aaps stability testing 101 title here - amazon web services€¦ · aaps stability testing 101 23...

Essentials of Stability Testing for Pharmaceutical Scientists: A Live Session of Stability Testing 101 eLearning Course (#380)

AAPS Stability Testing 101

1 10/26/2015

Outline of Todays Session

• Module 1 - Introduction and Global

Regulatory Expectations – Kenneth Norris

• Module 1 (cont’d) – Regulatory Expectations

of Stability procedures – Kim Huynh-Ba

• Module 2 – Product Specific Stability

Programs – Nanda Subbarao, Ph.D.

• Module 3 – Reduce Testing and Evaluation

of Stability Data – Anita Freed, Ph.D.

10/26/2015 AAPS Stability Testing 101 2

• Core Team : – Nanda Subbarao

– Kim Huynh-Ba

– Anita Freed

– Kenneth Norris

– Karen Lucas

– Mark Alasandro

– Yan Wu

• Chairs : Kenneth Norris and Kim Huynh-Ba

• AAPS Support Staff : Stacey May and Meredith Weston

• Organizing Section: APQ

• Organizing Focus Group: Stability

Stability Testing 101 Acknowledgements

3


List of Reviewers

AAPS Stability Testing 101 4

• Kim Huynh-Ba

• Ganapathy Mohan

• Tony DeStefano

• Mark Schreiber

• Stephen T. Colgan

• Jeffrey D. Hofer

• Leonel M. Santos

• Kenneth Norris

• Robert Reed

• Bekki Thomas

• Paula Webb

• Karen Lucas

• Ketan Shah

• Kathleen Brady

• Judy Lin

• Richard Nguyen

Development of the course

• Course was part of a 2014 APQ goal

• Final proposal prepared with the guidance of the Stability Focus group

• Proposal was submitted to EPDC in early 2014 and approved later in the year


AAPS Stability Testing 101 Module 1 – Introduction and Global Regulatory Expectations

Kenneth Norris

Pfizer Worldwide Research and Development


6 10/26/2015

AAPS Stability Testing 101 Introduction to Stability Testing

Radhika Rajagopalan, Ph.D.

Quality Assessment Lead

OLDP-OPQ, CDER-FDA


• 14 Lectures, 3 Modules (1-6, 7-9, 10-14)

– Introduction and Regulatory Expectation

– Product Specific Stability

– Evaluation and Utilization of Stability Data

• Module 1 Introduction and Regulatory

– Introduction by Radhika Rajagopalan

– Regulations on Stability Program Global

Stability Requirements by Yan Wu

Stability Testing 101

8


– QBD Approach for Stability by Jianmei Kochling

– Development and Validation of Stability Indicating

Methods by Kim Huynh-Ba

– Monitoring Organic impurities during Stability

Program (API and Drug Product) – Stress Testing

Industry Best Practices by Karen Alsante

– Photo-stability Testing and Q1B by Peter W.

Wueling


9


Module 2 - Product Specific Stability

– Stability of Parenteral by Mark Alasandro

– Stability Program for Generics (U.S) by

Radhika Rajagopalan

– Stability Program for Biologics by Tony

Mazzeo


10


Module 3 - Evaluation and Utilization of Data

– Bracketing and Matrixing of Stability Testing

(Q1D) by Brook Marshall

– Evaluation of Stability Data (Q1E) by Nanda

Subbarao

– Using Stability Data to Support Specification

setting by Robert Timpano and Dilip Choudhury

– Investigations of OOS/OOT by Paula Webb

– Stability to support Post Approval Changes by

Frank Diana


11


Learning Objectives

• Comprehensive understanding, and knowledge of stability testing topic for pharmaceuticals, and biologics

• Regulatory expectations for New Drug, and Abbreviated New Drug Applications (NDAs and ANDAs), and Post-approval submissions


Course Outcome

• Provide a comprehensive discouse

• Knowledge of regulator expectation

– IND/NDA, ANDA, & BLA

• Deeper understanding of various topics

13 AAPS Stability Testing 101

• To provide evidence on how quality of DS/DP varies with time – Temperature – Humidity – Light

Purpose of Stability Testing

Packaging and Storage conditions

Determine proper

Appearance (quality) Potency (efficacy) Purity/Impurity (quality and safety)

• Understand physical, chemical, biological (for biologics), and microbiological

attributes, as well as requirements for container and closure.

• Establish shelf life of DS and DP at defined storage conditions.


When? What conditions?

• Until Harmonized different conditions existed

Left for different interpretations

API storage

Intermediate conditions

Globalization meant climatic zones needed to be defined by some body of experts!


Why Harmonize?

• Multiple strengths, packages, batches, various storage conditions, test parameters, and test intervals

• Prior to 1990s led to redundancy and enormous amount of testing

• ICH formed in 1990

– USA, EU, Japan followed by Canada, Australia, Switzerland, Pam American nations


Use of Stability Data

– For conducting Pre-clinical, clinical (new drugs), Bioequivalent (generic) studies

– To support drug registration

– Post-approval changes

– Life saving drugs can be launched across the continents

It was such a high priority that in 1990s ICH compiled a common set of requirements for marketing authorizations (EU, Japan, USA; Observers from Canada, Swiss, and WHO)

17

AAPS Stability Testing 101 Regulations on Stability Program Global Stability Requirements

Yan Wu Associate Director, Analytical Chemistry in Development and Supply

Merck & Co.


WHO Stability Guidelines

• These guidelines seek to exemplify the core stability data package required for registration of active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs)

• Alternative approaches can be used when they are scientifically justified

• These guidelines apply to new and existing APIs and FPPs

• These guidelines are not applicable to stability testing for biologicals (for details on vaccines see WHO guidelines for stability evaluation of vaccines)


Guideline: WHO Technical Report Series, No. 953, 2009 Annex 2 – Stability testing of active pharmaceutical ingredients and finished pharmaceutical products

WHO Proposed Criteria and Long-Term Testing Conditions

Climatic Zone

Definition Criteria (Mean annual temperature measured in the open air/mean annual partial water vapor pressure)

Long-Term Testing Conditions

I Temperate climate

≤ 15 °C / ≤ 11 hPa 21 °C / 45% RH

II Subtropical and Mediterranean climate

> 15 to 22 °C / > 11 to 18 hPa 25 °C / 60% RH

III Hot and dry climate

> 22 °C / ≤ 15 hPa 30 °C / 35% RH

IVa Hot and humid climate

> 22 °C / > 15 ro 27 hPa 30 °C / 65% RH

IVb Hot and very humid climate

> 22 °C / > 27 hPa 30 °C / 75% RH


• Long-term stability study conditions are determined by the climatic condition under which the API/FPP is intended to be stored

• Testing at a more severe long-term condition can be an alternative to testing condition

• If 30 °C/65% RH or 30 °C/75% RH is the long term condition, there is no intermediate condition

• Storage conditions and lengths of studies chosen should be sufficient to cover storage and shipment

• Short-term environmental changes due to opening the doors of the storage facility are acceptable as unavoidable

• Effect of excursions due to equipment failure should be assessed, addressed and reported if judged to affect stability results

• Excursions that exceed the defined tolerances for more than 24 hours should be described in the study report and their effects assessed.


WHO Stability Guidelines - Storage Conditions for General Case

• For a product in a given container closure system, container size and fill, an appropriate approach for deriving the rate of water loss at low relative humidity is to multiply the rate of water loss measured at an alternative relative humidity at the same temperature, by a water loss rate ratio shown in the table below. A linear water loss rate at the alternative relative humidity over the storage period should be demonstrated

• For example, at a given temperature, e.g. 40 °C, the calculation rate of water loss during storage at NMT 25%RH is the rate of water loss measured at 75% RH multiplied by 3.0, the corresponding water loss rate ratio


WHO Stability Guidelines -Example for an Approach for Determining Water Loss

Low-humidity testing conditions

Alternative testing

conditions

Ratio of water loss rates

Calculation

25 °C/40% RH 25 °C/60%RH 1.5 (100-40)/(100-60)

30°C/35% RH 30 °C/65%RH 1.9 (100-35)/(100-65)

30 °C/35% RH 30 °C/75%RH 2.6 (100-35)/(100-75)

40 °C/NMT 25% RH 40 °C/75%RH 3.0 (100/25)/(100-75)

• Aqueous-based products packaged in semi-permeable containers should be evaluated for potential water loss in addition to physical, chemical, biological and microbiological stability.

• This evaluation can be carried out under conditions of low relative humidity

• An alternative approach to studies at low relative humidity as recommended in table above is to perform stability studies under higher relative humidity and deriving water loss at low relative humidity through calculation.


WHO Stability Guidelines - Storage Conditions for FPPs Packaged in Semi-permeable Containers

Study Storage condition Minimum time period covered by data at submission

Long-term 25 °C/40% RH or 30 °C/35% RH 12 months

Intermediate 30 °C/65% RH 6 months

Accelerated 40 °C/not more than (NMT) 25% RH 6 months

• A storage statement should be established for the label based on stability evaluation of FPP

• Terms such as “ambient conditions” or “room temperature” must be avoided


WHO Stability Guidelines - Statements and Labelling

Testing condition Recommended labeling statement

API FPP

25 °C/60% RH (long-term) 40 °C/75% RH (accelerated)

“Do not store above 25 °C” “Do not store above 25 °C”

25 °C/40% RH (long-term) 30°C/65% RH (intermediate, failure of accelerated)


30 °C/65% RH (long-term) 40°C/75% RH (accelerated)

“Do not store above 30 °C” “Do not store above 30°C”

30 °C/75% RH (long-term) 40 °C/75% RH (accelerated)


5 °C ± 3 °C “Store in a refrigerator (2 °C to 8 °C) “Store in a refrigerator (2 °C to 8 °C)

-20 °C ± 5 °C “Store in freezer” “Store in freezer”

Strategy for Developing Global Stability Strategy • Step 1. Develop overall line-of-sight strategy on which regions or countries the

product will be marketed to

• Step 2. Understand stability related regulations each of these regions or countries require

• Step 3. Develop global stability strategy plan with following considerations:

– Is the product stable enough to run 30°C/75%RH only as the long term condition for all zones?

– Is it possible to use intended manufacturing or packaging sites for registration stability batches?

– Are there any country specific requirements to consider? For example, if the product is going to be filed in Brazil, run photostability study on three batches instead of one batch; if the product is going to be filed in EU, run two batches of bulk hold time study instead.

– Is it possible to leverage some manufacturing site development batches to fulfill some countries site stability requirements?

• Step 4. Request for input from regulatory agencies on stability strategy as needed


Summary Global Stability

• Good understanding of global stability requirements will enable optimized design of stability programs that will help bring new products to global markets faster with less cost


AAPS Stability Testing 101 Quality by Design Approach for Stability

Jianmei Kochling, PhD

Director, Genzyme, a Sanofi Company


27 10/26/2015

• QbD : a systematic approach to product development. It begins with predefined objectives, emphasizes product and process understanding and process control, as well as sound science and quality risk management (ICH Q8R2)

• QbD in Stability : a systematic approach to understand factors and risks that affect the stability of the drug product through thorough understanding of physical and chemical properties, stabilities under stressed and real time testing conditions. Using the gained knowledge to design effective stability studies, focusing on highest risk attributes and time points, for drug’s lifetime management.

QbD and QbD in Stability

28


Quality by Design for Stability

Statistical data and modeling for product stability space and specs, stability protocol design, and product shelf life.

Product continuous improvement and lifecycle management

Identify

critical

quality

attributes

Identify

Product

Target

Profile

Risk Assessment

Thorough physical and chemical characterization, forced-deg. study and stability data

Product stability knowledge space

Use data from risk assessment

Use knowledge to design clinical phase stability studies, packaging and storage condition

Effective commercial stability studies

Stability monitoring and data trending


Why QbD for Stability?

Industry Benefits • Understand risks involved in product stability during

product development – Raw material, processes, excipients, packaging, and storage conditions

• Improve product and process design and understanding through full range of product stability knowledge

– Physical and chemical characterization

– Forced-degradation

– Accelerated stability

– Real time stability

• Quality risk management – Stability monitoring and trending

• Continuous process and product life cycle management

• Cost Saving – Increase efficiency of manufacturing process

– Minimize/eliminate potential compliance actions

– Facilitate innovation

– Reduced stability testing: matrixing and bracketing stability testing


Quality for Patients

Why QbD Stability (continuation)

• Regulatory Benefits – The information and knowledge gained from

pharmaceutical development studies and manufacturing experience provide scientific understanding to support the establishment of the design space, specifications, and manufacturing controls.

– Working or improvements within the approved design space without further regulatory review and reduction of post-approval supplements.

– With expanded and enhanced knowledge of product performance over a wider range of material attributes, processing options, and process parameters, opportunities exist for more flexible regulatory approaches (e.g., risk-based regulatory decisions, manufacturing process).

– Reduced stability testing. What is already allowed : matrixing and bracketing.


Benefits to Patients

Risking Assessment and Determination of Critical Quality Attributes

• Step 1: Evaluate each parameter – Combine available characterization, forced-deg, stress testing, and real time

stability knowledge

• Step 2: Parameter ranking to evaluate associated risks – Ranking Scores = probability x severity x detectability

• Step 3: Risk assessment and determination of critical quality attributes based on risks

– Ranking parameters by risk scores and evaluate the importance of these scores to product quality

• Step 4: Identify Critical Quality Attributes and Define Stability Control Strategy

– Stability-indicating methods and specifications

– Refer to ICH Q6 for specifications setting, 6A for small molecules and 6B for Biologics.


• API polymorph impacts solubility, stability, and bioavailability – Solid state characterization (XRPD, DSC, TGA, etc.)

• Impurities may be genotoxic – Impurity identification through forced-deg, SAR determination,

and genotoxicity determination

• Formulation composition impacts product stability and bioavailability – Excipients compatibility studies

– Formulation screening

– Solid state characterization

Full Range Characterization of Product to Define CQAs

Small Molecules


• Potency – Loss of potency is rarely detectable upon stability monitoring

• Impurities – Process-related impurities usually are not stability concerns – Degradation of intermediates upon storage can lead to new process-

related impurities • Degradants

– Control of degradants of known or unknown toxicity – Common stability-limiting attributes

• Dissolution (small molecules in general) – Related to bioavailability

– Affected by solubility, polymorphic form, particle size, formulation, etc. • Moisture

– Factor for chemical or physical instability

Possible Product CQAs


Stability Testing 101 eLearning

• Course was launched the week of October 19th

• Coupon code AAPSAM15


aaps stability testing 101 title here - amazon web services€¦ · aaps stability testing 101 23...

Documents