stability studies in pharmaceutical development - catalent

stability studies in pharmaceutical development

Kathy Waddle, MS

Wei Pan, Ph.D. RAC

Catalent Pharma Solutions

Catalent Pharma Solutions 1

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


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


Stability Quality by Design

Pharmaceutical product stability is a function of:

Drug Substance

Drug Substance

Manufacturing Process


ContainerClosure

ContainerClosure

Product Understanding


ExcipientsExcipients


Stability Studies During Pharmaceutical Product Lifecycle

Pre-clinical

Pre-clinical Phase IPhase I Phase IIPhase II Phase IIIPhase III

FileIND

FileNDA Approval

FinalLabeling

Discussions

FinalLabeling

Discussions

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

Drug Discovery

Drug Discovery

Phase IVPLCM

Rx to OTC

Phase IVPLCM

Rx to OTC


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


Stability Considerations During Early Development

+PACKAGED PRODUCT

API

EXCIPIENTS

DRUG PRODUCT


PackagingSelection


API Mechanisms of Instability - Chemical

• Identify functional groups and labile centers

—2º and 3º Amines --> N-oxide, hydroxylamine by oxidation

—Aldehyde --> Acid by oxidation

—Esters/Lactones -->Acid/Alcohol by hydrolysis

• Consider external contributing factors

—pH, temperature, humidity, light

• Perform forced degradation studies

—Acid/base

—Heat

—Oxidation

—Photolysis

Understand mechanisms of degradation of drug substance


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


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


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: it’s the ethyl ester of the API.

Hint: Know your chemistry.


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


Case Study 2


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


Case Study 2

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



• 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


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


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



Pre-clinical


FileIND

FileNDA Approval

FinalLabeling

Discussions

FinalLabeling

Discussions




application



Drug Discovery

Drug Discovery

Phase IVPLCM

Rx to OTC

Phase IVPLCM

Rx to OTC


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)


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 ControlCouncil: Stability January 2005


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 FDA’s current thinking of providing broad guidance

• In the meantime…refer to the following ICH documents…as alternative resources


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


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

Consensus building by EWG

Consensus Agreed

six parties

Regulatory Consultation Adopt Implement

Step1Step1 Step2Step2 Step3Step3 Step4Step4 Step5Step5


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/2736/99MHLW : Adopted June 3, 2003, PFSB/ELD Notification No. 0603001FDA : 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



The Four Climate Zones:

Zone I Temperate 21ºC±2ºC /45%RH ±5%RHZone II Subtropical &

Mediterranean 25ºC±2ºC/60%RH ±5%RHZone III* Hot & Dry 30ºC±2ºC/35%RH ±5%RHZone IV* Hot & Humid 30ºC±2ºC/65%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.


World View of Climatic Zone Determinations by Country


WHO Stability Guideline

• 193 Member States

• Split Climate Zone IV (hot and humid) to two zones

- Climate Zone IVA (hot & humid) 30ºC/65%RH

- Climate Zone IVB (hot & very Humid) 30ºC/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


WHO Stability Guidelines at a Glance



Additional Guidance Provided in WHO Document:

• Testing parameter recommendations

• Storage statement and labeling guidance

• Covers new drug and marketed product



Pre-clinical


FileIND

FileNDA Approval

FinalLabeling

Discussions

FinalLabeling

Discussions




application



Drug Discovery

Drug Discovery

Phase IVPLCM

Rx to OTC

Phase IVPLCM

Rx to OTC


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


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



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



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


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


Example 1 – A Really Simple Stability Protocol

Tablets in 30-count HDPE bottle for US market

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

Condition Initial 3M 6M 9M 12M 18M 24M 36M

[2]

X

[2]

X

-

Total Stored

25ºC/60%RH

-

-

-

[2]

X

[2]

(X)

[2]

X

[2]

X

[2]

X

[2]

X

[2]

X

[2]

X

[2]

(X)

[2]

(X)

[2]

X

-

24

30ºC/65%RH [2]

(X)

- - 12

40ºC/75%RH - - - 6


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 product’s 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)


Example 2 – a Simple Stability Protocol

Tablets in 30-count HDPE Bottle for Global Registration

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


[2]

X

[2]

X

[2]

X

Total Stored

25ºC/60%RH

-

-

-

[2]

X

[2]

X

[2]

X

[2]

X

[2]

X

[2]

X

[2]

X

[2]

X

[2]

X

[2]

X

[2]

X

-

24

30ºC/65%RH [2]

X

[2]

X

[2]

X

22

40ºC/75%RH - - - 6


Example 3 - a Complicated Stability Protocol

Sterile product in glass vials for US market (store inverted)

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


[4]

X

[50]

XPSL

-

Total Stored

25ºC/60%RH

-

-

-

[4]

X

[4]

(X)

[4]

X

[50]

XPSL

[4]

X

[50]

XPSL

[4]

X

[4]

X

[4]

(X)

[4]

(X)

[14]

XPL

-

200

30ºC/65%RH [50]

(XPSL)

- - 90

40ºC/75%RH - - - 36


Example 4–an Even More Complicated Stability Protocol

Sterile Product in a Semi - permeable Containers for Us Market

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


[4]

X

[50]

XPSL

-

Total Stored

25ºC/40%RH

-

-

-

[4]

X

[4]

(X)

[4]

X

[50]

XPSL

[4]

X

[50]

XPSL

[4]

X

[4]

X

[4]

(X)

[4]

(X)

[14]

XPL

-

200

30ºC/65%RH [50]

(XPSL)

- - 90

40ºC/20%RH - - - 40


Example 4–an Even More Complicated Stability Protocol

Sterile Product in Semi -permeable Containers for US Market

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 40°C/NMT 25% RH.


[10]W

[10]W

-

Total Stored

25ºC/40%RH

-

-

-

[10]W

[10](W)

[10]W

[10]W

[10]W

[10]W

[10]W

[10]W

[10](W)

[10](W)

[10]W

-

10

30ºC/65%RH [10](W)

- - 10

40ºC/20%RH - - - 10


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.


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


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


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 Data

Stability Data



Product shelf-life and

Storage Conditions

Product shelf-life and

Storage Conditions


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 theshelf 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.



Pre-clinical


FileIND

FileNDA Approval

FinalLabeling

Discussions

FinalLabeling

Discussions



Stability studies tomonitor product quality


Drug Discovery

Drug Discovery

Phase IVPLCM

Rx to OTC

Phase IVPLCM

Rx to OTC


application


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.


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.



US EU

Major ChangesSubstantial potential to have an adverse effect

Major ChangesSubstantial potential to have an adverse effect

Moderate ChangesModerate potential to have

an adverse effect

Moderate ChangesModerate potential to have

an adverse effect

Minor ChangesMinimal potential to have an

adverse effect

Minor ChangesMinimal potential to have an

adverse effect

Type IIType II

Type IBType IB

Type IAType IA



1. FDA/CDER (November 1995) Guidance for industry Scale up and post-approval changes: immediate release solid oral dosage forms.

2. FDA/CDER (September 1997) Guidance for industry Scale up and post-approval changes: modified release solid oral dosage forms.

3. FDA/CDER (May 1997) Guidance for industry Scale up and post-approval changes: non-sterile semisolid dosage forms.

4. FDA/CDER (January 1999) Guidance for industry Scale up and post-approval changes: immediate release and modified release solid oral dosage forms manufacturing equipment.

5. FDA/CDER (April 2004) Guidance for industry Changes to an approved NDA and ANDAs.

6. 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

7. EMEA (2006) Guideline on dossier requirement for Type IA and IB notification8. WHO (February 2007) Annex 6 variation guidance: guidance on variation to a

prequalified product Dossier

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stability studies in pharmaceutical development - catalent

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