reduce testing and evaluation of stability data · using stability data to support specification...

Reduce Testing and Evaluation of Stability Data

Anita L. Freed

Pfizer Inc.

AAPS Stability Testing 101

1 10/26/2015

Reduce Testing and Evaluation of Stability Data

• Lecture 10: AAPS Stability Testing 101 Bracketing and Matrixing Designs • J. Brooke Marshall

• Lecture 11: AAPS Stability Testing 101 Evaluation of Stability Data (Q1E) • Nanda Subbarao

• Lecture 12: AAPS Stability Testing 101 Using Stability Data to support Specification Setting (ICH Q6A) • Dilip Choudhury & Robert Timpano

• Lecture 13: AAPS Stability Testing 101 Investigations of OOS/OOT

• Paula Youngberg Webb

10/26/2015 AAPS Stability Testing 101 2

AAPS Stability Testing 101 Bracketing and Matrixing Designs

J. Brooke Marshall Senior Statistician

Center for Mathematical Sciences

Merck Manufacturing Division


3 10/26/2015

Outline • ICH Guideline Q1D

– Definitions and concepts

– Bracketing designs

– Matrixing designs

• Case Study

– Discuss potential bracketing and matrixing designs

– Compare performance of these designs in terms of prediction


Background • Bracketing and matrixing designs are reduced

study designs where not all factor combinations are tested for each batch at each stability time point

• Factors can include:

– Strength

– Container size and/or fill

– Container closure system

– Packaging type

• Stability condition would not be considered a factor


Full versus Reduced Designs • Full designs provide the maximum amount of data for

evaluation, but if there are many factors to be studied it can be more than is necessary and increase costs unnecessarily

• Reduced designs must provide enough data to adequately predict the retest period or shelf life of a new drug substance or product

• Data variability and product stability should be considered when choosing between these designs

• Data from full and reduced study designs are analyzed in the same manner

• The use of reduced designs must be properly justified 10/26/2015 AAPS Stability Testing 101 6

Case Study • Background:

– Reformulation of a drug product

– Four container sizes

– Same closure system

– 36-month expiry

• Discussed full (108 observations), bracketing and matrixing (1/2 and 1/3 reduction) designs

• Compared the bracket/matrix designs to the full design based on Scaled Prediction Variance (SPV)


AAPS Stability Testing 101 Evaluation of Stability Data (Q1e)

Nanda Subbarao Sr. Consultant, Biologics Consulting Group


8 10/26/2015

Outline

• Introduction to ICH Q1e – scope, principles

• DS re-test dates and DP expiry dates

• Studies to be presented and how

• Extrapolation – how, supportive data, statistical considerations, verification

• Data evaluation –regression analysis, pooling

• Summary 10/26/2015 AAPS Stability Testing 101 9

To justify the proposed Shelf life/Expiry periods • Present stability data systematically and include a

narrative covering the pertinent aspects. – Present in e.g. tabular, graphical formats

– Describing any trends and specification failures and provide an overall summary assessment

– Including data from formal long term, accelerated, as well as supporting studies

• Include, as appropriate, results from – Physical, chemical, biological, and microbiological tests, as well as

tests specific for the dosage form.

• Data as well as statistical assessment, mass balance where appropriate and narrative

– Qualitative attributes should be discussed


Statistical Analysis of Data

• Statistical analysis is not always needed or applicable, e.g.

– If data review clearly indicates no change, or

– Attribute is qualitative

• Which data is amenable to statistical analysis?

– Data for certain quantitative chemical attributes can be assumed to follow zero-order kinetics during long-term storage

– Kinetics of other quantitative attributes (e.g., pH, dissolution) is generally not known; apply if appropriate.


In Summary

• Present data clearly and completely – Present clear figures

• Statistical analysis is not mandatory – However it gives an advantage for extrapolation of shelf life/expiry

date

– Alternate approaches are acceptable as long as they are justified

• Extrapolation depends on certainty of the data – Low method variability, supportive data, statistical analysis, less

fragile molecules

– Can be used to get longer shelf life.

• Proposed shelf life must be confirmed


AAPS Stability Testing 101 Using Stability Data to support Specification Setting (ICH Q6A)

Dilip Choudhury & Robert Timpano Using Stability Data to support Specification Setting (ICH Q6A)


13 10/26/2015

Outline Scope

Purpose of Stability Testing Review

Overview of Specifications • What is a specification?

• Why are specifications needed?

• How are specifications established?

Approaches to using Stability knowledge to support Setting Specifications • Start with the End in Mind

• Science and Risk Based tools

• Statistical tools

Summary

References

Evaluation Questions


Start with the End in Mind

15

Is my product safe and efficacious?

• For how long? • In what packaging? • In what environment?

Product

Pack

Environment

Stability Data will be used to answer these questions. Stability Knowledge can be used to support selection of appropriate testing and specifications

0

0.1

0.2

0.3

0.4

0.5

0.6

0 6 12 18 24

% Degradation vs time

%Level

Months

Specification

• Stability Risk Assessments – Cause and Effect relationship between stability

challenges to the product and its resultant quality

– Aid in identifying the cause and effect relationship between stability input parameters (e.g. temperature and humidity) and product quality attributes (degradants)

• Statistical Approaches-Examples – Statistical approaches can be used to verify and

/or support specification setting

Scientific and Statistical Tools

16

DP Purposeful

degradation

studies

Formulation

stability screens

Excipient

compatibility

studies

Stability Risk Assessment

Potential Stability Shelf

Life Limiting Attributes

Stability

Input

Parameters

Gather

knowledge for

stability priorities/

gaps

Experimental

Strategies

Modify formulation

Modify the process

Add controls to

process or product

Utilise appropriate

packaging options

ICH

verification

CTD

Potential Shelf Life Limiting Attributes are typically taken from the material specification in

consideration of the Target Product Profile. Consider Attributes that may be susceptible to

change over time (Chemical, Physical and Microbiological),

Environmental

Conditions

(T, RH, Light, etc)

API Properties

(e.g. Polymorph,

particle size,

solvent levels)

Excipient

Properties (e.g.

metal content)

Parameters

Cause & Effect

Matrix

Quality Attributes

Input

Parameters

Prioritised

list of

knowledge

to gather

Development Phase

(Clinical): Iterative Loop

Confirm Stability

Recommendations

& Packaging

Start Post-POC

Process

Parameters

(e.g. Hold time

before coating)

Develop Stability

mitigation strategies

SL

LA

DS Purposeful

degradation

studies

Predictive

degradation

modeling

Stability

Knowledge

database

Right First Time Risk

Assessments & Activities

Prioritised list of

stability sensitivities

Identification of

Parameters with

potential to influence

SLLAs

Application of Stability Risk Assessment

17

Stability Knowledge

Science based Risk Assessment to Define

Gaps in Understanding

Mitigate stability

risks Iterative

Re-assessment as part of Stability Life Cycle &

Other Processes

Cases Stability can be used to verify and /or support specification setting in following cases (Examples)

Case 1: Setting Release Limits- Obtaining expiry with given variability

Case 2: Stable Molecules-Stability and Statistical analysis may support elimination of certain non-stability indicating tests (e.g. Assay, water content)

Case 3: Degradation observed on stability in combination with toxicology data may support appropriate specifications (widening or tightening)


AAPS Stability Testing 101 Investigations of OOS/OOT

Paula Youngberg Webb, M.S. Partner

JHWebb Consulting LLC


19 10/26/2015

Outline

• Introduction/Background

• FDA Guidance

• How to Conduct an Investigation

• New Impurity in the Middle of Stability

• Determine Root Cause

• Develop CAPA for Stability


Sources of OOS Test Results


Analytical Variability

Analytical Error

Manufacturing or Product Related

Analytical Variability

Analytical Error

Stability (rate of change)

Manufacturing or Product Related

Sources of Out of Specification

Test Results

B A T C H R E L E A S E

S T A B I L I T Y

How to Conduct an Investigation

• Phase I – Laboratory Investigation

– Robust initial assessment to determine accuracy of result – or if laboratory error occurred

• Phase II – Full Scale OOS Investigation

– If no laboratory error identified, conduct failure investigation to identify root cause and take appropriate corrective and preventive action


Develop CAPA for Stability

Steps of a CAPA process:

• Identify Nonconformity

• Investigate Cause

• Identify Actions

• Implement Changes

• Verify or Validate Actions

• Disseminate Information


Summary • Goal of an OOS investigation is to find the

root cause

• Investigation process must be defined in a procedure

• Investigate both analytical (Phase I) and batch manufacture (Phase II) as needed

• Evaluate impact on other batches or products or systems

• Ensure complete documentation of investigation and disposition rationale

AAPS Stability Testing 101 24 10/26/2015

Summary

• Investigation procedures must include:

– Directions for defining additional testing

– A responsible timeframe for completion of investigations

– Any required timeframes for notification to applicable regulatory authorities

– Approval of senior management required

– Retention of documentation

AAPS Stability Testing 101 25 10/26/2015

reduce testing and evaluation of stability data · using stability data to support specification...

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