Guidance for Industry

Container and Closure Integrity Testing in Lieu of

Sterility Testing as a Component of the Stability
Protocol for Sterile Products

DRAFT GUIDANCE - NOT FOR IMPLEMENTATION

This guidance document is being distributed for comment purposes only.

Draft released for comment on January 28, 1998.

Comments and suggestions regarding this draft document should be submitted by

March 30, 1998, to Dockets Management Branch (HFA-305), Food and Drug
Administration, 12420 Parklawn Drive, Rm. 1-23, Rockville, MD 20857. All
comments should be identified with the docket number 98D-0021. For questions
regarding this draft document contact Valerie A. Butler, Center for Biologics
Evaluation and Research, (HFM-17), Food and Drug Administration, 1401 Rockville
Pike, Suite 200N, Rockville, MD 20852-1448, 301-827-6210,
FAX: 301-443-4874.

U. S. Department of Health and Human Services

Food and Drug Administration
Center for Biologics Evaluation and Research (CBER)
Center for Drug Evaluation and Research (CDER)
Center for Devices and Radiological Health (CDRH)
Center for Veterinary Medicine (CVM)
January 1998
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TABLE OF CONTENTS

[Note: Page numbering may vary for documents distributed electronically.]

I. PURPOSE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

II. SCOPE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

III. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

IV. DEFINITIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

V. BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

VI. IMPLEMENTATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

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GUIDANCE FOR INDUSTRY1

CONTAINER AND CLOSURE INTEGRITY TESTING IN LIEU OF STERILITY
TESTING AS A COMPONENT OF THE STABILITY PROTOCOL FOR STERILE
PRODUCTS

I. PURPOSE

The purpose of this draft guidance document is to provide information for using methods other
than sterility testing to confirm container and closure integrity as a part of stability testing for
sterile products. This document is intended to provide recommendations and offer alternative
methods for the sterility test for sterile biological products, human and veterinary drugs, and
medical devices. This document is applicable only to stability testing, a means of confirming
expiration dating. This document provides information which should be considered when a
manufacturer proposes using alternative methods other than sterility testing to confirm the
integrity of a container and closure system throughout its dating period.

II. SCOPE

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, and enables recommended storage conditions, retest periods,
and shelf life to be established. This document applies only to the replacement of the sterility
test with an appropriate container and closure integrity test in the stability protocol, permitting
an alternative to sterility testing for proving the continued capability of containers to maintain
sterility and is not offered as a replacement for sterility testing for product release.

III. INTRODUCTION

1This draft guidance document was prepared by an InterCenter working group and represents the agency’s
current thinking on container and closure integrity testing for sterile products. It does not create or confer any
rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if
such approach satisfies the requirements of the applicable statute, regulations, or both. Submit written requests for
additional copies of this document to the Office of Communication, Training, and Manufacturers Assistance (HFM-
40), Food and Drug Administration, 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448. Send one
self-addressed adhesive label to assist that office in processing your requests. The document may also be obtained
by mail by calling the CBER Voice Information System at 1-800-835-4709 or 301-827-1800 or by fax by calling the FAX
Information System at 1-888-CBER-FAX or 301-827-3844. Persons with access to the INTERNET may obtain the
document using the World Wide Web (WWW). Connect to CBER at "http://www.fda.gov/cber/guidelines.htm".

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In accordance with 21 CFR 600.11(h) for biological products, 21 CFR 314.50(d)(1)(i)-(ii) for
human drug products, 21 CFR 514.1(b)(5) for veterinary products, and 21 CFR 809 for in
vitro diagnostic devices, (applicable only for those devices for which stability testing is required
either by regulation or the device has an expiration date on the label), sterile products are
required to be free from viable microbial contamination throughout the product's entire dating
period. Historically, assessment of conformance to this requirement has been met by
conducting sterility tests according to the methods specified in 21 CFR 610.12 (for biological
products) or the United States Pharmacopeia (USP) 23 <71> (for drug products), and 21
CFR 809 (only for in vitro diagnostic devices or products labeled with an expiration date).
Sterility testing for product release continues to be required using the methods in the
requirements for 21 CFR 610.12, and the Sterility Test USP <71>, or alternate methods
approved in marketing applications. Confirmation of continuing sterility is required to be part of
the stability program and the minimum testing usually requested by the following Centers--
Center for Biologics Evaluation and Research (CBER), Center for Drug Evaluation and
Research (CDER), Center for Veterinary Medicine (CVM), and Center for Devices and
Radiological Health (CDRH)-- is at the initial time point (release) and final testing interval (i.e.,
expiry). Additional testing is often requested at appropriate intervals, e.g., annually, (CVM and
CDRH do not have a requirement for annual testing). However, for reasons discussed below,
the utility and appropriateness of conducting sterility tests for this purpose are questionable, with
respect to the method's reliability, accuracy, and the conclusions which may be derived from
the results. As a consequence of the limitations of sterility tests enumerated below, alternative
methods available may more reliably confirm the integrity of the container and closure system in
the final form. In general, this draft guidance document does not suggest specific test methods
and specifications (except for references to USP methods), nor does it suggest comprehensive
lists of tests. These details should be determined based on good scientific principles for each
specific container closure system for particular product formulations, and routes of
administrations.

IV. DEFINITIONS

The definitions presented here are not intended to supersede the definitions of container and
package in FDA’s biologics regulation at 21 CFR 600.3.

A container closure system refers to the sum of packaging components that together contain
and protect the dosage form. A packaging system is equivalent to a container closure system.
A packaging component means any single part of a container 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

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(e.g., on large-volume parenterals (LVPs)), overwraps, administration accessories, and

container labels. A package or market package refers to the container closure system and
associated labeling and external packaging (e.g., cartons, shrink wrap, package insert) that
constitutes the article provided to a pharmacist or retail customer upon purchase. It does not
include external packaging used solely for the purpose of shipping such articles.
Packaging materials may refer to packaging components or to materials of construction.

V. BACKGROUND

Sterility tests have long been used to verify that products maintain their sterility throughout the
entire dating period. However, sterility testing has scientific and practical limitations which are
well known. Some of these are:
1) The statistical limitations of the sample size used for testing in any test program
also apply to sterility testing;
2) Sterility tests will only detect viable microorganisms present at the time of the
test;
3) Viable organisms present at the time of the test can only be detected if they are
capable of growth in the specified culture media;
4) 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
5) 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.

Occasionally, applicants have proposed use of "Antimicrobial Preservatives - Effectiveness

Test" USP <51> in lieu of the appropriate sterility test for products containing antimicrobial
preservatives. However, this test only measures 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 demonstrates only the
microbiological effectiveness of the preservative system against the test organisms. However,
the "Antimicrobial Preservatives - Effectiveness Test" USP <51> is an appropriate test to
perform on multi-dose containers at the end of the dating period.

Recent efforts to address these shortcomings have been attempted by the individual Centers of
FDA in both official and unofficial formats. The joint CDER/CVM document entitled,
"Guideline for Submitting Documentation for Sterilization Process Validation in Applications for
Human and Veterinary Drug Products" published in the Federal Register of December 3,
1993 (58 FR 63996) states:

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"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 . . . "

Within CDER, additional testing is recommended to demonstrate the maintenance of integrity of

the microbial barrier imparted by the container and closure system. These tests should be
performed annually and at expiration. It is preferred that the integrity of the microbial barrier be
assessed using an appropriately sensitive container and closure integrity test.

FDA published in the Federal Register of July 10, 1996 ( 61 FR 36466), the International
Conference of Harmonization (ICH) final guideline entitled, "Quality of Biotechnological
Products: Stability Testing of Biotechnological /Biological Products." 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. The
ICH final guideline is intended to supplement the tripartite ICH guideline entitled, "Stability
Testing of New Drug Substances and Products," published in the Federal Register of
September 22, 1994 (59 FR 48754), which reflects formal scientific principles for stability
testing of drugs, and provides a general indication of the information on product stability to be
generated, but leaves sufficient flexibility to encompass the variety of different practical
situations required for specific scientific situations and characteristics of the materials being
evaluated.

Alternatives to sterility testing as part of the stability program, such as replacing the sterility test
with container and closure integrity testing, might include any properly validated physical or
chemical container and closure 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 integrity tests (e.g., microbial
challenge or immersion tests). Such tests may more properly address the issue of the
contamination potential of the product over its shelf life. The advantages of using such container
and closure integrity tests in lieu of sterility tests in the stability program include:
1) Use of these tests may detect a breach of container and/or closure integrity
which occurred at some point in the shelf life of the product, and such a breach
may allow contamination of the product to occur;
2) Some of the alternate methods used to evaluate container and closure integrity
can conserve samples which 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

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4) The potential for false positive results may be reduced with some alternative test
methods when compared to sterility tests.

Consequently, the Agency has determined that it is appropriate that alternative methods for
assessment of continuing sterility are accepted in the stability program for pending new product
applications, investigative or unlicensed products and approved/licensed products.
Manufacturers and sponsors should consider the following with regard to sterile products:
1) A container and closure integrity test may replace the 21 CFR 610.12 sterility
test or USP <71> Sterility Test (or their equivalent) in a stability program at
time points other than the time of initial product release time point.
2) Container and closure integrity tests do not replace USP in sterility testing
methods for product release.
3) Any adequately validated container and closure integrity test method should be
acceptable provided the method uses satisfactory analytical detection
techniques and is compatible with the specific product being tested. A test
method is adequately validated if it has been proven through scientifically valid
studies to be capable of detecting a breach in container closure integrity.
4) An appropriate container and closure integrity test should be conducted
annually and at expiration or as otherwise required by applicable regulations or
Agency recommendations.
5) Preservative effectiveness tests are not acceptable alternative tests for
monitoring container and closure integrity or for demonstrating maintenance of
sterility.

VI. IMPLEMENTATION

It is recommended to include container and closure integrity tests in the stability testing
protocols for sterile product license applications or premarket notifications for in vitro
diagnostic devices.

Approved new product applications or licenses may be updated as indicated below to include
properly validated container and closure integrity tests in lieu of sterility testing according to
USP or Code of Federal Regulation methods (or equivalent).

Incorporation of alternative methods to evaluate maintenance of sterility into the stability

protocol should proceed via current mechanisms available for each of the application types.
Sponsors of approved new and abbreviated new drug applications may provide methods and
data under 21 CFR 314.70 for human drugs, and 21 CFR 514.8(d) for veterinary drugs,
labeled "Special Supplement - Changes Being Effected." Sponsors of approved product

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license applications (PLAs) should submit supplements with proper validation data in support of
the proposed change under 21 CFR 601.12 for biologics, labeled "Supplement - Changes
Being Effected," or if applicable "Supplement - Changes Being Effected in 30 Days." New
product applications or license applications may be amended prior to approval. Firms are
encouraged to select methods which are appropriate to the device or product in question, and
all test methods should be validated. A discussion of what the test method evaluates and how it
is applicable to microbial integrity should be included in the submission. Validation of particular
methods should be specific to the product container and closure system or product type.
Several alternative container and closure integrity test methods exist including, for example, dye
penetration tests, bubble tests, pressure/vacuum decay, trace gas permeation/leak tests, and
microbial challenge tests. Development of other innovative and container-closure-specific
methods is encouraged.

The number of samples to be tested should be similar to the sampling requirements provided in
USP <71> Sterility Test for drugs or in 21 CFR 610.12 for biologics. Retests are permissible,
but should use at least twice as many samples as tested for in "Stage I." Samples which pass
container and closure 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 integrity at one time interval (e.g., 12 months), and be stored
for use at later time periods (e.g., 24 months).