Pharmaceutical Stability Science and Regulations

Pharmaceutical Stability The Science and the Regulations

Prabu Nambiar, PhD, MBA, RAC

Vice President, Regulatory Affairs - CMC Vertex Pharmaceuticals Cambridge, MA, USA 02139 [email protected]

Pharmaceutical Stability Science and Regulations

Overview of The Talk

Stability Definition / Background Stability A Critical Quality Attribute Stability Studies Why a Statutory/Legal Requirement GMP Implications Stability during various phases of drug development ICH Stability Guidance Conclusion

Disclaimer: The scientific views and regulatory interpretations presented in these slides are the speakers perspectives and do not represent any specific company or regulatory agency position

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Pharmaceutical Stability Science and Regulations

Pharmaceutical Products (Drugs/Diagnostics/Devices): Articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease Articles intended to affect the structure or any function of the human body
Small molecules - Organic/Inorganic compounds Large molecules Proteins/Biologics Devices/Drug-Device Combinations

This presentation is primarily focused on small molecules

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Pharmaceutical Stability Science and Regulations

Stability of Pharmaceutical Product

Starting Materials

Synthesis Drug Substance

Formulation Excipients

Drug Product

Packaging Container/ Closure

Finished Product

Stability of Pharmaceutical Product

Capacity of a drug substance or drug product in a given packaging system to remain within established specifications to maintain its Quality (identity, strength, purity/impurity, potency) and deliver the desired Performance throughout the retest or expiration period
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Pharmaceutical Stability Science and Regulations

Why do Pharmaceutical (DS or DP) Properties Change Under Stress / Over Time?
The drug substance (small molecule/protein) is a chemical entity with many reactive functional groups (-OH, -SH, -NH2, COOH etc) Similarly, the excipients used in the formulation are also chemicals with reactive functional groups
Heat

Chemical Changes
Oxidation, Reduction, Hydrolysis, Photolysis, etc.

Pharmaceutical Product

Humidity (H2O) Air (O2) Light

Physical Changes
Aggregation, Precipitation, Particle-Size & Morphology Change

Other Changes (microbial growth)

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Pharmaceutical Stability Science and Regulations

Example
NaOOC O O CH3 HO HO OH

Drug Substance: Chemical Properties

Functional Groups Alcohol Carboxylic acid Ester Double bond Chiral centers Reactivity Oxidation, esterification, etherification Decarboxylation, esterification Hydrolysis, trans-esterification Oxidation Racemization

CH3

PRAVASTATIN SODIUM

Drug Substance: Physical Properties

Particle size / morphology / solvation

Drug product: Tablets Excipients: Lactose, MgO, Mg Stearate, Microcrystalline cellulose, Povidone, Croscarmellose Na Colorants: Yellow FeO, FD&C (aluminum lake)
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Pharmaceutical Stability Science and Regulations

NaOOC O HO OH

Chemical Reactivity Checklist

API/Excipient Functional Groups
Alcohol Carboxylic acid Ester / Lactones Double bond Amides / Esters /Peptides / Lactams ab unsaturated ketones Amines Imines / Ethers Thiols Chiral centers Aldehyde Chloride, Bromide etc -

O CH3 HO

CH3

Reactivity that can affect stability

Oxidation, esterification, etherification, Decarboxylation, esterification Hydrolysis, trans-esterification Oxidation Hydrolysis Addition, adduct formation Addition, N-oxidation, quaternary ammonium salt formation Hydrolysis Disulfide formation Racemization Reaction with amines (Schiffs base formation) Alkylation

PRAVASTATIN SODIUM

- Rearrangements, polymerization

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Pharmaceutical Stability Science and Regulations

Stability Regulations
There shall be a written stability testing program to assess the stability characteristics of drug products What is the Scientific Basis??

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Pharmaceutical Stability Science and Regulations

Scientific Basis of Stability Regulations

The quality, safety & efficacy of a pharmaceutical product are established based on Chemistry, Manufacturing and Controls (CMC), animal toxicology & human clinical studies. The quality (identity, strength, purity, impurity, potency) of the product established via the CMC/tox/clinical studies will define the quality of commercial product (specifications) that must be maintained throughout the product lifecycle. Any changes in product-quality outside the established specifications may cause the product to be unfit for intended use.....because of potential impact of the change on established safety & efficacy!
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Pharmaceutical Stability Science and Regulations Drug instability could lead to:
Reduction of labeled quantity Sub-potent drug product Super-potent drug product Modification of Content uniformity Modification of Bioavailability Toxicity due to degradants Loss of container-closure integrity Loss of microbial integrity/sterility Loss of cosmetic aspects Loss of functional aspects (device)

Unreliable quality Potential Safety/Tox and/or Efficacy Issues

Potentially Unsafe / ineffective product

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Pharmaceutical Stability Science and Regulations

Instability of a Pharmaceutical Product can affect its Quality (identity, strength, purity/impurity, potency) and therefore Safety and Efficacy of the product

Pharmaceutical Stability A Critical Quality Attribute (CQA)

It is the responsibility of the Health Agency to
Protect public health Prevent harm from unsafe drug products
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Pharmaceutical Stability Science and Regulations Stability Study is a Statutory/Legal Requirement

US FDA cGMP (21 CFR 211.166) There shall be a written stability testing program to assess the stability characteristics of drug products US FDA GLP (21 CFR 58.31(d) Assure that test and control articles or mixtures have been appropriately tested for identity, strength, purity, stability, and uniformity, as applicable ICH Q7A: GMP for API Requires stability monitoring of APIs: A documented, on-going testing program is needed to monitor the stability of APIs; results should be used to confirm appropriate storage conditions and retest or expiry dates

Same expectations from EMA/WHO/Health Canada/Other Agencies

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Pharmaceutical Stability Science and Regulations

Stability is a Key Area of Focus during GMP Inspections

http://www.fda.gov/foi/warning.htm
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Pharmaceutical Stability Science and Regulations

Pharmaceutical Stability Testing

Systematic experiments conducted on pharmaceutical products to understand and 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 re-test period for the drug substance or a shelf life for the drug product and recommended storage conditions. ICH

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Pharmaceutical Stability Science and Regulations Purpose of Stability Testing is.

To Build the Quality In (QbD)
To understand one of the basic properties of the API/Drug Assure Integrity/Quality of the material used in development (Tox/Clinical) API / DP Development (Identify the process & product parameters)
API: Synthetic Route, Solvents, Operating Conditions etc DP: Dosage form / Composition / Process / Operating Conditions / Equipment etc

Define API / DP Specifications (Analytical Test / Method / Limits) Define API Packaging / Storage condition / Re-test or expiry date Define DP Packaging / Storage condition / Shelf life API / DP shipping conditions

DP In-use Limitations
compatibility with diluents, other drugs, delivery devices

Intermediates (API / DP) Packaging / Storage condition / Shelf life

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Development Phase

Pharmaceutical Stability Science and Regulations Stability During Various Stages of Drug Development
Pre-IND Preclinical Research
API Drug Product Analytical
(Med Chem. / Process Chem.)

NDA Approval

Phase I

Phase II

File NDA

Phase III

Phase IV

CMC Activities

Process Development API Drug Product Analytical Development

Scale-up/Validation API Drug Product Analytical Development

Provide Phase III Clinical Supplies Develop commercial API Process Drug Product Process Analytical methods NDA Stability (ICH) - API - Drug Product Set API / DP Specs Re-test date & shelf life

Post-approval - CMC commitments -CMC changes -Line Extensions

CMC commitments - Postapproval Stability - Annual Stability
CMC changes - Improvements in Process, Scale, Site, Vendors etc., for API Drug Product - Stability (ICH) New Dosage forms - Development - Stability (ICH)

-Provide material for Pharm/Tox Studies

Provide Phase I /II Clinical Supplies

Understand & optimize API Process Formulation Drug Product Process Analytical Methods Developmental Stability -API -Drug Product

Objectives

Preliminary CMC Development (API/Anal. Meth) API / Solution

Stability

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Pharmaceutical Stability Science and Regulations

Stability Studies During Development / Post Approval
Early phases of clinical research Phase 1 / Phase 2
Goal at this stage is to establish the proof of concept Stability studies are intended to
Support the stability of the clinical supplies for duration of study Guide product/process development activities

Late stages as clinical research advances (Phase 3)

Goal is to confirm the safety and efficacy of the drug and become commercial
Commercial manufacturing process defined Final commercial dosage form(s), strength(s) and packaging in place Regulatory filing strategy in place (which countries etc)

Stability studies are intended to

Establish retest date for drug substance and shelf life for drug product to support the Registration of the product (NDA/MAA) Guide product/process development activities Continue to provide stability data to support the use of product in clinical study

Post-approval stability Activities

Goal at this stage is to meet regulatory commitments and life-cycle management
Ongoing registration stability studies / Post-approval commitment / Annual Stability Post-approval changes / Line extensions / Life-cycle management
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Pharmaceutical Stability Science and Regulations Regulatory Guidance

ICH Guidance for Stability Studies Q1A (R2) - Stability of New Drug Substances/Products Q1B - Photostability Q1C - Stability testing for new dosage forms Q1D - Bracketing and Matrixing Q1E - Evaluation of Stability data Q1F X - Climatic Zone III and IV WITHDRAWN

FDA stability guidance - withdrawn on June 1, 2006

(as part of cGMP for 21 Century initiative)

Submitting Documentation for the Stability of Human Drugs and Biologics (1987) Stability Testing of Drug Substances and Drug Products (Draft) (1998)

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Pharmaceutical Stability Science and Regulations

Key Features of Q1A

Covers stability information needed for marketing application in EU, Japan, and USA Outlines the core stability data package for new drug substances and products Many other countries have either adopted this as is or with some modification (Canada/Australia/NZ)

Major Points
Stress Testing (to understand degradation pattern & define stability indicating methods) Number of Batches /selection of Batches / Storage Conditions Amount of Data required at the time of filing
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Pharmaceutical Stability Science and Regulations

Key Features of Q1A Testing Conditions
General Case (Drug Substance / Drug Product)
Label Storage Condition
Stability Studies Study Conditions Min. Data Required for Filing

Long term Room Temperature

25C/60%RH or 30C/65%RH 30C/65%RH 40C/75%RH 5C/Ambient humidity

12 months

Intermediate Accelerated Long term

6 months 6 months 12 months

Refrigerated Freezer

Accelerated
Long term

25C/60%RH
-20C

6 months
12 months

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Pharmaceutical Stability Science and Regulations

Key Features of Q1A Testing Conditions
For Aqueous-Based Drug Products Packaged in Semi-permeable Containers
Label Storage Condition Room Temperature
Stability Studies Study Conditions Min. Data Required for Filing

Long term

25C/40%RH or 30C/35%RH

12 months

Intermediate
Accelerated

30C/65%RH
40C/NMT25%RH

6 months
6 months

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Pharmaceutical Stability Science and Regulations

Key Features of Q1A
Number of Batches and Selection of Batches
Material API Number of Batches / Scale At least 3 batches / Pilot scale Formulation N/A

Drug Product

At least 3 batches 2 of them should be pilot scale 3rd can be smaller

Same as proposed commercial product

(Pilot Scale = 10% of production scale; or 100,000 units, whichever is larger for solid orals)

Process: API and Drug Product should be manufactured by a process representative of commercial process
Container Closure: Same as proposed commercial packaging Testing Frequency: 0, 3, 6, 9, 12, 18, 24 months, then yearly for long-term testing 0, 3, 6 months for accelerated testing 0, 6, 9, 12 months for intermediate testing (if tested)

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Pharmaceutical Stability Science and Regulations

Stability Specifications (Tests/Methods/Limits) Attributes Investigated for Drug Substance
Physical Properties
Color/Appearance pH/Solubility/Melting Point Optical Rotation Density/Viscosity Particle size Morphology/Crystal structure

Chemical Properties
Reactivity/degradations Assay/Purity/Potency Degradants/Impurities Solvent content (e.g. H2O)

Spectroscopic Properties
IR, NMR, UV, MS, X-Ray

Microbial Properties
Sterility, Microbial limits

Validated analytical methods should be used Limits / Acceptance Criteria

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Pharmaceutical Stability Science and Regulations

Stability Specifications (Tests/Methods/Limits) Attributes Investigated for Drug Product
Physical Properties
Color/Appearance

Functional Properties
Solid Orals (Tablets/Capsules) Dissolution / Disintegration / brittleness Liquid Orals (Suspension/Syrups) Preservative content, Viscosity, pH, Weight loss Inhalation Products (Nebules/MDI/DPI) Dose uniformity, Number of actuations Aerodynamic particle size, Agglomeration, Foreign particles, Leak rate, Shot weight Parenteral Products Reconstitution time/Particulates Container closure integrity

Chemical Properties
Assay/Purity/Potency Degradants/Impurities Moisture content Leachables/Extractables

Microbial Properties
Sterility, Microbial limits

Validated analytical methods should be used Limits / Acceptance Criteria

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Transdermal Patches/Implants/Suppositories Adhesion, leakage Drug release, Softening

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Pharmaceutical Stability Science and Regulations

Stability Commitment (Drug Substance / Drug Product)
Primary Batches
If the submitted data do not cover the proposed shelf life at the time of approval, commitment should be made to continue the studies to firmly establish the shelf-life.

Production scale batches:

No commitment required if full term production scale data provided If production scale batch on stability but full term data not provided, commitment to continue studies If data provided on less than 3 production scale batches, commitment to add additional batches to study* If no production scale data, commitment to put first 3 production scale batches*

*For drug Substance = Long term stability *For drug product = Long term and accelerated stability
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Pharmaceutical Stability Science and Regulations

Q1B: Photostability Testing
Forced Photodegradation study Drug Substance Drug Product** Yes No Confirmatory studies No. of batches* 1 1 Conditions 1.2 million lux hours; Near-UV energy of 200 watt hours/square meter

* Two additional batches should be studied if the results are equivocal. ** Studies carried out sequentially; First fully exposed product, then product in the immediate pack and then in the market pack, if needed

Q1C: Stability Testing for New Dosage Forms

New dosage form: A pharmaceutical product, containing the same active substance as included in the existing approved drug product, differing in Route of administration (e.g., oral to parenteral) New functionality/delivery systems (e.g., immediate release to modified release tablet) Dosage forms / same administration route (e.g., capsule to tablet, solution to suspension) A reduced stability database at submission time (e.g., 6 months accelerated and 6 months long term data from ongoing studies) may be acceptable in certain justified cases.
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Pharmaceutical Stability Science and Regulations

Q1D: Bracketing and Matrixing Designs
Bracketing: Design of a stability schedule whereby only samples on the extremes of certain design factors (e.g., strength, container size and/or fill) are tested at all time points as in a full design, assuming that the stability of any intermediate levels is represented by the stability of the extremes tested. Matrixing: Design of a stability schedule where testing is performed on a selected subset of samples for one time point and on another subset of samples for a subsequent time point. Get buy-in from the agency ahead of implementing a complex design

Q1E: Evaluation of Stability Data

How to use stability data generated per ICH Q1A(R) to propose a retest period or shelf life When and how extrapolation can be considered when proposing a retest period for a drug substance or a shelf life for a drug product
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Pharmaceutical Stability Science and Regulations

GLOBAL REGULATORY CHALLENGES

ICH Climate Zones Map (2005)

Different Climatic zones

I: Temperate less than 20C (21C/ 45%RH), e.g., Germany, Russia, Canada II: Subtropical with possible high humidity (25C/60%RH), e.g., France, Australia, USA III: Hot and dry (30C/35%RH) Arid, e.g., Botswana, Chad, Syria, Iraq IV: Hot and humid (30C/ 70%RH) Tropical, e.g., Taiwan, Singapore, India, Brazil

ICH Q1 A
Covers Zones I and II Does not cover Zones III and IV

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STABILITY CHALLENGES FOR HOT & HUMID COUNTRIES Pharmaceutical Stability Science and Regulations
ICH Q1F For Zones III and IV (Hot & Dry or Hot & Humid)
Stability Studies Study Conditions Long term Accelerated Data Requirement 12 months 6 months

Stress Conditions: 50C/ambient humidity to cover extremely hot and dry conditions; 25C/80% RH to cover extremely high humidity conditions

30 C 2 C / 65% RH 5 % RH 40 C 2 C / 75% RH 5 % RH

WITHDRAWN

WITHDRWAN in June 2006

Reason:
Several countries/ regions have revised their own stability testing guidelines for larger safety margin (e.g. 30C/75%RH as long-term storage condition) Respective regions and WHO responsible for defining of storage conditions

Impact on ICH Q1A (R2):

Intermediate testing condition is unchanged: 30C/65%RH 30C/75% RH is acceptable, should the applicant decide to use them.
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Pharmaceutical Stability Science and Regulations

Other Considerations

Keep container closure attributes in mind

Physical / Functional Properties
Moisture/Vapor transmission, Light permeation Adhesion / Sealing / Elasticity / Fragility Corrosion

Chemical Properties
Chemical interactions / degradations Extraction & Leaching of additives / chemicals into drug product

Miscellaneous studies
In-use studies (e.g. IV antibiotics) Admixture compatibility with other drugs (e.g. IV antibiotics) Stability data for intermediates / Bulk product Temperature cycling study Shipping studies
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Pharmaceutical Stability Science and Regulations

Conclusions
Pharmaceutical stability is a critical quality attribute. Any deviation from the established stability profile could affect the quality, safety and efficacy Thorough understanding of the stability of the drug substance and drug product is important to build the quality in
Design the optimal pharmaceutical product, define efficient API / DP process and establish appropriate specifications and expiry dates Successful development, registration and commercialization

ICH Q1 A-E offers sound scientific principles and covers majority of the regions; but there are exceptions Stay tuned to changing regulations Developing global stability programs are challenging due to climatic variations and differences in local regulatory requirements Plan well and use science based approach; consult the experts/regulators, as needed
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Pharmaceutical Stability Science and Regulations

References
Q1A(R2) Stability Testing of New Drug Substances and Products http://www.fda.gov/cder/guidance/5635fnl.pdf Q1B Photostability Testing of New Drug Substances and Products http://www.fda.gov/cder/guidance/1318fnl.pdf Q1C Stability Testing for New Dosage Forms http://www.fda.gov/cder/guidance/1319fnl.pdf Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products http://www.fda.gov/cder/guidance/4985fnl.pdf Q1E Evaluation of Stability Data http://www.fda.gov/cder/guidance/5531fnl.pdf

Thank You
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