AAPS Stability Testing 101

Analytical Procedures for Stability Program

Kim Huynh-Ba

Executive Director

PHARMALYTIK

• Module 1 – Introduction and Regulatory Expectations

A – Regulatory expectations of Stability Program

• Presented by Ken Norris

B – Regulatory expectations of Stability Indicating Methods

• Presented by Kim Huynh-Ba

• Module 2 – Product Specific Stability Studies

• Presented by Nanda Subbarao

• Module 3 – Evaluation and Utilization of Stability Data

• Presented by Anita Freed

ST 101 eLearning Overview

Lecture #4: “Development and Validation of Stability Indicating Methods”

Presented by Kim Huynh-Ba

Reviewed by Leonel Santos & Richard Nguyen

Lecture #5: “Monitoring organic impurities during stability program (API and DP) – Stress testing Industry Best Practices

Presented by Karen Alsante, PhD

Reviewed by Mark Schreiber & Leonel Santos

Lecture #6: “Photo-stability Testing and Q1B”

Presented by Allen Templeton, PhD

Reviewed by: Robert Reed & Richard Nguyen

OVERVIEW of MODULE 1B

Lecture #4 Developing and Validating Stability Indicating Methods

Presented by Kim Huynh-Ba

Pharmalytik Consulting and Training

Newark, DE

Reviewed by Leonel Santos and Richard Nguyen

Lecture #4 Objectives

• Purpose of analytical testing

• Principles of method validation

• Regulatory Requirements – ICH Q2R1 and USP <1225>

• Forced degradation studies and Stability- indicating Methods

• Relationship of USP GC <1224>, <1225> and <1226>

• Change control of analytical procedures and Analytical Lifecycle Management

Purpose of Stability Testing

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. Stability testing permits the establishment of recommended storage conditions, retest periods, and shelf-lives.

Ref: ICH harmonized Tripartite Guideline for Stability Testing of New Drug Substances and Products [ICH Q1AR2]

Factors affecting Drug Stability

API related:

•Stability of the API from storage (temperature, humidity and light) •Interaction between the API and excipient – FD

Process related:

• Selection of different dosage form/excipients

• Manufacturing process of drug product (DP)

• Selection of marketing image

Packaging related:

• Selection of container closure packaging system

• Handling and Distribution of DP

• Marketing regions

A basic theme for the definitions of validation indicates

that validation pertains to demonstrating that the method

or process is

“…suitable for its intended use”

Validation goals

It is essential that the purpose of the method to be validated is clearly stated at the outset of the validation process.

21 CFR 211.160 21 CFR 211.166 21 CFR 211.192 Q1A(R2)

Q2 (R1) Q3A, B, C, D Guidance for

Industry: CMC Documentation

USP GC <1225>, <1226> and

<1224>

• includes biologics and acknowledges that animal testing (i.e. immunogenicity) may have unique features

• Still focusses on chromatography and chemistry-based assays

• Written less prescriptive and refers to ICH or USP instead.

• Lists parameters and emphasizes on robustness.

• Includes contents of analytical procedures

• Recognizes compendial methods and requests verification protocol

• Emphasizes on lifecycle management – Method Performance

– New technologies

FDA Draft Guidance Validation of Analytical Methods

Development and Validation Include:

Types of Analytical Procedures

• 4 different types

Validation Characteristics

• Specificity, accuracy, linearity/range, precision, robustness, LOD/LOQ, …

Stress Testing – Stability Indicating

• Thermolytic, hydrolytic, oxidative, photolytic

• Done at solid state and solution state

Different tests to be considered for stability program

• Validation is a process

• Change control process for analytical procedures to focus on knowledge base and method understanding

• Typical changes to the method

• Validation vs Verification vs re-Validation vs Co-Validation

• Using compendial methods in stability program

• Manage method lifecycle** and trend method performance

Establish Change to the method

Remember that any change ignored or mishandled during any validation study

can negate the whole study!

** Change Control for Analytical Procedure throughout Product Lifecycle Wednesday AM, from 9:40-12:00, in 311 ABC

Lecture #5 Monitoring organic impurities during Stability Program (API and Drug Product) - Stress Testing Industry Best Practices

Presented by Karen Alsante

Pfizer PharmaTherapeutics Pharm Sci Analytical R&D, Groton, CT

Reviewed by Leonel Santos and Mark Schreiber

Lecture #5 Objectives

• Stress testing Goals – Studies and Methodology

• ICH Guidance Q1A (R2)

• Specific information but not very practical

Next generation interactive SharePoint Degradation Workflow demonstrated

Scientific Rationale for experimental conditions and maximum duration explored

Stress testing industry best practices to be discussed

1- PREDICT DEGRADANTS

Predict most likely degradants.

2- DESIGN PROTOCOL Develop based on the chemistry

of the API/drug product formulation.

3- PERFORM EXPERIMENTS Sample at appropriate points using

‘reasonable’ stress conditions.

4- CHALLENGE METHODOLOGY Screen degradation samples

using suitable methodology (HPLC).

5- EVALUATE PURITY/POTENCY Obtain purity/potency data including mass

balancewhere appropriate.

6- SELECT KPSS/TRACK PEAKS Determine the primary degradants.

Track KPSS across orthogonal methods.

7- IDENTIFY DEGRADANTS Utilize LC-MS, LC-NMR,.

8- DOCUMENT Prepare reports and share degradation

structures and mechanisms.

Stress Testing Process Map

Design Experiments

Knowledge

Space

Conditions recommended for stress testing studies to

develop a complete QbD knowledge space

Experimental Conditions

Concluding Questions

Would FDA and other agencies agree with our conclusion?

Would we feel comfortable stating that a method is “stability-indicating” if we do not know where ANY degs elute?

What if recommended stress conditions outlined produce NO observed degradation products?

Deg Workflow to Improve Process

Degradation lessons learned are captured

Search Pharma D3

Run Predictive Software Zeneth

Design/ Execute

experimental protocol

Identify Actual

Degradants

Compare Actual and Predicted

Degradants

Teach Zeneth/ Archive

Pharma D3

Lecture #6 A primer on PhotoStress Studies for Pharmaceutical Products

Presented by Allen Templeton And Leonardo Allain, Lee Klein, W. Peter Wuelfing Merck, Inc West Point, PA

Reviewed by Robert Reed and Richard Nguyen

Lecture #6 Objectives

1. Review of Forced Degradation Testing Concepts

2. Fundamentals of Photochemistry

3. Regulatory Guidance on Stability

4. Pharmaceutical Best Practices for Photo-Stability Testing

5. Case Studies

6. Appendix / Literature references on topic

Photostability Testing of New Drug Substances and Products (ICH Q1B)

• Q1B is an Annex guideline to ICH Q1A (R2)

• Emphasizes that light testing “should be an integral part of stress testing” – to demonstrate that light exposure does not result in

„unacceptable‟change as defined by applicant

• Provides recommendations for photostability testing – primarily addresses the generation of data for NCE‟s in

regulatory submissions

Why we do forced stress testing?

Forced stressing is a broad topic

Thoughts on forced stress:

• Intrinsic concept is key – you should find “signal” degradates

• Signal = those most likely to form in product

• You can degrade anything eventually but will that process result

in a realistic degradation product?

• “No reaction” is also very important as it indicates an inactive

pathway

• Thought should be given to “how much stressing is enough”

Reference: Pharmaceutical Stress Testing – Baertschi, Alsante, Reed (ed.) 2011

Regulatory Guidance Exists Guidance Topic Date

ICH Q1A (R2) Stability Testing of New Drug Substance and Products

2003

ICH Q1B Photo-stability 1996

ICH Q1C - F Stability study set up and evaluation

1996 -2006

ICH Q3A/B Drug Substance and Product Substance Impurity Control

2006

ICH Q3A-D Control of impurities

2006 - 2014

ICH M7 Control of PM Impurities

2014

Guidance to carry out stability studies for substance and product registration

Guidance to evaluate and control impurities found in stability studies

Photostability Testing of New Drug Substances and Products (ICH Q1B)

• Emphasizes that light testing “should be an integral part of stress testing*”

– To demonstrate that light exposure does not result in ‘unacceptable’ change as defined by applicant

– Light is a real environmental source for degradation

• So… evaluate it.

• Provides recommendations for photostability testing

– Primarily addresses the generation of data for NCE’s in regulatory submissions

– Light source options

– Measurement of light intensity

* Stress testing discussed earlier as a broad topic

ICH Q1B Light Source Options

Option I - exposure to a single lamp (from ICH)

Any light source with output similar to D65 (international standard for outdoor daylight) or ID65 (equivalent indoor indirect daylight standard - window filtered) emission standard – suggested to filter out below 320 nm

1Typical outdoor UV A/B A = 315 – 400 nm B = 280 – 315 nm C = 100 – 280 nm (abs by OL) Window filters < 320 nm Vis > 380 nm (violet) “All – in – one” approach

Reference to consider 1 Clapham, Templeton, Klein, Kleinman Practical Aspects of Conducting Photostability In Pharmaceutical Stress Testing 2011

More common overlap with conjugated drug molecules

Xenon or Metal Halide Lamp

ICH Q1B Light Source Options

Option II - exposure to two lamps (from ICH)

Cool white fluorescent lamp, ISO 10977

A near UV fluorescent lamp with output from 320 to 400 with maximum at 350-370 nm (UV A and B)

Cool white - mimics indoor lighting well This approach is often preferred due to ability to readily differentiate causative wavelengths (Vis vs. UV) Specific lamp spectral power (SPD) distribution should be considered

Common overlap with drug molecules

W/(

m2 ∙ n

m)

Wavelength (nm)

Example near UV

fluorescent lamp

Cool White Fluorescent

Light Standard ISO10977 (1993)

1.2 million lux hours (VIS) 200 W∙hr/m2 (UV)

Irradiance = UV Illuminance = Vis

Forced degradation studies

• Assessment of overall photostability

• Method development purposes

• Degradation product pathway elucidation

• Range of exposure conditions can be use

– 2-10x Q1B has been proposed

– Consider attenuating until 10 – 20% loss of active to measure “signal” degradates

– Guidance only calls for forced stress studies on drug substance

– Apply knowledge to drug product studies with excipients present

• Excipients can act as photosensitizers

Types of Photostability Studies

Confirmatory testing studies

• Information for handling, packaging and labeling

• Support registration submissions

• Analogous to other accelerated stability testing (i.e. 40C/75%RH)

• Option II – Minimum of 1.2 million lux hours (VIS)

– Minimum of 200 W∙hr/m2 (UV)

• ~ 3 months of continuous exposure to indoor UV and Vis lighting

• ~ 3 days in sunny window

• Performed on single batch of drug substance and drug product

Types of Photostability Studies (cont.)

Sample Considerations for Testing

From ICH Q1B DS - Sample should be spread so that the powder thickness is not more than 3 mm DP - Tablets should be placed in a single layer to maximize exposure

For further discussion see: Baertschi and Thatcher Chapter in Photostability and Stabilization Technology, CRC Press 2007

- Drug substance phase (crystal, amorphous, salt)

- Limit sublimation, evaporating, melting (use of a transparent container cover?)

- Transmittance of container lid if used (transparent?)

- Temperature control or a control sample blocked from light (foil)

- Drug Product -- DS Phase (crystal, amorphous, salt)

- Crowding and shadows that could reduce exposure

- Step wise testing from DP to packaged to inform whether a control strategy is needed

- Consider in-use studies (IV, creams, etc.)

Selection of Samples?

• Photostability of a dosage form depends on: properties of drug molecule, excipients in formulation, physical state of formulation.

• Solutions > Solids

• Test different forms of the product during the production of finished product

• Consider testing placebo alongside the active formulation

• ICH suggests one development batch followed by confirmation of one representative batch for registration (DS and DP)

What is the scope/impact

of potential changes

(eg. discoloration)?

What are the

causative wavelengths?

What is the mechanism?

Can it be eliminated?

Do I have appropriate

test methods in place?

Can I change the

formulation to make

photostable?

What controls do I

need in mfg/pkg, etc?

Positioning for

successful confirmatory

testing

Putting it all together: Developing an appropriate action plan

Thank you! Thank you! Thank you!

Any Question?

KIM HUYNH-BA

Executive Director

PHARMALYTIK

Kim.huynhba@pharmalytik.com

www.pharmalytik.com

Without data, You are just Another Person with an Opinion.