FDA Guia Industry.doc

8/12/2019 FDA Guia Industry.doc

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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 forSterile Products

For questions on the content of the guidance, contact CBERs Office of Compliance and Biologics

Quality at 30!"#$!303% C&ERs Office of 'harmaceutical (cience at 30!$)*!##"% C&R+s

Office of &eice Ealuation at #-0!#$*!3$-$% or C./s Office of e1 2nimal &rug Ealuation

at 30!"#$!*)*3


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U. S. Department of Health and Human Services

ood and Drug !dministration

Center for "iologics #valuation and $esearch

Center for Drug #valuation and $esearch

Center for Devices and $adiological HealthCenter for %eterinary &edicine

ebruary '(()


3/11

Guidance for Industry

Container and Closure System IntegrityTesting in Lieu of Sterility Testing as a

Component of the Stability Protocol for

Sterile Products

Additional copies of this guidance are available from:

Ofice of Communication, Training and Manufacturers Assistance, HFM-4Center for !iologics "valuation and #esearch

Food and $rug Administration

%4% #oc&ville 'i&e, (uite )*, #oc&ville, M$ )+)-%44+

nternet:http:..///0fda0gov.cber.guidelines0htm

'hone: +-+1-423 or 1%-+)2-%+

or

Ofice of Training and Communication

$ivision of $rug nformation, HF$ -)4

Center for $rug "valuation and #esearch


Fishers 5ane, #oc&ville, M$ )+2

'hone: 1%-+)2-421nternet:http:..///0fda0gov.cder.guidance.inde60htm

or

$ivision of (mall Manufacturers, nternational, and Consumer Assistance 7$(MCA8, HF9-))Center for $evices and #adiological Health


%1 'iccard $rive, #oc&ville, M$ )+

'hone: +-1+-)4%

nternet:http:..///0fda0gov.cdrh.guidance0 html"mail: dsmicacdrh0fda0gov

Fa6: )4-)2-1%%or

Communications (taf, HF ;-%)Center for ;eterinar< Medicine 7C;M8


2%3 (tandish 'lace

#oc&ville, M$ )+

nternet at http:..///0fda0gov.cvm.guidance.published0 htm
http://www.fda.gov/cber/guidelines.htmhttp://www.fda.gov/cber/guidelines.htmhttp://www.fda.gov/cder/guidance/index.htmhttp://www.fda.gov/cder/guidance/index.htmhttp://www.fda.gov/cdrh/guidancehttp://www.fda.gov/cdrh/guidancemailto:[email protected]://www.fda.gov/cvm/guidance/publishedhttp://www.fda.gov/cder/guidance/index.htmhttp://www.fda.gov/cdrh/guidancemailto:[email protected]://www.fda.gov/cvm/guidance/publishedhttp://www.fda.gov/cber/guidelines.htm


4/11

Contains *onbinding $ecommendations

Table of Contents

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.44

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GUID!*C# +$ I*DUST$2

Container and Closure System Integrity Testing in Lieu of Sterility

Testing as a Component of the Stability Protocol for Sterile

Products

This guidance represents the Food and $rug Administration=s 7F$A =s8 current thin&ing on

this topic0 t does not create or confer an< rights for or on an< person and does not

operate to bind F$A or the public0 >ou can use an alternative approach if the approachsatisfies the re?uirements of the applicable statutes and regulations0 f


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as the >sta6ility protocol>:, recommending an alternatie to sterility testing for supporting the

continued capa6ility of containers to maintain sterility 5he guidance document does not applyto sterility testing methods for product sterility testing prior to release, as container and closure

system integrity tests cannot demonstrate a product?s initial sterility

5his guidance document proides information that 1e recommend you consider 1hen youpropose using alternatie methods to sterility testing to confirm the integrity of a container andclosure system throughout the product?s shelf life or dating period 5he recommendations in this

guidance document apply to 6oth pre! and post!approal sta6ility protocols for sterile 6iological

products, human and animal drugs, including inestigational and 6ul= drugs For medical deices,the recommendations in this guidance document apply to sta6ility protocols for those deices

la6eled as sterile

4f you currently perform sterility testing as a sta6ility!indicating test as part of a sta6ility

protocol, you may continue to do so 4f your product is approed for an alternatie to sterilitytesting as a component of your sta6ility protocol, this document is not intended to recommend

additional testing requirements

F&2s guidance documents, including this guidance, do not esta6lish legally enforcea6leresponsi6ilities 4nstead, guidances descri6e the F&2s current thin=ing on a topic and should 6e

ie1ed only as recommendations, unless specific regulatory or statutory requirements are cited

5he use of the 1ordshould in F&2s guidances means that something is suggested orrecommended, 6ut not required

II. I*T$+DUCTI+*

'roducts la6eled as sterile are e@pected to 6e free from ia6le micro6ial contamination throughoutthe product?s entire shelf life or dating period For products la6eled as sterile, 1e consider sterility

to 6e a sta6ility characteristic 2s a result, the sta6ility protocol should include confirmation of

continuing sterility throughout the product?s shelf life or dating period 5he minimum sterilitytesting generally performed as a component of the sta6ility protocol for sterile products is at the

initial time point 9release: and final testing interal 9ie, e@piration: 2dditional testing is often

performed at appropriate interals 1ithin this time period 9eg, annually: +o1eer, as discussed6elo1 sterility tests for the purpose of demonstrating continuing sterility hae limitations, 1ith

respect to the method?s relia6ility, accuracy, and the conclusions that may 6e deried from the

results Because of the limitations of sterility tests descri6ed 6elo1, sterility tests are not

recommended as a component of a sta6ility program for confirming the continued sterility

throughout a product?s shelf life or dating period 2lternatie methods may 6e more relia6le inconfirming the integrity of the container and closure system as a component of the sta6ility

protocol for sterile products

5his guidance document does not suggest specific test methods and acceptance criteria 9e@cept for

references to A(' methods:, nor does it proide comprehensie lists of tests ou should determine

these details 6ased on good scientific principles for each specific container and closure system

ta=ing into consideration particular product formulations and, 1here applica6le, routes ofadministration

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444 D#I*ITI+*S

5he definitions presented here are for the purposes of this guidance only

2 container and closure sQuality of Biotechnological 'roducts (ta6ility 5esting of

BiotechnologicalHBiological 'roducts>, prepared under the auspices of the 4nternationalConference on +armoni7ation of 5echnical Requirements for Registration of 'harmaceuticals

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for +uman Ase 94C+ Final Duideline:35he 4C+ Final Duideline is intended to proide

guidance to applicants regarding the type of sta6ility studies that should 6e proided in support ofmar=eting applications for 6iotechnologicalH6iological products -

%. !/T#$*!TI%#S

2lternaties to sterility testing as part of the sta6ility protocol, such as replacing the sterility test1ith container and closure system integrity testing, might include any properly alidated physical

or chemical container and closure system integrity test 9eg, 6u66le tests, pressureHacuum decay,

trace gas permeationHlea= tests, dye penetration tests, seal force or electrical conductiity andcapacitance tests, etc:, or micro6iological container and closure system integrity tests 9eg,

micro6ial challenge or immersion tests: (uch tests may 6e more useful than sterility testing in

demonstrating the potential for product contamination oer the products shelf life or dating

period 5he adantages of using such container and closure system integrity tests in lieu ofsterility tests in the sta6ility protocol for sterile products include

(uch alternate methods may detect a 6reach of the container andHor closure system

prior to product contamination%# (ome of the alternate methods used to ealuate container and closure integrity can

consere samples that may 6e used for other sta6ility tests%

3 2lternatie test methods may require less time than sterility test methods 1hichrequire at least seen days incu6ation% and

- 5he potential for false positie results may 6e reduced 1ith some alternatie test

methods 1hen compared to sterility tests

3For eterinary products, generally, see .4C+ DI$, >(ta6ility 5esting of e1 BiotechnologicalHBiological.eterinary /edicinal 'roducts,> ** FR )$$, 2pril 3, #00, and .4C+ DI39R:, >(ta6ility 5esting of e1.eterinary &rug (u6stances and /edicinal 'roducts 9Reision:,> $ FR )


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Occasionally, applicants hae proposed the use of a preseratie effectieness test in lieu of the

appropriate sterility test for products containing antimicro6ial preseraties +o1eer, these tests

only measure the effectieness of preseraties against a panel of fie different test organisms5his method cannot confirm product sterility since it does not confirm the presence or a6sence of

contamination, 6ut rather only demonstrates the micro6iological effectieness of the preseratiesystem against the fie test organisms in question For these reasons, preseratie effectienesstests are not accepta6le alternatie tests for monitoring container and closure system integrity or

for demonstrating maintenance of sterility +o1eer, such tests are appropriate to perform as part

of the sta6ility protocol on multi!dose containers at the end of the product?s shelf life or datingperiod, to erify antimicro6ial preseratie effectieness and preseratie content

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Lhen see=ing to implement container and closure system integrity testing as an alternatie to

sterility testing as a component of the sta6ility protocol for sterile products, 1e recommend thatyou consider the follo1ing

2 container and closure system integrity test may replace sterility testing in a sta6ility

program at time points other than the product sterility test prior to release%# Container and closure system integrity tests do not replace sterility testing methods

for product sterility testing prior to release%

3 2ny alidated container and closure system integrity test method should 6e accepta6leproided the method uses analytical detection techniques appropriate to the method and

is compati6le 1ith the specific product 6eing tested 2 test method is adequately

alidated if it has 6een proen through scientifically accepted studies to 6e capa6le of

detecting a 6reach in container and closure system integrity% and- 2n appropriate container and closure system integrity test should 6e conducted

annually and at e@piration, or as other1ise required 6y applica6le regulations

.44 !PP/IC!TI+* SU"&ISSI+*

For ne1 mar=eting applications for sterile products, 1e recommend that you include container and

closure system integrity tests in your sta6ility protocol 'ending ne1 mar=eting applications may6e amended prior to approal

4f you 1ish to incorporate a alidated container and closure system integrity test to demonstrate thecontinued capa6ility of containers to maintain sterility for an approed product,


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Human drugs3 (u6mit methods and data la6eled J(pecial (upplement ! Changes Being

EffectedK for ne1 and a66reiated ne1 drug applications under M 3-$0

!nimal drugs3 (u6mit methods and data as J(upplement ! Changes Being EffectedK under M

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FDA Guia Industry.doc