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stability studies in pharmaceutical development

Kathy Waddle, MS Wei Pan, Ph.D. RAC Catalent Pharma Solutions

Agenda

Overview of stability studies during drug product Lifecycle Stability considerations during early development Review ICH and WHO stability guidelines Stability requirements to support registration Post approval stability

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Importance of Product Stability


Definition of Product Quality Free of contamination and reproducibly delivers the therapeutic benefit promised in the label to the consumer

Definition of Stability Consistent product quality and therapeutic benefit over the product shelf-life under various environment conditions

Consumer Expect Stability!


Gary Buehler, Director, OGD, FDA, AAPS SFG Stability Workshop, Sept 2007

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Stability Quality by Design


Pharmaceutical product stability is a function of:
Drug Drug Substance Substance Excipients Excipients

Product Understanding
Manufacturing Manufacturing Process Process Container Container Closure Closure

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Stability Studies During Pharmaceutical Product Lifecycle

File IND

File NDA

Approval

Drug Drug Discovery Discovery

PrePreclinical clinical

Phase II Phase

Phase II Phase II

Phase III Phase III

Final Final Labeling Labeling Discussions Discussions

Phase IV Phase IV PLCM PLCM Rx to OTC Rx to OTC

Stability studies to support formulation development and clinical studies

Stability studies to support marketing application

Stability studies to monitor product quality and support post approval changes

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Stability Considerations During Early Development

Limited regulatory requirement


conduct stability studies to demonstrate clinical trial materials meet specifications during the course of trial

Stability studies are done to gain understanding of the compounds/formulation in development


Chemical and physical property of API Excipient compatibility Manufacturing process Interaction with packaging materials

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Stability Considerations During Early Development

API

Manufacturing Process DRUG PRODUCT

Packaging Selection

PACKAGED PRODUCT

EXCIPIENTS

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API Mechanisms of Instability - Chemical


Identify functional groups and labile centers
2

and 3 Amines --> N-oxide, hydroxylamine by oxidation --> Acid by oxidation -->Acid/Alcohol by hydrolysis

Aldehyde

Esters/Lactones

Consider external contributing factors


pH,

temperature, humidity, light

Perform forced degradation studies


Acid/base Heat Oxidation Photolysis

Understand mechanisms of degradation of drug substance

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API Mechanisms of Instability - Physical

Polymorphs

Polymorphic transition Hydrate/solvate formation Dehydration/desolvation Crystallization of amorphous materials

Particle size/surface area Other quality attributes


Resuspendibility Aggregation

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Excipient Compatibility
ICH Q8 guidance recommends evaluating drug-excipient interactions as part of the design of a stable formulation. For solutions and suspensions, the solution studies indicate which buffer to use and the optimum pH. For solids, the compatibility studies are more extensive with the objective to establish which excipients can be used with the intended drug.
- Binary excipients compatibility studies - Trial formulations (DOE)

- Q8(R2): Pharmaceutical Development, Nov 2005

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Case Study 1
An compound with a carboxyl functional group is the candidate for a HFA MDI formulation development. Due to poor aqueous solubility, ethanol was chosen as co-solvent and the experimental formulation was put on accelerated stability. A degradant peak was observed and it reached >3% at 3 month time point.

The sample was send to the LC-MS lab for peak ID. Question: What is the structure of the degradant? Answer: its the ethyl ester of the API.
Hint: Know your chemistry.

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Case Study 2
Trace level of Aldehydes in common excipients
Cause of gelatin cross-linking Reactive with primary and secondary amine Present as trace level impurities or formed by excipient degradation (e.g. PEG or Tween)

-Leonardo Allain and W. Peter Wuelfling, Merck Research Labs, AAPS Stability Workshop, 2009

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Case Study 2

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Case Study 2

Compendial: PVP and Ethylcellulose in USP Wet chemistry techniques (one is enzymatic and the other is colorimetric)

100 ppm limit test 100 ppm formaldehyde ~ 10% API (mol/mol) (assuming 0.5 g formulated drug with 2-5% drug load)

LOD of Merck GC derivatization method: 0.1 ppm

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Case Study 2
Excipients Avicel HPMC PEG 400 PEG 4000 Tween 80 Triglycerides Polyoxyl 35 Opadry white Kollicoat Formaldehyde (ppm) 1.1 12.3 65.0 0.5 1.5 -20 0.2 1.4 4.7 13.7

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Manufacturing Process
Choose manufacturing conditions to improve stability
- Exposure to solvents

Exposure to temperature
- Drying time and temperature

Stability of in-process materials Drug Product may be tested to identify critical process parameters

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Container Closure Systems


Linked to mechanisms of instability

Does it need to be protected from light or moisture?

Potential drug absorption or adsorption to container closure Effect of container orientation Potential for leachables

container, closure, glue and ink

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Case Study - Stability of Sterile Product M in Glass and Plastic Packages

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Stability Studies During Pharmaceutical Product Lifecycle

File IND

File NDA

Approval

Drug Drug Discovery Discovery

PrePreclinical clinical

Phase II Phase

Phase II Phase II

Phase III Phase III

Final Final Labeling Labeling Discussions Discussions

Phase IV Phase IV PLCM PLCM Rx to OTC Rx to OTC

Stability studies to support formulation development and clinical studies

Stability studies to support marketing application

Stability studies to monitor product quality and support post approval changes

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Stability Studies for Registration

the purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity and light, and to establish a retest period for the drug substance or a shelf-life for the drug product and recommended storage conditions -ICH Q1A(R2): Stability testing of new drug substance and product (2003)

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Stability Guidelines

ICH (US, Japan, EU) WHO Regional


US: FDA (1998 draft and 1987 guidance withdrawn, June 1 2006) EU: EMEA (European Medicines Agency), CPMP Japan: MHLW (Ministry of Health, Labor and Welfare: Drug Approval and Licensing Procedures in Japan, 2008) ASEAN (Association of Southeast Asia Nations) Brazil (Resolucao-Re No 1, July 29, 2005) China (Chinese Pharmacopeia 2005) SADC (Southern African Development Community), Medicines Control Council: Stability January 2005

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FDA Stability Guidelines

FDA withdraws stability and CMC information related guidance documents on June 1, 2006:

Not because following them will lead to problem with drug registration But because these documents are overly prescriptive, which is not consistent with the FDAs current thinking of providing broad guidance In the meantimerefer to the following ICH documentsas alternative resources

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Stability Studies to Support Global Registration


In order to be able to reduce the amount of stability testing required, the number of different long-term testing conditions must be reduced to a sufficient extent. This approach was proposed by Paul Schumacher in 1972 (1) and by Wolfgang Grimm in 1986 (2), and in 1998 (3) when they defined four different long-term testing conditions, which match with the climatic conditions of the target markets categorized in just four different climatic zones.
-WHO Technical Report Series, No. 953, 2009: Stability testing of active pharmaceutical ingredients and finished pharmaceutical products

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ICH Guidelines
Founded 1990 ICH region European Union, Japan and US Regulators and pharmaceutical industry representatives Stability was one of the first issues discussed and harmonized

Step1 Step1 Consensus building by EWG

Step2 Step2 Consensus Agreed six parties

Step3 Step3

Step4 Step4

Step5 Step5

Regulatory Consultation

Adopt

Implement

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ICH Stability Guidelines


ICH Stability Guideline Q1A(R2): Stability Testing of New Drug Substances and Products (Second Revision) Reached implementation step (step 5) in the ICH Tripartitate Region
EU : Adopted by CPMP, March 2003, issued as CPMP/ICH/2736/99 MHLW : Adopted June 3, 2003, PFSB/ELD Notification No. 0603001 FDA : Published in the Federal Register, Vol, 68, No. 225, Friday, November 21, 2003; pages 65717-18

Also adopted by some non-ICH countries including Canada, Australia Switzerland

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ICH Stability Guidelines


The Four Climate Zones:
Zone I Zone II Zone III* Zone IV* Temperate Subtropical & Mediterranean Hot & Dry Hot & Humid 25C2C/60%RH 5%RH 30C2C/35%RH 5%RH 30C2C/65%RH 5%RH 21C2C /45%RH 5%RH

Q1F: Stability Data Package for Registration Applications in Climatic Zones III and IV was withdrawn June 2006 and decided to leave definition of storage conditions in Climatic Zones III and IV to the respective regions and WHO.

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World View of Climatic Zone Determinations by Country

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ICH Stability Guidelines

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ICH Stability Guidelines

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WHO Stability Guideline


193 Member States Split Climate Zone IV (hot and humid) to two zones
- Climate Zone IVA (hot & humid) 30C/65%RH - Climate Zone IVB (hot & very Humid) 30C/75%RH

Evaluation of climate condition by each Member State results in the recommendation of long term storage conditions More severe conditions are acceptable
-WHO Technical Report Series, No. 953, 2009: Stability testing of active pharmaceutical ingredients and finished pharmaceutical products

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WHO Stability Guidelines at a Glance

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WHO Stability Guideline

Additional Guidance Provided in WHO Document: Testing parameter recommendations Storage statement and labeling guidance Covers new drug and marketed product

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WHO Stability Guideline

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Stability Studies During Pharmaceutical Product Lifecycle

File IND

File NDA

Approval

Drug Drug Discovery Discovery

PrePreclinical clinical

Phase II Phase

Phase II Phase II

Phase III Phase III

Final Final Labeling Labeling Discussions Discussions

Phase IV Phase IV PLCM PLCM Rx to OTC Rx to OTC

Stability studies to support formulation development and clinical studies

Stability studies to support marketing application

Stability studies to monitor product quality and support post approval changes

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Key Elements of a Stability Protocol


21CFR 211.166 (a)
There shall be a written testing program designed to assess the stability characteristics of drug products. The results of such stability testing shall be used in determining appropriate storage conditions and expiration dates. The written program shall be followed and shall include:

Sample size and test intervals Storage condition Reliable, meaningful and specific test methods Store the drug product in the proposed container for marketing Testing of drug product for reconstitution at time of dispensing as well post reconstitution

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Key Elements of a Stability Protocol


Purpose (R&D, NDA, ANDA, Commercial, etc) Regulatory compliance/intended Market (US, EU, Global, etc) Name of the product and dosage strengths Container closures (and orientations, if applicable) Test methods and specification Storage condition and test intervals Sampling plan Bracketing and/or matrixing rational (if utilized) Data reporting and statistical analysis (proposed) Signature and change control Proposed expiration dating period

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Container Closure Systems


Solid Orals US HDPE bottles PVC, PVC/PVDC, or ACLAR blisters Bulk Storage/bulk sales
- Double PE bags - PET/PE/Aluminum Foil/PE Barrier bags

Solid Orals Europe Primarily PVC, PVC/PVDC blisters Often opaque rather than clear blisters
- color: white, blue or green

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Container Closure Systems


Climate Zone 4 Solid Orals Glass or HDPE Bottles Blister
- Cold-formed aluminum foil-foil blister - PVC, PVC/PVDC or ACLAR blister
- Only for moisture insensitive, stable dosage forms

Regional Solid Oral Simple blister with Al/PE film over wrap Glass bottle

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Test Methods/Specifications
Q6 : Specifications for New Drug Substances and Products - Q6A: Specifications: Chemical Substances,
Oct 1999

- Q6B: Specifications: Biotechnological/Biological Products, March 1999

Q2(R1): Validation of Analytical Procedures: Text and Methodology, Oct 1994 Q3A(R2): Impurities in New Drug Substances (Revised Guideline) Oct 2006 Q3B(R2): Impurities in New Drug Products (Revised Guideline) June 2006 Q1E : Evaluation of Stability Data, February 2003

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Example 1 A Really Simple Stability Protocol


Tablets in 30-count HDPE bottle for US market
Condition 25C/60%RH Initial [2] X 30C/65%RH 3M [2] X [2] (X) 40C/75%RH [2] X 6M [2] X [2] (X) [2] X 9M [2] X [2] (X) 12M [2] X [2] (X) 6 18M [2] X 24M [2] X 36M [2] X 12 Total Stored 24

X = Appearance (n=1), Assay/RS (n=2),Dissolution (n=6), Water Content (n=2) [ ] = number of bottles pulled ( ) = Optional testing only when significant changes occurs under accelerated conditions

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Definitions of Significant Change


1. A 5% change in assay from its initial value; or failure to meet the acceptance criteria for potency when using biological or immunological procedures. 2. Any degradation products exceeding its acceptance criterion. 3. Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test. 4. Failure to meet the acceptance criterion for pH; or 5. Failure to meet the acceptance criteria for dissolution for 12 dosage units.
-ICH Q1A(R2)

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Example 2 a Simple Stability Protocol


Tablets in 30-count HDPE Bottle for Global Registration
Condition Initial 3M 6M 9M 12M 18M 24M 36M Total Stored

25C/60%RH

[2] X

[2] X [2] X

[2] X [2] X [2] X

[2] X [2] X -

[2] X [2] X -

[2] X [2] X -

[2] X [2] X -

[2] X [2] X -

24

30C/65%RH

22

40C/75%RH

[2] X

X = Appearance (n=1), Assay/RS (n=2),Dissolution (n=6), Water Content (n=2) [ ] = number of bottles pulled Note: There is no intermediate condition for Zone III/IV

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Example 3 - a Complicated Stability Protocol


Sterile product in glass vials for US market (store inverted)
Condition Initial 3M 6M 9M 12M 18M 24M 36M Total Stored

25C/60%RH

[4] X

[4] X [4] (X)

[4] X [4] (X) [14] XPL

[4] X [4] (X) -

[50] XPSL [50] (XPSL) -

[4] X -

[50] XPSL -

[50] XPSL -

200

30C/65%RH

90

40C/75%RH

[4] X

36

X = Appearance including color and clarity, Assay/RS, Preservative content, pH P = Particulate matter by HIAC S = Sterility, Bacterial Endotoxin, Antimicrobial effectiveness, Container Closure integrity L = Leachables [ ] = number of bottles pulled ( ) = Optional testing only when significant changes are observed under accelerated conditions

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Example 4an Even More Complicated Stability Protocol


Sterile Product in a Semi - permeable Containers for Us Market
Condition Initial 3M 6M 9M 12M 18M 24M 36M Total Stored

25C/40%RH

[4] X

[4] X [4] (X)

[4] X [4] (X) [14] XPL

[4] X [4] (X) -

[50] XPSL [50] (XPSL) -

[4] X -

[50] XPSL -

[50] XPSL -

200

30C/65%RH

90

40C/20%RH

[4] X

40

X = Appearance including color and clarity, Assay/RS, Preservative content, pH P = Particulate matter HIAC S = Sterility, Bacterial Endotoxin, Antimicrobial effectiveness, Container Closure Integrity L = Leachable, [ ] = number of bottles pulled ( ) = Optional testing only when significant changes are observed under accelerated conditions

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Example 4an Even More Complicated Stability Protocol


Sterile Product in Semi -permeable Containers for US Market Condition
25C/40%RH 30C/65%RH Initial 3M 6M 9M 12M 18M 24M 36M

Total Stored
10 10

[10] W -

[10] W [10] (W) [10] W

[10] W [10] (W) [10] W

[10] W [10] (W) -

[10] W [10] (W) -

[10] W -

[10] W -

[10] W -

40C/20%RH

10

W = Weight Loss (n=10) Note1 : The same 10 units are used for weight loss test as in-and-out of the chamber stability samples. The stability coordinator and lab analyst need to coordinate testing to minimize the time the samples are out of the chamber. Note 2: A 5% loss in water from its initial value is considered a significant change for a product packaged in a semi-permeable container after an equivalent of 3 months storage at 40C/NMT 25% RH.

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Batch Selections
Stability studies should be performed on each individual strength and container size of the drug product unless bracketing or matrixing is applied. At least three primary batches

Final formulation Manufacturing process simulating production batch Product with same quality and meeting same specification

In container closure system as proposed for marketing At least two of the three are pilot scale* The third batch can be smaller, if justified Using different batches of API (if possible)
* For solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is the larger.

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Stability Data at Submission

For NDAs: Three primary batches 12 months long term 6 months accelerated 6 months intermediate if significant changes @ accelerated May statistically project expiry up to 6 months past real time data

For ANDAs One batch 3 months accelerated 3 months satisfactory accelerated data may permit 24 month expiry

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Other Stability Studies

In-use stability

Minimum of two batches At beginning and toward end of shelf-life

Photostability

One batch In the proposed container and closure systems ICH Q1B option 1 or option 2

Thermocycling or excursion study

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Stability Data at Submission


Based on the data and product understanding, a sponsor should provide: Proposed expiration dating period and justification Proposed label storage condition and justification Proposed in-use label storage condition and in-use time period and justification, if applicable

Stability Stability Data Data

Product Product Understanding Understanding

Product shelf-life Product shelf-life and and Storage Conditions Storage Conditions

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Stability Commitment
When available long term stability data on primary batches do not cover the proposed shelf life granted at the time of approval, a commitment should be made to continue the stability studies post approval in order to firmly establish the shelf life.
Submission data from 3 production batches, continue long term study through proposed shelf-life. Submission data from <3 production batches, set more production batches on to make up the required three with same protocol. Submission data not from production batches, first 3 production batches to set on stability through proposed shelf-life long term and 6 months accelerated.

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Stability Studies During Pharmaceutical Product Lifecycle

File IND

File NDA

Approval

Drug Drug Discovery Discovery

PrePreclinical clinical

Phase II Phase

Phase II Phase II

Phase III Phase III

Final Final Labeling Labeling Discussions Discussions

Phase IV Phase IV PLCM PLCM Rx to OTC Rx to OTC

Stability studies to support formulation development and clinical studies

Stability studies to support marketing application

Stability studies to monitor product quality and support post approval changes

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Stability Studies Post Approval


After approval, routine stability study is conducted to monitor product quality Only long term condition is required Can drop testing point from standard ICH (through PAS) Can be used to extend expiry (through annual report) May want to add a expiry test point Stability failure can result in field alert* and/or product recalls

21CFR 314.81 Sponsors are required to report to FDA district office within 3 working days of a problem being identified.

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Stability Studies for Post-Approval Changes


change in the manufacturing process; change in the composition of the formulation; change of the immediate packaging; change in the manufacturing process of an API. Additional stability testing (3 or 6 months long term and accelerated) are often required to support the changes.

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Stability Studies for Post-Approval Changes


US
Substantial potential to Substantial potential to have an adverse effect have an adverse effect

EU

Major Changes

Type II

Moderate potential to have Moderate potential to have an adverse effect an adverse effect

Moderate Changes

Type IB

Minor Changes
Minimal potential to have an Minimal potential to have an adverse effect adverse effect

Type IA

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Stability Studies for Post-Approval Changes


1. 2. 3. 4. 5. 6. 7. 8. FDA/CDER (November 1995) Guidance for industry Scale up and post-approval changes: immediate release solid oral dosage forms. FDA/CDER (September 1997) Guidance for industry Scale up and post-approval changes: modified release solid oral dosage forms. FDA/CDER (May 1997) Guidance for industry Scale up and post-approval changes: non-sterile semisolid dosage forms. FDA/CDER (January 1999) Guidance for industry Scale up and post-approval changes: immediate release and modified release solid oral dosage forms manufacturing equipment. FDA/CDER (April 2004) Guidance for industry Changes to an approved NDA and ANDAs. CHMP/CVMP (December 2005) Guideline on stability testing for applications for variations to a marketing authorization CPMP/QWP/576/96 Rev 1 EMEA/CVMP/373/04 EMEA (2006) Guideline on dossier requirement for Type IA and IB notification WHO (February 2007) Annex 6 variation guidance: guidance on variation to a prequalified product Dossier

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