Case: 1:16-cv-00651 Document #: 47-1 Filed: 11/08/16 Page 1 of 10 PageID #:1993
`Case: 1:16-cv—00651 Document #: 47-1 Filed: 11/08/16 Page 1 of 10 PagelD #:1993
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`EXHIBIT 1
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`EXHIBIT 1
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`Case: 1:16-cv-00651 Document #: 47-1 Filed: 11/08/16 Page 2 of 10 PageID #:1994
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`Guidance for Industry
`Container and Closure System Integrity
`Testing in Lieu of Sterility Testing as a
`Component of the Stability Protocol for
`Sterile Products
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`For questions on the content of the guidance, contact CBER’s Office of Compliance and
`Biologics Quality at 301-827-3031; CDER’s Office of Pharmaceutical Science at 301-796-1228;
`CDRH’s Office of Device Evaluation at 240-276-3747; or CVM’s Office of New Animal Drug
`Evaluation at 301-827-6963.
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`U. S. Department of Health and Human Services
`Food and Drug Administration
`Center for Biologics Evaluation and Research
`Center for Drug Evaluation and Research
`Center for Devices and Radiological Health
`Center for Veterinary Medicine
`February 2008
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`Case: 1:16-cv-00651 Document #: 47-1 Filed: 11/08/16 Page 3 of 10 PageID #:1995
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`Guidance for Industry
`Container and Closure System Integrity
`Testing in Lieu of Sterility Testing as a
`Component of the Stability Protocol for
`Sterile Products
`
`Additional copies of this guidance are available from:
`
`Office of Communication, Training and Manufacturers Assistance, HFM-40
`Center for Biologics Evaluation and Research
`Food and Drug Administration
`1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448
`Internet: http://www.fda.gov/cber/guidelines.htm
`Phone: 800-835-4709 or 301-827-1800
`or
`Office of Training and Communication
`Division of Drug Information, HFD-240
`Center for Drug Evaluation and Research
`Food and Drug Administration
`5600 Fishers Lane, Rockville, MD 20857
`Phone: 301-827-4573
`Internet: http://www.fda.gov/cder/guidance/index.htm
`or
`Division of Small Manufacturers, International, and Consumer Assistance (DSMICA), HFZ-220
`Center for Devices and Radiological Health
`Food and Drug Administration
`1350 Piccard Drive, Rockville, MD 20850
`Phone: 800-638-2041
`Internet: http://www.fda.gov/cdrh/guidance.html
`Email: dsmica@cdrh.fda.gov
`Fax: 240-276-3151
`or
`Communications Staff, HFV-12
`Center for Veterinary Medicine (CVM)
`Food and Drug Administration
`7519 Standish Place
`Rockville, MD 20855
`Internet at http://www.fda.gov/cvm/guidance/published.htm
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`Case: 1:16-cv-00651 Document #: 47-1 Filed: 11/08/16 Page 4 of 10 PageID #:1996
`Contains Nonbinding Recommendations
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`Table of Contents
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`I.
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`II.
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`PURPOSE AND SCOPE................................................................................................1
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`INTRODUCTION...........................................................................................................2
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`III. DEFINITIONS ................................................................................................................3
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`IV.
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`V.
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`VI.
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`BACKGROUND .............................................................................................................3
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`ALTERNATIVES...........................................................................................................4
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`IMPLEMENTATION ....................................................................................................5
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`VII. APPLICATION SUBMISSION ....................................................................................5
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`Case: 1:16-cv-00651 Document #: 47-1 Filed: 11/08/16 Page 5 of 10 PageID #:1997
`Contains Nonbinding Recommendations
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`GUIDANCE FOR INDUSTRY1
`Container and Closure System Integrity Testing in Lieu of Sterility
`Testing as a Component of the Stability Protocol for Sterile
`Products
`
`PURPOSE AND SCOPE
`
`
`This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this
`topic. It does not create or confer any rights for or on any person and does not operate to bind
`FDA or the public. You can use an alternative approach if the approach satisfies the
`requirements of the applicable statutes and regulations. If you want to discuss an alternative
`approach, contact the appropriate FDA staff. If you cannot identify the appropriate FDA staff,
`call the appropriate number listed on the title page of this guidance.
`
`I.
`
`This guidance document provides recommendations to you, manufacturers, for using methods
`other than sterility testing to confirm container and closure system integrity as a part of the
`stability protocol for sterile biological products, human and animal drugs, and medical devices.
`This guidance document finalizes the draft guidance of the same title dated January 1998
`(January 28, 1998, 63 Federal Register (FR) 4272).
`
`Manufacturers of drugs and biologics purporting to be sterile must test each batch or lot, as the
`case may be, to ensure that the product in question conforms to sterility requirements. 21 CFR
`211.167(a); 21 CFR 610.12. Such drugs and biologics are also subject to stability testing
`requirements. 21 CFR 211.166. The stability testing requirements include maintaining a written
`testing program designed to assess stability characteristics. Manufacturers of medical devices
`must validate processes, including sterilization for a device purporting to be sterile. 21 CFR
`820.75. Stability testing should be part of the design validation of such devices. In vitro
`diagnostic products for human use are required to be labeled with stability information. 21 CFR
`809.10. For products labeled as sterile, we consider sterility to be a stability characteristic.
`
`The purpose of stability testing is to provide evidence on how the quality of a substance or
`product varies with time under the influence of a variety of environmental factors such as
`temperature, humidity, and light, which enables you to establish or modify recommended storage
`conditions, retest periods, and shelf life or dating period, as the case may be.2 This guidance
`document applies only to the replacement of the sterility test with an appropriate container and
`closure system integrity test in the stability written testing program (referred to in this guidance
`
`
`1 This guidance document was prepared by an intercenter working group with representatives from the Center for
`Biologics Evaluation and Research, Center for Devices and Radiological Health, Center for Drug Evaluation and
`Research, and the Center for Veterinary Medicine.
`2 "Dating period" being the term used for biologics, as defined at 21 CFR 600.3(l), and "shelf life" being the term
`used for other drugs.
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`1
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`Case: 1:16-cv-00651 Document #: 47-1 Filed: 11/08/16 Page 6 of 10 PageID #:1998
`Contains Nonbinding Recommendations
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`as the "stability protocol"), recommending an alternative to sterility testing for supporting the
`continued capability of containers to maintain sterility. The guidance document does not apply
`to sterility testing methods for product sterility testing prior to release, as container and closure
`system integrity tests cannot demonstrate a product's initial sterility.
`
`This guidance document provides information that we recommend you consider when you
`propose using alternative methods to sterility testing to confirm the integrity of a container and
`closure system throughout the product's shelf life or dating period. The recommendations in this
`guidance document apply to both pre- and post-approval stability protocols for sterile biological
`products, human and animal drugs, including investigational and bulk drugs. For medical
`devices, the recommendations in this guidance document apply to stability protocols for those
`devices labeled as sterile.
`
`If you currently perform sterility testing as a stability-indicating test as part of a stability
`protocol, you may continue to do so. If your product is approved for an alternative to sterility
`testing as a component of your stability protocol, this document is not intended to recommend
`additional testing requirements.
`
`FDA’s guidance documents, including this guidance, do not establish legally enforceable
`responsibilities. Instead, guidances describe the FDA’s current thinking on a topic and should be
`viewed only as recommendations, unless specific regulatory or statutory requirements are cited.
`The use of the word should in FDA’s guidances means that something is suggested or
`recommended, but not required.
`
`II.
`
`Products labeled as sterile are expected to be free from viable microbial contamination
`throughout the product's entire shelf life or dating period. For products labeled as sterile, we
`consider sterility to be a stability characteristic. As a result, the stability protocol should include
`confirmation of continuing sterility throughout the product's shelf life or dating period. The
`minimum sterility testing generally performed as a component of the stability protocol for sterile
`products is at the initial time point (release) and final testing interval (i.e., expiration).
`Additional testing is often performed at appropriate intervals within this time period (e.g.,
`annually). However, as discussed below sterility tests for the purpose of demonstrating
`continuing sterility have limitations, with respect to the method's reliability, accuracy, and the
`conclusions that may be derived from the results. Because of the limitations of sterility tests
`described below, sterility tests are not recommended as a component of a stability program for
`confirming the continued sterility throughout a product's shelf life or dating period. Alternative
`methods may be more reliable in confirming the integrity of the container and closure system as
`a component of the stability protocol for sterile products.
`
`This guidance document does not suggest specific test methods and acceptance criteria (except
`for references to USP methods), nor does it provide comprehensive lists of tests. You should
`determine these details based on good scientific principles for each specific container and closure
`system taking into consideration particular product formulations and, where applicable, routes of
`administration.
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`INTRODUCTION
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`2
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`Case: 1:16-cv-00651 Document #: 47-1 Filed: 11/08/16 Page 7 of 10 PageID #:1999
`Contains Nonbinding Recommendations
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`III. DEFINITIONS
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`The definitions presented here are for the purposes of this guidance only.
`
` A
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` container and closure system refers to the entirety of packaging components that together
`contain and protect the product.
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` A
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` packaging component means any single part of a container and closure system. Typical
`components are containers (e.g., ampules, vials, bottles), container liners, closures (e.g., screw
`caps, stoppers), closure liners, stopper overseals, container inner seals, administration ports (e.g.,
`on large-volume parenterals), overwraps, administration accessories, and container labels.
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`IV.
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`Sterility tests have long been used to verify that products maintain their sterility throughout the
`product's entire shelf life or dating period. However, sterility testing has scientific and practical
`limitations, which are well known. Some of these are:
`
`
`BACKGROUND
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`1. Sterility tests will only detect viable microorganisms present at the time of the test;
`2. Viable organisms present at the time of the test can only be detected if they are
`capable of growth in the specified culture media;
`3. Sterility tests may be subject to potential interference due to adventitious microbial
`contamination introduced at the time of testing, resulting in false positive readings;
`and
`4. Sterility tests are always destructive of the samples tested and do not offer the
`opportunity to reexamine the same samples in the event of either positive or negative
`findings.
`
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`Some Centers of FDA have sought to address these shortcomings and communicated the
`information to you in the guidance document: "Guidance for Industry for the Submission
`Documentation for Sterilization Process Validation in Applications for Human and Veterinary
`Drug Products" (December 3, 1993, 58 FR 63996). Section V. A., page 16 of the guidance
`states:
`
`
`The ability of the container-closure system to maintain the integrity of its
`microbial barrier, and, hence, the sterility of a drug product throughout its shelf
`life, should be demonstrated. […] As previously stated, sterility testing at the
`initial time point is not considered sufficient to demonstrate the microbial
`integrity of a container-closure system. […].
`
`In the Federal Register of July 10, 1996 (61 FR 36466), we published a notice regarding the final
`guideline entitled "Quality of Biotechnological Products: Stability Testing of
`Biotechnological/Biological Products", prepared under the auspices of the International
`Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals
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`3
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`Case: 1:16-cv-00651 Document #: 47-1 Filed: 11/08/16 Page 8 of 10 PageID #:2000
`Contains Nonbinding Recommendations
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`ALTERNATIVES
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`for Human Use (ICH Final Guideline).3 The ICH Final Guideline is intended to provide
`guidance to applicants regarding the type of stability studies that should be provided in support
`of marketing applications for biotechnological/biological products. 4
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`V.
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`Alternatives to sterility testing as part of the stability protocol, such as replacing the sterility test
`with container and closure system integrity testing, might include any properly validated
`physical or chemical container and closure system integrity test (e.g., bubble tests,
`pressure/vacuum decay, trace gas permeation/leak tests, dye penetration tests, seal force or
`electrical conductivity and capacitance tests, etc.), or microbiological container and closure
`system integrity tests (e.g., microbial challenge or immersion tests). Such tests may be more
`useful than sterility testing in demonstrating the potential for product contamination over the
`product’s shelf life or dating period. The advantages of using such container and closure system
`integrity tests in lieu of sterility tests in the stability protocol for sterile products include:
`
`
`1. Such alternate methods may detect a breach of the container and/or closure system
`prior to product contamination;
`2. Some of the alternate methods used to evaluate container and closure integrity can
`conserve samples that may be used for other stability tests;
`3. Alternative test methods may require less time than sterility test methods which
`require at least seven days incubation; and
`4. The potential for false positive results may be reduced with some alternative test
`methods when compared to sterility tests.
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`3 For veterinary products, generally, see: VICH GL17, "Stability Testing of New Biotechnological/Biological
`Veterinary Medicinal Products," 66 FR 19177, April 13, 2001, and VICH GL3(R), "Stability Testing of New
`Veterinary Drug Substances and Medicinal Products (Revision)," 71 FR 19525, April 14, 2006.
`
` 4
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` The ICH Final Guideline is intended to supplement the tripartite ICH guideline entitled, “Stability Testing of New
`Drug Substances and Products,” the notice for which is published in the Federal Register of September 22, 1994 (59
`FR 48754). This guideline reflects formal scientific principles for stability testing of human drugs, and provides a
`general indication of the information to be generated on product stability, but leaves sufficient flexibility to
`encompass the variety of different practical approaches required for specific scientific situations and characteristics
`of the materials being evaluated.
`
` A
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` revision of the September 22, 1994, ICH guideline with the same title (Q1A (R)) (66 FR 56332, November 7,
`2001) was issued to add information to certain sections and to provide clarification to other sections. The most
`important changes were as follows: (1) stress testing of the drug substance was moved from the glossary to the main
`text; (2) the text on test procedures was made consistent with ICH guidance “Q6A Specifications: Test Procedures
`and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances” (65 FR 83041,
`December 29, 2000)), and relevant cross-references to other ICH guidelines were introduced; (3) the text on testing
`frequency was amended for accelerated testing conditions; (4) storage conditions are described in more detail, and
`testing at low temperature and testing of aqueous liquids in semipermeable containers are specifically addressed; (5)
`the postapproval commitment is clearly described; and (6) the guidance was made editorially consistent. A second
`revision of the guideline, “Guidance for Industry Q1A (R2) Stability Testing of New Drug Substances and
`Products,” (68 FR 65717, November 21, 2003) was issued to harmonize intermediate storage conditions for zones I
`and II with long-term storage conditions for zones III and IV.
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`Case: 1:16-cv-00651 Document #: 47-1 Filed: 11/08/16 Page 9 of 10 PageID #:2001
`Contains Nonbinding Recommendations
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`Occasionally, applicants have proposed the use of a preservative effectiveness test in lieu of the
`appropriate sterility test for products containing antimicrobial preservatives. However, these
`tests only measure the effectiveness of preservatives against a panel of five different test
`organisms. This method cannot confirm product sterility since it does not confirm the presence
`or absence of contamination, but rather only demonstrates the microbiological effectiveness of
`the preservative system against the five test organisms in question. For these reasons,
`preservative effectiveness tests are not acceptable alternative tests for monitoring container and
`closure system integrity or for demonstrating maintenance of sterility. However, such tests are
`appropriate to perform as part of the stability protocol on multi-dose containers at the end of the
`product's shelf life or dating period, to verify antimicrobial preservative effectiveness and
`preservative content.
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`VI.
`
`When seeking to implement container and closure system integrity testing as an alternative to
`sterility testing as a component of the stability protocol for sterile products, we recommend that
`you consider the following:
`
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`IMPLEMENTATION
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`1. A container and closure system integrity test may replace sterility testing in a stability
`program at time points other than the product sterility test prior to release;
`2. Container and closure system integrity tests do not replace sterility testing methods
`for product sterility testing prior to release;
`3. Any validated container and closure system integrity test method should be
`acceptable provided the method uses analytical detection techniques appropriate to
`the method and is compatible with the specific product being tested. A test method is
`adequately validated if it has been proven through scientifically accepted studies to be
`capable of detecting a breach in container and closure system integrity; and
`4. An appropriate container and closure system integrity test should be conducted
`annually and at expiration, or as otherwise required by applicable regulations.
`
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`VII. APPLICATION SUBMISSION
`
`For new marketing applications for sterile products, we recommend that you include container
`and closure system integrity tests in your stability protocol. Pending new marketing applications
`may be amended prior to approval.
`
`If you wish to incorporate a validated container and closure system integrity test to demonstrate
`the continued capability of containers to maintain sterility for an approved product,5 you must
`submit the appropriate application supplement, as follows:
`
`
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`5 As previously mentioned, if you currently perform sterility testing as a stability-indicating test as part of a stability
`protocol, you may continue to do so. Also, if your product is approved for an alternative to sterility testing as a
`component of your stability protocol, this document is not intended to impose additional testing requirements.
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`5
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`Case: 1:16-cv-00651 Document #: 47-1 Filed: 11/08/16 Page 10 of 10 PageID #:2002
`Contains Nonbinding Recommendations
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`Human drugs: Submit methods and data labeled “Special Supplement - Changes Being
`Effected” for new and abbreviated new drug applications under § 314.70.
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`Animal drugs: Submit methods and data as “Supplement - Changes Being Effected” under §
`514.8.
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`Biological products: Submit a supplement with proper validation data in support of the
`proposed change as a “Supplement - Changes Being Effected” under § 601.12.
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`Medical devices: Submit a PMA supplement with proper validation data in support of the
`proposed change under § 814.39.
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`You should include in your application supplement a discussion of what the test method
`evaluates and how it is applicable to microbial integrity. You should select methods that are
`appropriate to the product in question, and validate all test methods. Validation of particular
`methods should be specific to the product container and closure system or product type. Several
`alternative container and closure system integrity test methods exist, as described above. We
`encourage you to develop innovative methods of testing the integrity of specific container and
`closure systems.
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`The use of media-filled containers is generally acceptable for initial validation studies. It may be
`acceptable to use media-filled containers instead of product-filled containers for testing during
`the product's shelf life or dating period, if the product contains a material, such as a preservative,
`which would bias the results of the container and closure system integrity test. If you propose to
`use media-filled containers for some or all of the testing, you should include data in your
`application supplement to support this request.
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`If you manufacture a number of products that use the same type of container and closure system,
`you may validate your integrity test method using a bracketing matrix.6 It is not necessary to
`perform validation studies on each product.
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`The number of samples to be tested should be statistically appropriate. Samples which pass
`container and closure system integrity testing may be further utilized in the stability testing for
`that specific test period or interval; however, the test should be non-destructive and the sample
`unaltered by the container and closure testing method itself. Samples should not, however, be
`tested for container and closure system integrity at one time interval (e.g., 12 months), and then
`stored for further stability testing at later time periods (e.g., 24 months).
`
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`6 See ICH guidance “Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and
`Products” (68 FR 2339, January 16, 2003).
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`6
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