable processes. Figure 4 shows an unstable process. The process is constantly changing. The average shifts up and down. The variation increases and decreases. The total variation increases due to the shifting.

Ti m

e

Total Variation

Figure 4 Unstable process.

Appendix 2

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Instead, stable processes are desired as shown in Figure 5. Stable processes produce a consistent level of performance. The total variation is reduced. The process is more predictable.

Ti m

e

Total Variation

Figure 5 Stable process. However, stability is not the only thing required. Once a consistent performance has been achieved, the remaining variation must be made to safely fit within the upper and lower specification limits. Such a process is then said to be stable and capable. Such a process can be relied on to consistently produce good product as illustrated in Figure 6.

CAPABLE

Spec Limits

Ti m e

NOT CAPABLE

Figure 6 Process capability.

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A capability study is used to determine whether a process is stable and capable. It involves collecting samples over a period of time. The average and standard deviation of each time period is estimated and these estimates plotted in the form of a control chart. These control charts are used to determine if the process is stable. If it is, the data can be combined into a single histogram to determine its capability. To help determine if the process is capable, several capability indices are used to measure how well the histogram fits within the specification limits. One index called Cp is used to evaluate the variation. Another index Cpk is used to evaluate the centering of the process. Together these two indices are used to decide whether the process meets its requirements. The values required to pass depend on the severity of the defect (major, minor, critical) that the manufacturer considers acceptable. While capability studies evaluate the ability of a process to consistently produce good product, these studies do little to help achieve such processes. Reducing variation and the achievement of stable processes requires the use of numerous variation reduction tools. Variation of the output is caused by variation of the inputs. Consider the example of a simple system, such as a pump for moving fluids (Figure 7):

Figure 7 The pump. An output is flow rate. The pump uses a piston to draw a fluid into a chamber through one opening and then pushes it back out another opening. Valves are used to keep the fluid moving in the right direction. Flow rate will be affected by piston radius, stroke length, motor speed and valve backflow to name a few. The target flow rate is achieved by designing the piston radius, stroke length, motor speed, etc. The actual flow rate will vary due to variation in wear of the piston, wear of the bearings, wear of the

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valves, variation of the motor speed, temperature/viscosity of the fluid, etc. Variation of the inputs is transmitted to the output as shown in Figure 8.

Transmitted Variation Output

Relationships Between Input and Output

Variation of Input

Input

Figure 8 Transmission of variation. Reducing variation requires identifying the key input variables affecting the outputs, designing the process to take advantage of relative input sensitivities (the relationships between cylinder radius, stroke length, motor speed and output) and establishing controls on input variation (wear, motor speed, temperature/viscosity, etc.) to ensure that the outputs conform to their established specifications. In general, one should identify the key input variables, understand the effect of these inputs on the output, understand how the inputs behave and, finally, use this information to establish targets (nominals) and tolerances (windows) for the inputs. Various techniques can be used. One type of designed experiment called “a screening experiment” can be used to identify the key inputs. Another type of designed experiment called “a response surface study” can be used to obtain a detailed understanding of the effects of the key inputs on the outputs. Capability studies can be used to understand the behavior of the key inputs. Armed with this knowledge, robust design methods can be used to identify optimal targets for the inputs and tolerance analysis can be used to establish operating windows or control schemes that ensure the output consistently conforms to requirements. The obvious approach to reducing variation is to tighten tolerances on the inputs. This improves quality but generally drives up costs. The robust

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design methods provide an alternative. Robust design (Figure 9) works by selecting targets for the inputs that make the outputs less sensitive (more robust) to the variation of the inputs as shown below. The result is less variation and higher quality but without the added costs. Several approaches to robust design exist including Taguchi methods, dual response approach and robust tolerance analysis.

Output

Robust

Sensitive

Input

Figure 9 Robust design. Another important tool is a control chart (Figure 10).

Worst Case Upper (Acceptance) Limit Control (Action) Level

x x

x

x

x xx x

x

x

x x x

x

x

x x

x

Target Control (Action) Level Lower (Acceptance) Limit Worst Case

Time

Figure 10 Control chart.

x = average of a set of observations

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By monitoring the results of changes of inputs through control charting, the resultant variation in output can be determined and inherent variation of the process identified. Ultimately, control charting may be used to continuously monitor the process and ensure a state of validated control. Control or action levels can be determined to adjust the process and maintain the process within the control limits. Many other tools also exist for identifying key inputs and sources of variation including component swapping studies, multi-vari charts, analysis of means (ANOM), and variance components analysis, and analysis of variance (ANOVA). When studying variation, good measurements are required. Many times an evaluation of the measurement system should be performed using a gauge R&R or similar study. A.3 Descriptions of the tools A brief description of each of the cited tools follows: Acceptance Sampling Plan — An acceptance sampling plan takes a sample of product and uses this sample to make an accept or reject decision. Acceptance sampling plans are commonly used in manufacturing to decide whether to accept (release) or to reject (hold) lots of product. However, they can also be used during validation to accept (pass) or to reject (fail) the process. Following the acceptance by a sampling plan, one can make a confidence statement such as: "With 95% confidence, the defect rate is below 1% defective." Analysis of Means (ANOM) — Statistical study for determining if significant differences exist between cavities, instruments, etc. It has many uses including determining if a measurement device is reproducible with respect to operators and determining if differences exist between fill heads, etc. It is a simpler and more graphical alternative to Analysis of Variance (ANOVA). Analysis of Variance (ANOVA) — Statistical study for determining if significant differences exist between cavities, instruments, etc. Statistically, this is defined as a methodology for evaluating the results of factorial experiments designed to determine the relative influence of the factors and interactions that cause variation in a process. It is an alternative to Analysis of Means (ANOM). Capability Study — Capability studies are performed to evaluate the ability of a process to consistently meet a specification. A capability study is performed by selecting a small number of units periodically over time. Each period of time is called a “subgroup.” For each subgroup, the average and range are calculated. The averages and ranges are plotted over time using a control chart to determine if the process is stable or consistent over time. If

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so, the samples are then combined to determine whether the process is adequately centered and the variation is sufficiently small. This is accomplished by calculating capability indices. The most commonly used capability indices are Cp and Cpk. If acceptable values are obtained, the process consistently produces product that meets the specification limits. Capability studies are frequently used toward the end of the validation to demonstrate that the outputs consistently meet the specifications. However, they can also be used to study the behavior of the inputs in order to perform a tolerance analysis. Challenge Test — A challenge test is a test or check performed to demonstrate that a feature or function is working. For example, to demonstrate that the power backup is functioning, power could be cut to the process. To demonstrate that a sensor designed to detect bubbles in a line works, bubbles can be purposely introduced. Component Swapping Study — Study to isolate the cause of a difference between two units of product or two pieces of equipment. Requires the ability to disassemble units and swap components in order to determine if the difference remains with original units or moves with the swapped components. Control Chart — Control charts are used to detect changes in the process. A sample, typically consisting of five consecutive units, is selected periodically. The average and range of each sample is calculated and plotted. The plot of the averages is used to determine if the process average changes. The plot of the ranges is used to determine if the process variation changes. To aid in determining if a change has occurred, control limits are calculated and added to the plots. The control limits represent the maximum amount that the average or range should vary if the process does not change. A point outside the control limits indicates that the process has changed. When a change is identified by the control chart, an investigation should be made as to the cause of the change. Control charts help to identify key input variables causing the process to shift and aid in the reduction of the variation. Control charts are also used as part of a capability study to demonstrate that the process is stable or consistent. Designed Experiment (Design of Experiments or DOE) — The term “designed experiment” is a general term that encompasses screening experiments, response surface studies, and analysis of variance. In general, a designed experiment involves purposely changing one or more inputs and measuring resulting effect on one or more outputs.

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Dual Response Approach to Robust Design — One of three approaches to robust design. Involves running response surface studies to model the average and variation of the outputs separately. The results are then used to select targets for the inputs that minimize the variation while centering the average on the target. Requires that the variation during the study be representative of long term manufacturing. Alternatives are Taguchi methods and robust tolerance analysis. Failure Modes and Effects Analysis (FMEA) — An FMEA is systematic analysis of the potential failure modes. It includes the identification of possible failure modes, determination of the potential causes and consequences and an analysis of the associated risk. It also includes a record of corrective actions or controls implemented resulting in a detailed control plan. FMEAs can be performed on both the product and the process. Typically an FMEA is performed at the component level, starting with potential failures and then tracing up to the consequences. This is a bottom up approach. A variation is a Fault Tree Analysis, which starts with possible consequences and traces down to the potential causes. This is the top down approach. An FMEA tends to be more detailed and better at identifying potential problems. However, a fault tree analysis can be performed earlier in the design process before the design has been resolved down to individual components. Fault Tree Analysis (FTA) — A variation of a failure analysis. See FMEA for a comparison. Gauge R&R Study — Study for evaluating the precision and accuracy of a measurement device and the reproducibility of the device with respect to operators. Mistake Proofing Methods — Mistake proofing refers to the broad array of methods used to either make the occurrence of a defect impossible or to ensure that the defect does not pass undetected. The Japanese refer to mistake proofing as Poka-Yoke. The general strategy is to first attempt to make it impossible for the defect to occur. For example, to make it impossible for a part to be assembled backwards, make the ends of the part different sizes or shapes so that the part only fits one way. If this is not possible, attempt to ensure the defect is detected. This might involve mounting a bar above a chute that will stop any parts that are too high from continuing down the line. Other possibilities include mitigating the effect of a defect (seat belts in cars) and to lessen the chance of human errors by implementing self-checks. Multi-Vari Chart — Graphical procedure for isolating the largest source of variation so that further efforts concentrate on the largest source of variation.

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Response Surface Study — A response surface study is a special type of designed experiment whose purpose is to model the relationship between the key input variables and the outputs. Performing a response surface study involves running the process at different settings for the inputs, called trials, and measuring the resulting outputs. An equation can then be fit to the data to model the effects of the inputs on the outputs. This equation can then be used to find optimal targets using robust design methods and to establish targets or operating windows using a tolerance analysis. The number of trials required by a response surface study increases exponentially with the number of inputs. It is desirable to keep the number of inputs studied to a minimum. However, failure to include a key input can compromise the results. To ensure that only the key input variables are included in the study, a screening experiment is frequently performed first. Robust Design Methods — Robust design methods refers collectively to the different methods of selecting optimal targets for the inputs. Generally, when one thinks of reducing variation, tightening tolerances comes to mind. However, as demonstrated by Taguchi, variation can also be reduced by the careful selection of targets. When nonlinear relationships exist between the inputs and outputs, one can select targets for the inputs that make the outputs less sensitive to the inputs. The result is that while the inputs continue to vary, less of this variation is transmitted to the output. The result is that the output varies less. Reducing variation by adjusting targets is called “robust design.” In robust design the objective is to select targets for the inputs that result in on-target performance with minimum variation. Several methods of obtaining robust designs exist including robust tolerance analysis, dual response approach and Taguchi methods. Robust Tolerance Analysis — One of three approaches to robust design. Involves running a designed experiment to model the output's average and then using the statistical approach to tolerance analysis to predict the output's variation. Requires estimates of the amounts that the inputs will vary during long-term manufacturing. An alternative is the Taguchi method. Screening Experiment — A screening experiment is a special type of designed experiment whose primary purpose is to identify the key input variables. Screening experiments are also referred to as fractional factorial experiments or Taguchi L-arrays. Performing a screening experiment involves running the process at different settings for the inputs, called trials, and measuring the resulting outputs. From this, it can be determined which inputs affect the outputs. Screening experiments typically require twice as many trials as input variables. For example, 8 variables can be studied in 16 trials. This makes it possible to study a large number of inputs in a reasonable amount of time. Starting with a larger number of variables reduces the

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chances of missing an important variable. Frequently a response surface study is performed following a screening experiment to gain further understanding of the effects of the key input variables on the outputs. Taguchi Methods — One of three approaches to robust design. Involves running a designed experiment to get a rough understanding of the effects of the input targets on the average and variation. The results are then used to select targets for the inputs that minimize the variation while centering the average on the target. Similar to the dual response approach except that while the study is being performed, the inputs are purposely adjusted by small amounts to mimic long-term manufacturing variation. Alternatives are the dual response approach and robust tolerance analysis. Tolerance Analysis — Using tolerance analysis, operating windows can be set for the inputs that ensure the outputs will conform to requirements. Performing a tolerance analysis requires an equation describing the effects of the inputs on the output. If such an equation is not available, a response surface study can be performed to obtain one. To help ensure manufacturability, tolerances for the inputs should initially be based on the plants and suppliers ability to control them. Capability studies can be used to estimate the ranges that the inputs currently vary over. If this does not result in an acceptable range for the output, the tolerance of at least one input must be tightened. However, tightening a tolerance beyond the current capability of the plant or supplier requires that improvements be made or that a new plant or supplier be selected. Before tightening any tolerances, robust design methods should be considered. Variance Components Analysis — Statistical study used to estimate the relative contributions of several sources of variation. For example, variation on a multihead filler could be the result of shifting of the process average over time, filling head differences and short-term variation within a fill head. A variance components analysis can be used to estimate the amount of variation contributed by each source.

Annex B: Example Validation Foreword Heat sealing processes, as described in this example, use equipment to seal plastic pouches which perform as sterility barriers for disposable medical devices. Seal integrity is crucial for maintenance of sterility. Testing of seal integrity is usually destructive testing, and the process therefore is a special process which requires validation. This Annex is presented only to give a simple and brief example of the nature of a process validation. The heat seal process described should not

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be considered a model for all heat seal validations. Additionally, this example may be modified according to different quality systems, documentation methods and cultures of regions and/or countries which use this guidance. There are many other circumstances and variables that might be considered when validating an actual heat seal process. This example uses only three simple input variables: time, temperature and pressure. There may be many more input variables, such as operator training, material thickness and melt indexes of the plastic pouches. Additionally, all the details surrounding the rationale for specific sample sizes, control limits, etc. are not given. ABC Medical Device Company Process Validation Protocol PVP 98-101 Title: Heat Sealer Validation Products to be covered: Sterile Gizmos — Codes 12345 through 12789 Equipment/Process to be Validated: Supplier Co., Model xyz, ABC Manufacturing Equipment Register: MER 98-1248 / Heat Sealing Process: SOP 2012-14 Process/Product Change Control Number: PPCN 98-364 Objective: Supplier Co. has developed a new and improved heat sealer that should improve process flow and reduce set-up time. The heat sealer will be validated to ensure it performs with existing sterile barrier pouch materials and existing process procedure SOP 20-12-14. SOP 20-12-14 identifies a design requirement for a seal strength of 2 to 4 kg and a target of 3 kg. The most difficult pouches to seal are the smallest (PN 96-122) and the largest (PN 88010). The target process capability is a Cpk of >1. Reference Documents: 1. 2. 3. 4. 5. 6. 7. 8. 9.

Heat Seal Process Procedure, SOP 20-12-14 Statistical Methodologies, SOP 3-8-51, SOP 3-9-12, SOP 3-13-81 Master Device Records, Codes 12xxx Manufacturing Equipment Register, MER 98-1248 Supplier Co. Model xyz Heat Sealer Operating Manual Process Validation Master Plan: PVP-98001 Lab Processes and Calibration: SOP 9-2-5 Production Processes and Calibration: SOP 20-1-2 Clean Room Procedures: SOP 1-12-77

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Validation Plan: The Supplier Co. Model xyz Heat Sealer will be subjected to the Installation Qualification, Operational Qualification and Performance Qualification procedures outlined in the Master Validation Plan: PVP-98001. Statistical methods in SOP 3-x-x will be used as appropriate. The Installation Qualification will utilize the heat sealer operating manual to define requirements for electrical and air pressure requirements. The heat sealer will be installed, checked and calibrated in Clean Room 3 during a weekend, before the weekend scrub-down. Particular attention will be paid to the exhaust of pressurized air into the clean room, so that the requirement for integrity of the environment is not compromised. A checklist of requirements will be completed and results approved. Operational Qualification will be completed in three phases. First, during production down time, the heat sealer will be subjected to an initial burnin to observe the stability of the measurements of clamp closure time, temperature build and pressures. Pouches will be sealed, but detailed assessments of seal integrity will not be completed. Data for clamp closure time, temperature build and pressures will be recorded. Variations in these measures will be subjected to a screening experiment (SOP 3-8-51) to determine possible worst case situations and the risk of weak seals or overburning of the pouches. Initial optimal heat seal settings will also be established. The second phase of operational qualification will center the process and determine initial process capability. The process will be conducted off line, but during production, in the clean room and with production personnel. Production personnel will be trained on the use of the new heat sealer. Heat seals will be completed for pouches PN 96-122 and PN 88-010. Heat sealer settings for the time, temperature and pressure will be used which were determined to be optimal during the initial phase of operational qualification. Accelerated sampling plan 1-A from SOP 3-9-12 will be used and the results control charted. The seal strength target result will be 3 kg and the variation monitored. The number of runs, samples and evaluations will continue until it is determined that the CP is >1 per SOP 3-13-81. Optimal heat sealer settings will be determined for the next phase. The third phase of operational qualification will determine the sensitivity of the process to variations in time, temperature and pressure. The normal production process will be used. Production personnel will be trained on the use of the new heat sealer. Worst case combinations of time, temperature and pressure will be evaluated. Runs will be completed (1) with the optimal settings, (2) with a short dwell time, low temperature and low pressure; and (3) with a long dwell time, high temperature and high pressure. Action levels for adjustment of the heat sealer will be determined as a result of this phase.

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Performance qualification will commence after satisfactory completion of operational qualification. Optimal settings for the heat sealer will be used and the heat seal action levels for adjustment of time, temperature and pressure will be used. Accelerated sampling plan 2-C from SOP 3-9-12 will be used and the results control charted. Variations in seal strength will be investigated and root causes determined. When process stability is demonstrated, and the process variation demonstrates a value of CPk > 1 per SOP 3-13-81, the process will be considered validated and SOP 20-12-14 will be used to control the process. Measurement / Testing Equipment and Calibration: 1. Stopwatch, Process Development Lab, Calibrated per SOP 9-2-5 2. Remote IR Thermometer RST-12, Process Development Lab, Calibrated per SOP 9-2-5 3. Pressure gauge, 0–500kPa, Process Development Lab, Calibrated per SOP 9-2-5 4. VAR meter, ID 683, Process Development Lab, Calibrated per SOP 9-2-5 5. Heat Seal Pull Tester, PE 8167, Production, Calibrated per SOP 20-1-2 Equipment Maintenance: During validation, the heat sealer will be maintained per the Supplier Co. Operating Manual. Upon completion of the validation, Manufacturing Equipment Register, MER 98-1248 will be updated to include maintenance and calibration of the heat sealer. Revalidation: Upon completion of the validation, the Process Validation Master Plan: PVP98001 will be updated to include the heat sealer in the master validation schedule.

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Validation Team Protocol Approval:

John Smith

Date: 15 Nov. 1998

Title: Sr. Quality Engineer

Date: 15 Nov. 1998

Title: Production Supervisor

Date: 15 Nov. 1998

Title: Plant Manager

Date: 15 Nov. 1998

Title: R&D Project Leader

Date: 15 Nov. 1998

Title: Plant Quality Manager

John Smith

Paula Johnson Paula Johnson

Randy Jacoby Randy Jacoby

Sue Brown Sue Brown

Claudia Becker Claudia Becker

Protocol Registered in Doc Center:

Priscilla Johnson

Date: 18 Nov. 1998

Title: Document Center Manager

Priscilla Johnson

Installation Qualification Results PVP 98-101 Installation Checklist Requirements were established from the heat sealer operating manual, clean room procedures (SOP 1-12-77) and heat seal process procedure (SOP 20-1214). Requirement

Source

Electrical supply Air pressure Ergonomic positioning Spare parts

heat sealer operating heat sealer operating heat sealer operating heat sealer operating and SOP 20-12-14 SOP 1-12-77 SOP 1-12-77 SOP 20-12-14 SOP 20-12-14

Clean air exhaust Cleanability around equipment Accessibility for maintenance Capability for sizes of pouches

Status manual manual manual manual

conforms conforms conforms conforms conforms conforms conforms conforms

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Initial Burn-in The heat sealer operated as described in the heat sealer operating manual and as required by SOP 20-12-14. Calibration All gauges and measuring devices on the heat sealer were successfully calibrated per SOP 20-1-2. Lab Notebook Reference Quality Engineering Lab Notebook, JWS, 98-4, pages 46–62. Issues / Commentary No new issues were identified. The environmental challenge of the air exhaust was met by adding an oil based air filter to the exhaust line of the heat sealer. The particulate matter was monitored per SOP 9-15-84 and no changes from normal levels were detected. The heat sealer installation was successful. Validation Team Protocol Approval:

John Smith

Date: 15 Dec. 1998

Title: Sr. Quality Engineer

Date: 15 Dec. 1998

Title: Production Supervisor

Date: 15 Dec. 1998

Title: Plant Manager

Date: 15 Dec. 1998

Title: R&D Project Leader

Date: 15 Dec. 1998

Title: Plant Quality Manager

John Smith

Paula Johnson Paula Johnson

Randy Jacoby Randy Jacoby

Sue Brown Sue Brown

Claudia Becker Claudia Becker

IQ Results Registered in Doc Center:

Priscilla Johnson Priscilla Johnson

Date: 18 Dec. 1998

Title: Document Center Manager

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Operational Qualification Results PVP 98-101 Phase One Clamp closure time, temperature build and pressures were measured over a four-hour time frame with initial heat seal settings for time, temperature and pressure. Control charts were completed as follows: Clamp Closure Time in Seconds Upper Limit — 2.0 Seconds

x x x x x

x x

x x

x

x x

x

x x Target — 1.5 Seconds x x Lower Limit — 1.0 Seconds

Temperature in Degrees Centigrade Upper Limit — 170°C

x x

x x

x x

x

x

x x x

x x

x x x

Target — 160°C

x x x

Lower Limit — 150°C

x

Pressure in kPa Upper Limit — 350 kPA

xx x x x

xx

x x x

x x x

xx

x x x

Target — 325 kPA

Lower Limit — 300 kPA

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From this analysis, it is apparent that the temperature is the most variable within the lower and upper limits for temperature. Also, temperatures were under the limit for the first 15 to 20 minutes, as the sealer requires this time to warm up. This screening experiment demonstrated that temperature might be the primary factor influencing heat seal integrity. Initial optimal heat sealer settings were established: temperature controller setting of 7.5, closure time setting of 1.5 seconds and pressure setting of 325 kPa. Phase Two Response surface studies were conducted to determine the effects of key inputs on seal strength. Variations in settings were used and the resultant seal strength for ten pouches was calculated. The following table summarizes the results: Trial Run 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

Pouch Size Small Large Small Large Small Large Small Large Small Large Small Large Small Large Small Large Small Large Small Large Small Large Small Large Small Large Small

Time 1.0 1.0 1.5 1.5 2.0 2.0 1.0 1.0 1.5 1.5 2.0 2.0 1.0 1.0 1.5 1.5 2.0 2.0 1.0 1.0 1.5 1.5 2.0 2.0 1.0 1.0 1.5

Temperature

Pressure

150 150 150 150 150 150 160 160 160 160 160 160 170 170 170 170 170 170 150 150 150 150 150 150 160 160 160

300 300 300 300 300 300 300 300 300 300 300 300 300 300 300 300 300 300 325 325 325 325 325 325 325 325 325

Seal Strength Average Average Average Average Average Average Average Average Average Average Average Average Average Average Average Average Average Average Average Average Average Average Average Average Average Average Average

2.1, 2.3, 2.2, 2.5, 2.4, 2.8, 3.0, 3.1, 3.3, 3.4, 2.9, 2.8, 3.1, 3.2, 2.7, 2.9, 2.8, 3.0, 2.2, 2.3, 2.2, 2.5, 2.4, 2.8, 3.0, 3.1, 3.3,

6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ

1.2 1.8 1.6 1.3 1.5 1.0 0.4 0.6 0.5 0.6 0.3 0.4 0.6 0.5 0.6 0.4 0.6 0.7 1.7 1.5 1.3 1.4 1.7 1.2 0.3 0.5 0.4

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Results, continued: Trial Run 28 29 30 31 32 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54

Pouch Size Large Small Large Small Large Large Small Large Small Large Small Large Small Large Small Large Small Large Small Large Small Large

Time 1.5 2.0 2.0 1.0 1.0 1.0 1.5 1.5 2.0 2.0 1.0 1.0 1.5 1.5 2.0 2.0 1.0 1.0 1.5 1.5 2.0 2.0

Temperature

Pressure

160 160 160 170 170 150 150 150 150 150 160 160 160 160 160 160 170 170 170 170 170 170

325 325 325 325 325 350 350 350 350 350 350 350 350 350 350 350 350 350 350 350 350 350

Seal Strength Average Average Average Average Average Average Average Average Average Average Average Average Average Average Average Average Average Average Average Average Average Average

3.4, 2.9, 2.8, 3.1, 3.2, 2.3, 2.2, 2.5, 2.4, 2.8, 3.0, 3.1, 3.3, 3.4, 2.9, 2.8, 3.1, 3.2, 2.7, 2.9, 2.8, 3.0,

6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ 6σ

0.3 0.2 0.3 0.5 0.4 1.8 1.6 1.3 1.5 1.0 0.4 0.6 0.5 0.6 0.3 0.4 0.6 0.5 0.6 0.4 0.6 0.7

Based on these results, it is apparent that the lower temperature limit of 150°C will result in unacceptable variations in seal strength (overall average of 2.38 kg, 6σ of 1.42). Variations in time and pressure within specified limits have little to do with seal strength. An additional 36 runs were repeated with a lower temperature limit of 155°C and variations of time and pressure similar to the first 54 runs. The data is not included in this report, but is available in the lab notebook referenced below. The results of these runs demonstrated an overall average of 2.92 kg, 6σ of 0.5. The Cp for these runs had a value of 1.8. Optimal heat sealer settings were determined to be a temperature controller setting of 8.2, a time of 1.5 seconds and pressure of 325 kPa. Phase Three Normal production processes were used to seal pouches with product and heat seal settings at (1) optimal levels; (2) low temperature, low pressure and short time, and (3) high temperature, high pressure and long time. 190 products were produced at each combination of settings. Results The run with optimal levels resulted in an average seal strength of 3.08 kg, 6σ of 0.3, the run with low settings resulted in an average seal strength of

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2.8 kg, 6σ of 0.5, and the run with high settings resulted in an average seal strength of 2.9 kg, 6σ of 0.6. Lab Notebook Reference Quality Engineering Lab Notebook, JWS, 98-4, pages 63–98. Issues / Commentary The input that transmits the most variation to the heat sealing process is temperature. The lower limit of temperature was adjusted to 155°C from 150 °C. The heat sealer must have a warm-up time period of at least 20 minutes with normal cycling to have stable temperature control. Based on these results, when the process is run within input limits, the seal strength target of 3.0 kg should be met with a Cpk of 1.8 per SOP 3-1381. Initial action levels for adjustment of the heat sealer should be seal strengths of 2.6 kg and 3.2 kg, which should be 3σ variation from the average of 2.9 during operational qualification. The heat sealer Operational Qualification was successful. Validation Team OQ Results Approval

John Smith

Date: 5 Jan. 1999

Title: Sr. Quality Engineer

John Smith

Paula Johnson

Date: 5 Jan. 1999

Title: Production Supervisor

Date: 5 Jan. 1999

Title: Plant Manager

Date: 5 Jan. 1999

Title: R&D Project Leader

Date: 5 Jan. 1999

Title: Plant Quality Manager

Paula Johnson

Randy Jacoby Randy Jacoby

Sue Brown Sue Brown

Claudia Becker Claudia Becker

OQ Results Registered in Doc Center:

Priscilla Johnson Priscilla Johnson

Date: 10 Jan. 1998

Title: Document Center Manager

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Performance Qualification Results PVP 98-101 Normal production of codes 12345 and 12789 were run utilizing pouches PN 96-122 and PN 88-010. Optimal heat sealer settings were used. The heat sealer was allowed to warmup with normal cycling for half an hour prior to use. A week of production was completed for each code. Accelerated sampling plan 2-C from SOP 3-9-12 was used and the result control charted. Following is a typical control chart: Seal Strength Upper Acceptance Limit 4.0 kg Action Level 3.2 kg

x x

x

x

x xx x

x

x

x x x

x

x

x x

x

Target 3.0 kg Action Level 2.6 kg

Lower Acceptance Limit 2.0 kg

The resultant Cpk was 1.75 for the overall process during this performance qualification. The comparison of the Cp results for each day demonstrated that the process was both stable and capable. The following Cp values were calculated: PN 96-122: 1.8, 1.9, 1.7, 1.6, 1.7; PN 88-010: 1.6, 1.8, 1.7, 1.9, 2.0. The centering of results about the target was very close. Overall average seal strength was 2.93 kg with a target of 3.0 kg. The action levels were never reached, and therefore no adjustments were made and no root causes identified. Lab Notebook Reference Quality Engineering Lab Notebook, JWS, 99-1, pages l–48. Issues / Commentary The process has demonstrated stability and capability. The Manufacturing Equipment Register, MER 98-1248, has been updated to include maintenance and calibration of the new heat sealer.

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GHTF Study Group 3 - Quality Systems Process Validation Guidance - July, 1999 Page 38

The Process Validation Master Plan, PVP-98001 has been updated to include the new heat sealer in the revalidation process. The Heat Seal Process Procedure, SOP 20-12-14, has been updated to include the new heat sealer and the revised operating procedure for temperature warm-up and lower temperature control limit has been changed from 150°C to 155°C. All production and QA employees have been trained and the training schedule in SOP 20-12-14 has been revised accordingly. Validation Team PQ Results Approval

John Smith

Date: 31 Jan. 1999

Title: Sr. Quality Engineer

Date: 31 Jan. 1999

Title: Production Supervisor

Date: 31 Jan. 1999

Title: Plant Manager

Date: 31 Jan. 1999

Title: R&D Project Leader

Date: 31 Jan. 1999

Title: Plant Quality Manager

John Smith

Paula Johnson Paula Johnson

Randy Jacoby Randy Jacoby

Sue Brown Sue Brown

Claudia Becker Claudia Becker

PQ Results Registered in Doc Center::

Priscilla Johnson Priscilla Johnson

Date: 5 Feb. 1999

Title: Document Center Manager

Appendix 2

143 GHTF Study Group 3 - Quality Systems Process Validation Guidance - July, 1999 Page 39

Final Report PVP 98-101 We have reviewed the requirements of the protocol; the IQ, OQ and PQ reports and compared these to the requirements of the reference documents. All requirements have been met and the process is validated. Validation Team Final Report Approval

John Smith

Date: 5 Feb. 1999

Title: Sr. Quality Engineer

John Smith

Paula Johnson

Date: 5 Feb. 1999

Title: Production Supervisor

Date: 5 Feb. 1999

Title: Plant Manager

Date: 5 Feb. 1999

Title: R&D Project Leader

Date: 5 Feb. 1999

Title: Plant Quality Manager

Paula Johnson

Randy Jacoby Randy Jacoby

Sue Brown Sue Brown

Claudia Becker Claudia Becker

Final Report Registered in Doc Center:

Priscilla Johnson Priscilla Johnson

Date: 10 Feb. 1999

Title: Document Center Manager

Index A

C

A4220, product data sheet, 62 Acceptance criteria in Installation Qualification, 23–24 in instrument calibration, 31 in Operational Qualification, 30, 32, 34, 35 for process capability study, 40 Acceptance sampling plan, 127 Alarm in Operational Qualification, 32–33 verification tests, 33 Alloyd packaging machine, 88 Analysis of means (ANOM), 127; see also Statistical methods Analysis of variance (ANOVA), 127; see also Statistical methods Aseptic filling processes, validation for, 111 Assembly processes, validation for, 112 Association for the Advancement of Medical Instrumentation (AAMI), 76 ASTM 4169, 3 ASTM burst test F1140, 8 ASTM tensile test F88, 8 ASTM 4169 testing system, 8

Capability studies, 124–126 conduct of, 127–128 purpose of, 127 Carbon chamber test, 60 CEN 868, 76, 77 Center for Devices and Radiological Health (CDRH), 95 Checklists installation, 135 in validation protocol, 56, 73, 74 Circuit boards, verification for, 111 Clamp closure time, in example validation, 137 Cleaning/maintenance procedure, in validation protocol, 73 Cleaning processes, validation for, 112 Clean room ambient conditions, validation for, 111 Coleman, Karen, 76, 77, 78 Color, verification for, 111 Concurrent validation, 119 Contract packager procedures, in validation protocol, 56, 73, 74 Control chart, 126–127 example of, 126 in performance qualification, 141 Control plan, development of, 120 Cosmetic Act (1938), 17 Criteria process, baseline parameters for, 56, 68 Critical control points determining, 97 monitoring, 98 Cutting processes validation for, 112 verification for, 111

B Biological hazards, in HACCP, 96–97 Burst pressure measurements, 41 Burst strength, 18 Burst tests, 82

145

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Cycle temperature, in Operational Qualification, 34, 35

D DCS production area monitoring, 74 Decision tree, in process validation, 110–111 Deficiencies, documentation of, 83, 84–85 Design, package, see Package design Design of experiments (DOE), 128 Design testing, 7 Deviations in Installation Qualification, 28 in Operational Qualification, 36 Device manufacturer, responsibilities of, 61 Diagrams, in Installation Qualification, 25–26 Distribution, and package design, 3 Documentation for industry-generated support, 76–77 in Installation Qualification, 27 of deficiencies, 83, 84–85 warning letters, 80–81, 84 Dwell in sealing process, 19 monitoring of, 99

E Equipment, qualification of, 5; see also Installation Qualification; Operational Qualification; Performance Qualification Essential Control Point (ECP) defined, 97 monitoring of, 99–100 ETO sterilization process, 82 Example validation, 131–143 Exceptional conditions in Installation Qualification, 28 in Operational Qualification, 36

F Failure modes and effects analysis (FMEA), 129 Fault tree analysis (FTA), 129

FDA 483, 58, 84 FDA 483 response, 85–86 Field examinations, 89 Filling processes aseptic, 111 validation for, 112 Fill volume, statistical approach to, 122 Film, specifications for, 61 Flowcharts for prototype qualifications, 12 validation, 13 Flow rate, in capability study, 124–125 Food and Drug Act (1976), medical device amendments to, 75 Food and Drug Administration (FDA), U.S., 75 and HACCP controls, 95 Form 483 of, 58, 84 Form QSR 810.160 of, 2 on medical device packaging, 1 process validation defined by, 17 process validation guidelines of, 53 Quality System Regulations of, 1

G Gaskets, in sealing process, 20 Global Harmonization Task Force (GHTF), process validation guidance of, 105 Good manufacturing practices (GMPs), 75 deviations from, 80–81, 84, 87–88, 89 requirements, 17 Guidelines alterations of, 18 defined, 17 for process validation of drugs and devices, 75 Gurley densometer, 60

H Hayssen Model RT 113 packaging machine, 88 Hazard analysis, in HACCP, 96–97 Hazard analysis and critical control point (HACCP) corrective actions in, 100 critical control points in, 97 critical limits in, 98

Index

147

defined, 95–96 hazard analysis in, 96–97 monitoring in, 98–100 principles of, 96 record-keeping procedure in, 101 verification procedures in, 100 "Head space," evaluation of, 11 Heat seal, process validation for, 131–143 Heat sealer acceptance criteria for, 23–24, 30 inspection of, 24 Installation Qualification protocol for, 18, 22 instrument calibration verification for, 31–32 manufacturer's manuals for, 25 Operational Qualification for, 18, 29 preventative maintenance procedures for, 27 system description, 23, 30 warm-up time period for, 140 Heat sealer validation equipment in, 134 measurement in, 134 objective of, 132 validation plan for, 133–134 Heat seal process procedure, 142 Heat treating processes, validation for, 111 High Vacuum Auto Clave, 60 Histogram, statistical variation on, 121

I Injunction, consent decree of permanent, 90–91 Injunction recommendation, example of, 87–89 Injunctive relief, seeking, 89 Inspection of system component installation, 24 permanent injunction following, 90 Installation Qualification (IQ), 5 documentation of standard operating procedures in, 26–27 for heat sealer, 18, 22–28 in example validation, 133 in process validation, 108, 115 objective of, 22 protocol development for, 114

results, 135, 137–140 review, 31 Instrument calibration verification, in OQ, 31–32 Instrument list, for Installation Qualification, 25 Integrity testing, 85 ISO 11607 Packaging for Terminally Sterilized Medical Devices, 1, 76–77 on qualification of materials, 14 on validation, 2 standard simulations in, 3 ISTA-1A, 3 ISTA-1 testing system, 8

L Laboratory simulations, in package design, 11 Lap sponges, deficiencies in packaging of, 87–89 Law, defined, 17 Leak tests, 82 Lid material, 51 Lyophilization processes, validation for, 111

M Manufacturers' manuals, in Installation Qualification, 25 Manufacturers, responsibilities of, 61 Manufacturing equipment register, 141 Master device records, 88 Matrix for sealing conditions, 72 Medical device amendments (1976), 75 Medical device industry, technologies in, 107 Medical device manufacturers, responsibilities of, 115 Medical device packages, international compliance activities for, 77, 78; see also Packages Medical device packaging HACCP for, 95–101 and suppliers to industry, 15 Medical Device Packaging Validation, 75 Mistake proofing, 129

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Monitoring in HACCP, 98–100 of quality characteristics, 117 Multi-vari chart, 129

N National Academy of Sciences (NAS), on HACCP approach, 95 National Advisory Committee on Microbiological Criteria for Foods (NACMCF), 95 Nonconformities, 120 Normal curve, applied to histogram, 122; see also Statistical methods

O Operational Qualification (OQ), 5 for heat sealer, 18, 29–36 in example validation, 133 in process validation, 108, 116 objective of, 29 outputs of, 117 protocol development for, 114 supplemental data sheet for, 36 tests, 32 Overwraps, 7

P Package design distribution and, 3 elements of, 7–10 laboratory simulations, 11 problems in, 10, 10t testing protocols for, 11–13, 12 validation, 2–3, 8 Package field examinations, 82 Package integrity defined, 9 evaluation of, 82, 85 Package process, validation of, 4–5; see also Validation Packages categorization of medical, 3–4, 4t effective, 8–9 function of, 8, 9t integrity of, 9, 82, 85 materials for, 13–14 Package validation; see also Validation elements of, 21

file, 52, 57 integrity testing in, 85 problems of, 76, 78 Packaging and material compatibility, 77 nonporous materials for, 14 porous materials for, 14 process, 53 validation protocol for, 66–67 Packaging machines, 88 Packaging noncompliances, 76, 77t Paper high vac sterilizable surgical, 60 Type G, 60 Peel tests, 82 Performance Qualification (PQ), 5 in example validation, 134 in process validation, 109, 116–117 outputs of, 117 protocol development for, 114 results, 141 pH, verification for total, 111 Plastic injection molding processes, validation for, 111 Plating processes, validation for, 111 Poka-Yoke, 129 Post sterile inspection, procedure addressing, 86 Post-sterilization testing, 54 Pouch printed peel, 63 product data sheet for, 62 specifications for, 60, 61, 62 Tyvek, 23.30 Pressures in example validation, 137 in sealing process, 19 monitoring of, 99 Preventative maintenance procedures (PMs), in Installation Qualification, 27 Primary package, 7 Problem recognition, 75 Process packaging, 53 sealing, 18–19 Process capability, 123, 123f Process capability studies, 19, 37–49 acceptance criteria in, 40 burst pressure measurements in, 41 documentation for, 37 equipment in, 38 "matrix for sealing conditions" in, 42–47 procedure, 39

Index

149

purpose, 38 responsibilities, 38 scope, 38 "temperature data sheets" in, 48–49 testing, 40 and validation protocol, 53, 70–72 Process validation, 58; see also Validation decision tree for, 110–111 defined, 17, 107 evaluation of, 85 FDA's new guidelines for, 53 heat seal example, 131–143 in process validation guidance, 109 initiating, 112–113 output of, 120 statistical methods for, 112, 120–131 tools for, 112 Process validation guidance, 105 definitions in, 108–109 maintenance, 117–118, 119 outline for, 106 purpose of, 108 scope of, 108 specific processes in, 109–112 within quality system, 109–110 Process validation master plan, 134, 142 Process validation of drugs and devices (1987), guidelines for, 75 Process validation protocol in process validation guidance, 109 objective of, 132 Product Data Sheet A4220, 62 Production area monitoring, DCS, 74 Production information sheet, 61 Prospective validation, 119 Protocol development, for validations, 113–115 Prototype qualification, flowchart for, 12 Pump for moving fluids, capability study of, 124–126

Q QARN, 83 QSR 810.160, FDA, 2 Quality assurance, in process validation guidance, 109 Quality audit report, 64 Quality System Regulations (QSR), 1

R Recall, example of, 88

Record-keeping, in HACCP program, 101 Regulation and evaluation of deficiencies, 79–81 defined, 17 injunction recommendation in, 87–91 of packaging validation activities, 76, 87–91 of sterilization effects, 75–76, 82–83 permanent injunction for, 90 Regulatory letter, 88 Response surface study, 130 Retrospective validation, 119; see also Validation Return receipt, for warning letter, 80 Revalidation considerations of, 55 for heat sealers, 134 reasons for, 118 Robust design, 125–126, 126 dual response approach to, 129 methods, 130 Taguchi methods, 131 tolerance analysis, 130 Robust tolerance analysis, 126 Rotowrap packaging machine, 88

S Safety verification, in Operational Qualification, 32–33 Safety verification tests, 33 Scaling, equipment validation studies for, 83 Schematics, in Installation Qualification, 25–26 Screening experiments, 125, 130 Sealer adverse findings related to, 58 validation of, 58 Sealing, defined, 19 Sealing conditions, matrix for, 42 Sealing jaw pressures, 72 Sealing process, 18–19 consistency of, 69 contamination of, 20 critical parameters in, 19 environmental conditions for, 20 tools for, 20 Seal integrity measurement of, 18 monitoring of, 99, 101 testing of, 8–9, 131 Seals, package

150 sterilization effects on, 75, 79–81 validation of final, 62 visual identification of defects in, 99 Seal strength measurement of, 18 monitoring of, 99, 101 product data sheet for, 62 statistical approach to, 122 tests for, 8, 82 variations in settings for, 138–139 Secondary package, 7 Shelf life, considerations of, 9–10 Simulations requirements for, 13, 13t standard, 3 Simulation studies criteria for, 13, 14t laboratory, 11 Stable process, statistical, 123 Standard operating procedures (SOPs) for Installation Qualification, 26 in Operational Qualification, 31 Statistical control chart, for package process validation, 21 Statistical methods, 120 acceptance sampling plan, 127 analysis of means, 127 analysis of variance, 127 capability study, 127–128 challenge test, 128 component swapping study, 128 control chart, 126–127, 128 designed experiment, 128 dual response approach to robust design, 129 failure modes and effects analysis, 129 fault tree analysis, 129 gauge R&R study, 129 histogram of data, 121, 122 mistake proofing methods, 129 multi-vari chart, 129 process capability, 123 response surface study, 130 robust design, 125–126, 126, 130 robust tolerance analysis, 130 screening experiment, 130–131 stable processes in, 123 standard deviation, 121 Taguchi methods, 131 tolerance analysis, 131 transmission of variation in, 125 unstable processes in, 122 variance components analysis, 131 variation in, 121

Validating Medical Packaging Sterile packaging sealing processes, validation for, 111 Sterility, and seal integrity, 131 Sterilization, 96–97 ETO, 79 manufacturer's dependence on, 96 of medical products, 3 package integrity after, 75–76, 82–86 testing following, 85 validation for, 111 Sterilization effects, deficiencies in evaluation of, 75, 79–81 Supplemental data sheet, in installation qualification, 28 Suppliers, qualifications of, 15 Surgical scrub brushes, deficiencies in packaging of, 87–89 System design, monitoring, 98–100

T Taguchi L-arrays, 130 Taguchi methods, 114, 129, 131 Temperature in sealing process, 19 monitoring of, 99 Temperature build, in example validation, 137, 138, 139 Tensile strength, 18 Tertiary package, 7–8 Testing design, 7 Tests for seal strength, 8, 82 in process capability studies, 40 post-sterilization, 54 safety verification, 33 Test sequences, for medical device packages, 11–13 Thermoform/fill/seal; TFFS, 3 Time verification, in Operational Qualification, 34, 35 Tolerance analysis, 131 Tray, production of, 51 Tray/lid combination package validation file for, 52 validation file for, 51 Turbidity, verification for, 111 Tyvek material, 23, 30, 51

U Unstable process, statistical, 122 Utilities, in Installation Qualification, 24

Index

151

V Validation conduct of, 112–117, 119 defined, 2 design vs. process, 76 example, 131–143 flowchart for, 12, 13 maintaining, 117–118, 119 of package process, 107–108 package design, 2–3, 7–15 package process, 4–5, 17–21 prospective, 119 protocols developed for, 113–115 statistical methods for, 120–131 Validation file, 57 conclusions of, 54–55 for tray/lid combination, 52 Validation protocol, 51 adverse findings in, 58 and GMP compliance, 75 historical data for, 118–119 for Installation Qualification, 22–28 for Operational Qualification, 29–36 packaging, 66–67 process capability study in, 70–72 product data sheet, 62 quality audit report in, 64 ratings summary, 65

table of contents, 59 Validation studies, on package sealing equipment, 83 Validation team, 112–113 final report approval, 143 OQ results approval, 140 PQ results approval, 142 protocol approval, 135, 136 Variance components analysis, 131 Variation statistical, 121 transmission of, 125 Verification in HACCP, 100 in process validation guidance, 109 of processes, 111 Verification trials on package process validation, 20–21 vs. routine processing, 5 Visual exams, limitations of, 86 Visual identification, reliability of, 99

W Warning letters, 80–81, 84 Wire length, statistical approach to, 122 Wiring harnesses, verification for, 111