asq-fda 6-23-05 chpa stability working group1 36 th annual asq-fdc/fda conference june 23, 2005 chpa...

ASQ-FDA 6-23-05 CHPA Stability Working ASQ-FDA 6-23-05 CHPA Stability Working GroupGroup

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3636thth Annual ASQ-FDC/FDA Conference Annual ASQ-FDC/FDA ConferenceJune 23, 2005June 23, 2005

CHPA Guidelines on Stability Testing of CHPA Guidelines on Stability Testing of OTC Monograph Drug ProductsOTC Monograph Drug Products

Karen L. Lucas Patricia WerschulzKaren L. Lucas Patricia Werschulz Pfizer Consumer Healthcare BMS Worldwide ConsumerPfizer Consumer Healthcare BMS Worldwide Consumer


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OverviewOverview

BackgroundBackground Who and What is the CHPA Stability Who and What is the CHPA Stability

Working Group (SWG)?Working Group (SWG)? What are we trying to fix in the OTC What are we trying to fix in the OTC

World?World? Risks vs. Benefits of Having a GuidelineRisks vs. Benefits of Having a Guideline Where are we today & What’s next?Where are we today & What’s next?


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BackgroundBackground

• InIn August 2002 August 2002, CHPA was approached by a member , CHPA was approached by a member company to obtain support in addressing FDA’s lack company to obtain support in addressing FDA’s lack of guidance on stability testing requirements for OTC of guidance on stability testing requirements for OTC Monograph Drug Products.Monograph Drug Products.

• As a starting point toward further dialogue with both As a starting point toward further dialogue with both the agency and industry, the development of a the agency and industry, the development of a draft draft stability guideline document was proposedstability guideline document was proposed. .

• In In May 2003May 2003, CHPA granted approval to form the , CHPA granted approval to form the Stability Working Group (SWG).Stability Working Group (SWG).


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Stability Working Group Members

•Karen L. Lucas, Pfizer Consumer Healthcare - ChairpersonKaren L. Lucas, Pfizer Consumer Healthcare - Chairperson

•Patricia Werschulz, Bristol-Myers SquibbPatricia Werschulz, Bristol-Myers Squibb

•Jeffrey Needels, Novartis Consumer HealthJeffrey Needels, Novartis Consumer Health

•David Wiggins, Schering PloughDavid Wiggins, Schering Plough

•Judy Lee, Purdue PharmaJudy Lee, Purdue Pharma

•Bruce Henning, Bayer Healthcare Consumer CareBruce Henning, Bayer Healthcare Consumer Care

•Jane Cai, Johnson & Johnson Consumer Jane Cai, Johnson & Johnson Consumer

•Eleanor Freeman, McNeil ConsumerEleanor Freeman, McNeil Consumer

•Mary W. Seibel, Procter & Gamble Health Care Mary W. Seibel, Procter & Gamble Health Care

•Tony Psihoules, Colgate-PalmoliveTony Psihoules, Colgate-Palmolive

•Bill Van Meter, PerrigoBill Van Meter, Perrigo

•Frederick Razzaghi, CHPA - FacilitatorFrederick Razzaghi, CHPA - Facilitator


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A Need was Identified……..A Need was Identified……..SWG’s GoalSWG’s Goal

Prior to this CHPA guideline, the non-prescription industry Prior to this CHPA guideline, the non-prescription industry did not have directly applicable stability testing guidance for did not have directly applicable stability testing guidance for OTC monograph drug products not regulated by an OTC monograph drug products not regulated by an NDA/ANDA.NDA/ANDA.

Historically, non-prescription drug companies developed Historically, non-prescription drug companies developed their stability testing programs based upon their best their stability testing programs based upon their best interpretation and practical application of the most current interpretation and practical application of the most current FDA guidance for new drug products. FDA guidance for new drug products.


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A Need was Identified……A Need was Identified……SWG’s Goal (cont’d)SWG’s Goal (cont’d)

Because of the Because of the unique requirementsunique requirements associated with new associated with new OTC drug products, the direct application of the FDA OTC drug products, the direct application of the FDA guidance is frequently guidance is frequently inappropriate inappropriate andand impractical impractical. . Drug products with an OTC monograph will typically be Drug products with an OTC monograph will typically be well characterizedwell characterized with a: with a:– significant body of informationsignificant body of information– well known safety profile well known safety profile – long history of use in multiple dosage forms. long history of use in multiple dosage forms.

For this reason, the OTC Industry (under the CHPA) is For this reason, the OTC Industry (under the CHPA) is proposing this guideline for non-prescription (OTC) drug proposing this guideline for non-prescription (OTC) drug products not regulated by an NDA/ANDA. products not regulated by an NDA/ANDA.


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A Need was Identified…….A Need was Identified…….SWG’s Goal (cont’d)SWG’s Goal (cont’d)

SWG’s Goal:SWG’s Goal:– To create an To create an OTC Stability GuidelineOTC Stability Guideline in order to in order to

establish establish science-based science-based best practicesbest practices and and minimum minimum requirementsrequirements for the development and launch of for the development and launch of OTC Monograph Drug Products in the U.S. (that OTC Monograph Drug Products in the U.S. (that are not regulated by an NDA/ANDA).are not regulated by an NDA/ANDA).


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We Recognized The Problem…..We Recognized The Problem….. Rx World (NCEs):Rx World (NCEs):

ICH Q1A and FDA (3 batches, LT & ACC, 12 months data) ICH Q1A and FDA (3 batches, LT & ACC, 12 months data)

Generic World (NCEs with experience):Generic World (NCEs with experience): 1987 and draft 1998 FDA Stability Guidelines1987 and draft 1998 FDA Stability Guidelines

OTCs (extensive experience, good safety record, Monograph Drugs):OTCs (extensive experience, good safety record, Monograph Drugs): The existing FDA stability references applicable to OTC monograph The existing FDA stability references applicable to OTC monograph

products (e.g.. the Joel Davis "Dating Game" memo from 1978, and FDA products (e.g.. the Joel Davis "Dating Game" memo from 1978, and FDA Inspector Technical Guide ITG-41 from 1985) are somewhat dated. Inspector Technical Guide ITG-41 from 1985) are somewhat dated. Something more recent is preferable in order to justify the OTC Something more recent is preferable in order to justify the OTC Industry's approach to stability testing.Industry's approach to stability testing.

Current practice is for companies to use ICH Q1A. Q1A is the most Current practice is for companies to use ICH Q1A. Q1A is the most recent guidance that has been developed. It represents the most recent guidance that has been developed. It represents the most conservative set of stability requirements. Clearly, OTCs do not require conservative set of stability requirements. Clearly, OTCs do not require as much testing, and in practice, companies are not strictly following as much testing, and in practice, companies are not strictly following ICH.ICH.

Bottom Line:Bottom Line:The NCE requirements are excessive!The NCE requirements are excessive!


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What are we trying to fix???What are we trying to fix???

We recognize that there are a number of We recognize that there are a number of Warning Letters & RecallsWarning Letters & Recalls for inadequate for inadequate and/or no established Stability Programs and/or no established Stability Programs within OTC Companies.within OTC Companies.

This guidance will help This guidance will help CHPA Member CHPA Member CompaniesCompanies develop develop adequate adequate Stability Stability Programs and reach a “Programs and reach a “higher state” of higher state” of compliance.compliance.


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Warning Letters & Recalls Warning Letters & Recalls (1997 – 2003)(1997 – 2003)

Warning Letters to OTC Companies:Warning Letters to OTC Companies: • Failure to establish a written Stability Program – 33Failure to establish a written Stability Program – 33• Failure to follow written Stability Program – 19Failure to follow written Stability Program – 19• No data available to support labeled expiration -11No data available to support labeled expiration -11• Inadequate Stability Program - 10Inadequate Stability Program - 10• Methods not stability indicating - 3Methods not stability indicating - 3

Recalls by OTC Companies:Recalls by OTC Companies:• Data does not support labeled expiration – 6Data does not support labeled expiration – 6• Failed dissolution – 5Failed dissolution – 5• Sub-potency (stability failure) – 4Sub-potency (stability failure) – 4• Other stability failure – 3Other stability failure – 3• Non-uniformity in potency results – 1Non-uniformity in potency results – 1• Degradation failure - 1Degradation failure - 1


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Risks to IndustryRisks to Industry(Having a Guidance)(Having a Guidance)

We may provide a starting point for FDA to use toWe may provide a starting point for FDA to use to over-regulateover-regulate the OTC Industry. the OTC Industry.

May May decrease flexibilitydecrease flexibility of some individual CHPA of some individual CHPA Member CompaniesMember Companies not already meeting not already meeting minimum minimum standards.standards.

Uncertainty about Uncertainty about Industry acceptanceIndustry acceptance.. This would only be This would only be ONE partONE part of of FDA’s “Quality FDA’s “Quality

SystemSystem”.”.


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Benefits to Industry Benefits to Industry (Having a Guidance)(Having a Guidance)

Helps us to Helps us to minimizeminimize the the Regulatory Burden:Regulatory Burden:– lower the Regulatory Risklower the Regulatory Risk through science – use our through science – use our

knowledge and experience to base decisions!knowledge and experience to base decisions!– Reduces risk especially for CHPA member-companies Reduces risk especially for CHPA member-companies

that do not have an established Stability Program!that do not have an established Stability Program! – Self-regulation works to advantage of Government, Self-regulation works to advantage of Government,

Industry & Consumer!Industry & Consumer!– Helps to avoid / Helps to avoid / minimize Over-Regulation.minimize Over-Regulation.– In alignment with FDA’s cGMPs for the 21In alignment with FDA’s cGMPs for the 21stst Century Century

Initiative: A Risk-Based Approach!Initiative: A Risk-Based Approach! Science-based Risk Management: Science-based Risk Management: we can use science & we can use science &

knowledge to base decisions. knowledge to base decisions. Creates a “Level Playing Field” for everyone.Creates a “Level Playing Field” for everyone.


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Benefits to Industry Benefits to Industry (Having a Guidance)….cont’d(Having a Guidance)….cont’d

Gives us the Gives us the opportunityopportunity to reduce the amount of stability to reduce the amount of stability testing required prior to launch testing required prior to launch in the US.in the US.

Reduce “Time-to-Market”/ Satisfies a Business Need:Reduce “Time-to-Market”/ Satisfies a Business Need:– Allows business units to plan better (Increase Efficiency).Allows business units to plan better (Increase Efficiency).– Provides companies a “fast-track” option for Provides companies a “fast-track” option for

development of OTCs.development of OTCs.– Allows flexibility to reduce or eliminate testing under Allows flexibility to reduce or eliminate testing under

specific circumstances.specific circumstances.– Allows flexibility to use smaller scale batches.Allows flexibility to use smaller scale batches.

Creates an “Identity” for the uniqueness of the OTC Creates an “Identity” for the uniqueness of the OTC Industry.Industry.

Every company is essentially at risk because ICH Q1A does Every company is essentially at risk because ICH Q1A does NOT apply to OTCs!NOT apply to OTCs!


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Our “Targeted State” Our “Targeted State” (What we would like to see):(What we would like to see):

Clear stability requirements.Clear stability requirements. Elimination of Non-Value Added (NVA) activitiesElimination of Non-Value Added (NVA) activities.. Demystify stability requirements for non-technical Demystify stability requirements for non-technical

people.people. Ability to plan more accurately & reliably.Ability to plan more accurately & reliably. LeverageLeverage to simplify our complex / inefficient to simplify our complex / inefficient

approach.approach. Zero adverse impact on “time-to-market”.Zero adverse impact on “time-to-market”. Science-based Risk Management!Science-based Risk Management!

Bottom Line:Bottom Line: ““Allow science to run our Stability Programs”. OTCs have more Allow science to run our Stability Programs”. OTCs have more

experience, history, safety.experience, history, safety.


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How Did We Get To…How Did We Get To… Where We Are Today? Where We Are Today?

A Voluntary Alternative Method for doing OTC Monograph A Voluntary Alternative Method for doing OTC Monograph Drug Product Stability was posted on the CHPA Website for Drug Product Stability was posted on the CHPA Website for Industry comments through June 18, 2004.Industry comments through June 18, 2004.

We had asked CHPA member-companies to look at their We had asked CHPA member-companies to look at their internal procedures and comment where the discrepancies were internal procedures and comment where the discrepancies were against the proposed guideline. against the proposed guideline.

6 CHPA member-companies responded with feedback / 6 CHPA member-companies responded with feedback / comments.comments.

Published as a a Published as a a CHPA Voluntary Guideline CHPA Voluntary Guideline (along with (along with Industry comments)Industry comments) as ofas of 10/8/04. 10/8/04.


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Objectives of the GuidelineObjectives of the Guideline

To define the To define the minimum stability data minimum stability data packagepackage to support the commercial to support the commercial distribution of OTC monograph drug distribution of OTC monograph drug products in the United States per climatic products in the United States per climatic zone II. The stability data package will zone II. The stability data package will be based on development stability studies. be based on development stability studies. These studies will be used to establish the These studies will be used to establish the tentative expiration dating period and tentative expiration dating period and label storage statement for the OTC label storage statement for the OTC monograph drug product.monograph drug product.


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Objectives of the GuidelineObjectives of the Guideline

This guideline recognizes that a This guideline recognizes that a significant body of scientific significant body of scientific information may exist for OTC drug information may exist for OTC drug products. products. Alternative approachesAlternative approaches may be used when they are may be used when they are scientifically justified. scientifically justified.


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Scope of the GuidelineScope of the Guideline This guideline This guideline applies applies specifically to OTC specifically to OTC

monograph drug product stability. monograph drug product stability.

This guideline This guideline does notdoes not currently seek to currently seek to cover the stability testing of: cover the stability testing of: – Non-prescription drug products regulated Non-prescription drug products regulated

by an NDA/ANDAby an NDA/ANDA– Drug substancesDrug substances– Drug products used in clinical trialsDrug products used in clinical trials– Marketed product stabilityMarketed product stability


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Scope of the GuidelineScope of the Guideline

Additionally, this guideline is Additionally, this guideline is not applicable not applicable toto::– Specific details of the sampling and testing Specific details of the sampling and testing

for particular dosage forms in their for particular dosage forms in their proposed container closuresproposed container closures

– Safety studiesSafety studies


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Details of the GuidelineDetails of the Guideline SELECTION OF BATCHESSELECTION OF BATCHES

– Data should be available on Data should be available on at least one primary at least one primary batchbatch of the drug product. of the drug product. Additional primary Additional primary batches may be necessarybatches may be necessary for new product for new product formulations and instances where no similar formulations and instances where no similar formulations exist. formulations exist.

– Same formulation / same container closure system Same formulation / same container closure system as proposed for marketing. as proposed for marketing.

– Manufacturing process should simulate that to be Manufacturing process should simulate that to be applied to production batches and should provide applied to production batches and should provide product of the same quality and meeting the same product of the same quality and meeting the same specification as that intended for marketing. specification as that intended for marketing.

– Batch(es) should be at least pilot scale (1/10 Batch(es) should be at least pilot scale (1/10 Production Scale); a scientific rationale may be Production Scale); a scientific rationale may be used to justify a smaller batch size. used to justify a smaller batch size.


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Details of the GuidelineDetails of the Guideline TESTING FREQUENCYTESTING FREQUENCY

– The frequency of testing should be designed in The frequency of testing should be designed in order to adequately determine the stability profile order to adequately determine the stability profile for the drug product - typically 0, 3, 6, 12, and 24 for the drug product - typically 0, 3, 6, 12, and 24 months, and annually thereafter through the months, and annually thereafter through the proposed shelf-life. Other time points (such as 9, proposed shelf-life. Other time points (such as 9, 18, 30 months) may also be appropriate. 18, 30 months) may also be appropriate.

– When the drug product fails to meet the When the drug product fails to meet the established shelf-life criteria at the accelerated established shelf-life criteria at the accelerated storage condition (such as 40C/75%RH), storage condition (such as 40C/75%RH), alternative accelerated conditionsalternative accelerated conditions may be used to may be used to insure that at minimum, some acceptable insure that at minimum, some acceptable accelerated data is available to show that the accelerated data is available to show that the product can withstand the typical excursions product can withstand the typical excursions experienced in the distribution chain once the experienced in the distribution chain once the product is marketed. product is marketed.


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Details of the Guideline (cont’d)Details of the Guideline (cont’d)

STORAGE CONDITIONSSTORAGE CONDITIONS

– GENERAL CASE:GENERAL CASE: Long Term 25 ± 2°C / 60 ± 5% RH Long Term 25 ± 2°C / 60 ± 5% RH Accelerated 40 ± 2°C / 75 ± 5% RHAccelerated 40 ± 2°C / 75 ± 5% RH

– DRUG PRODUCTS PACKAGED IN SEMI-DRUG PRODUCTS PACKAGED IN SEMI-PERMEABLE CONTAINERS:PERMEABLE CONTAINERS:

Long Term 25 ± 2°C / 40 ± 5% RHLong Term 25 ± 2°C / 40 ± 5% RH Accelerated 40 ± 2°C / NMT 25% ± 5% RHAccelerated 40 ± 2°C / NMT 25% ± 5% RH


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Details of the Guideline (cont’d)Details of the Guideline (cont’d) EVALUATION OF STABILITY DATA:EVALUATION OF STABILITY DATA:

– A scientific approach should be adopted in the A scientific approach should be adopted in the presentation and evaluation of stability presentation and evaluation of stability information for establishing a tentative expiry information for establishing a tentative expiry period. The scientific assessment should include period. The scientific assessment should include the results from physical, chemical and the results from physical, chemical and microbiological data on the dosage form as well as microbiological data on the dosage form as well as a a “body of knowledge”“body of knowledge” which may consist of: which may consist of:

Results from research and development Results from research and development batches on batches on similar or closely related similar or closely related formulations.formulations.

Results from research and development Results from research and development batches on batches on similar or closely related marketed similar or closely related marketed products.products.

Data published in the Data published in the literatureliterature, as well as , as well as results from the specific stability study.results from the specific stability study.


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– When the data from an accelerated When the data from an accelerated stability study remains within established stability study remains within established limits, while maintaining potency, a limits, while maintaining potency, a tentative expiry period can be assigned tentative expiry period can be assigned prior to marketing the product. prior to marketing the product.

– A 24-month expiry period may be assigned A 24-month expiry period may be assigned upon successful completion of three months upon successful completion of three months accelerated testing. accelerated testing.


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– Using sound scientific judgmentUsing sound scientific judgment, shorter expiry , shorter expiry periods may be assigned based on less than three periods may be assigned based on less than three months of accelerated testing and longer tentative months of accelerated testing and longer tentative expiry periods may be justified using extended expiry periods may be justified using extended periods of accelerated testing. periods of accelerated testing.

– Any longer tentative expiry period or extension of Any longer tentative expiry period or extension of an expiration dating period should be made based an expiration dating period should be made based on the previous histories of similar products, on the previous histories of similar products, sound scientific judgment, calculations using the sound scientific judgment, calculations using the Arrhenius equation, all with appropriate Arrhenius equation, all with appropriate documentation. documentation.


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Why Follow this Alternative Approach?Why Follow this Alternative Approach?

The OTC Industry plays a role in the overall The OTC Industry plays a role in the overall healthcare of the nation. This Guideline would help healthcare of the nation. This Guideline would help us create an identity for the uniqueness of the OTC us create an identity for the uniqueness of the OTC Industry. Alternatives to adopting a “Voluntary Industry. Alternatives to adopting a “Voluntary Standard” would include following the cumbersome Standard” would include following the cumbersome ICH stability requirements or wait for the FDA to ICH stability requirements or wait for the FDA to develop such a Guideline on this topic. develop such a Guideline on this topic.

We all participate in this business and benefit from it, We all participate in this business and benefit from it, therefore we all should at least have a minimum therefore we all should at least have a minimum standard to continue to put quality OTC products on standard to continue to put quality OTC products on the market for consumers.the market for consumers.


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Where We Would Like to Go From Where We Would Like to Go From Here?Here?

Continue to engage in or share our information Continue to engage in or share our information with the Industry via conferences, meetings, etc.with the Industry via conferences, meetings, etc.

Phase IIPhase II – The Stability Working Group has – The Stability Working Group has commenced activities to update the Guideline to commenced activities to update the Guideline to include include changeschanges to marketed OTC Monograph to marketed OTC Monograph Drug Products. Drug Products.

Revisit the Guideline at the CHPA Executive Level Revisit the Guideline at the CHPA Executive Level if FDA endorsement is ever sought.if FDA endorsement is ever sought.


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Thank You For Attending!Thank You For Attending!

asq-fda 6-23-05 chpa stability working group1 36 th annual asq-fdc/fda conference june 23, 2005 chpa...

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