COMMERCIAL PRODUCT STABILITY

Transcription

1 COMMERCIAL PRODUCT STABILITY Being Responsible for your Tweener, Senior Citizen and Hospice Stage Products Melissa Lambert Global Head Stability in Quality & Compliance Management, R&D Director Quality for Wellness Category, Global Manufacturing Supply Consumer Health GlaxoSmithKline

2 OUTLINE Introduction Why Stability? Proper Product Development and Launch Stability Package Commercial Stability Basics Sources of Change and Change Management as it applies to Stability Life Cycle Stages of Products and what it means to your Stability Program When, where and how to cut back on testing When, where and how to ramp up on testing

3 A LITTLE BIT ABOUT ME Melissa Lambert Beecham Products which became SmithKline Beecham and which is now GlaxoSmithKline (acquired Block Drugs) for 27 years Global Manufacturing Supply as well as Research & Development Microbiology, Laboratory Information Management Systems, Process and System Validation, Quality and Stability Rx/ OTC Switch, NDA and Monograph Drugs, Quasi Drugs, Medical Devices, Dietary Supplements, Cosmetics, Foods and Sundries

4 WHY STABILITY? Identity mixups Efficacy Sub or Super Potency Safety Potency and Degradants Quality Customer critical parameters Regulated Stability is required by many authorities for various product types

5 QUALITY ISSUES Quality issues will lead to costumer complaints which are reported to some regulatory agencies Poor quality leads to lack of trust and impacts company reputation Leads to consumers passing products on the shelf and choosing a competitors product

6 WHY STABILITY? To ensure product meets established criteria throughout expiry when stored as directed (per label storage statement) throughout the distribution chain of the product Manufacturing all the way up to patient use at the end of shelf-life Excursions outside of label storage statements

7 PROPER PRODUCT DEVELOPMENT AND LAUNCH STABILITY PACKAGE Pivotal/ Clinical Batches The amount of data at the start of product commercialization will vary Timelines Regulatory commitments No data on specific formulation if it is a minimal change to an existing or historic product Concurrent Data New product that requires regulatory submission will go to the agency with a minimum of 6 months acclerated and 12 months long term data By the time approval is received there could be 18 months or more worth of long term data

8 PROPER PRODUCT DEVELOPMENT AND LAUNCH STABILITY PACKAGE Bulk Hold Studies Photostability Studies In-Use or Period After Opening Studies Excursion Studies Freeze/ Thaw High Temperature Cycling and/ or Static Product/ Package Interaction (PPI) Studies

9 PROPER PRODUCT DEVELOPMENT AND LAUNCH STABILITY PACKAGE Expiry and Label Storage Statement Supported Store below 25C or equivalent Store below 30C or equivalent Do not Freeze Keep in a cool, dry place Keep frozen Keep refrigerated Keep protected from light

10 PROPER PRODUCT DEVELOPMENT AND LAUNCH STABILITY PACKAGE Provides a baseline on the stability profile of the product Product drift Out of Trend Outliers Future changes

11 INFORMATION SHARE/ TRANSFER FROM DEVELOPMENT TO COMMERCIAL Document Developmental Learnings: Raw Materials Active Pharmaceutical Ingredient Fully Characterized CMC section information Excipients Functional Excipients fully characterized Perservatives CMC section information

12 INFORMATION SHARE/ TRANSFER FROM DEVELOPMENT TO COMMERCIAL Document Developmental Learnings: Manufacturing and Packaging Process with Critical Steps Identified CMC sections Packaging Components Product contact materials Specifications CMC section

13 INFORMATION SHARE/ TRANSFER FROM DEVELOPMENT TO COMMERCIAL Document Developmental Learnings: Stability Indicating Analytical Methods Determined from development work Degradation products The sensitivity of the method Release and Stability Specifications Based upon stability data trends Process capabilities Variation Data Trends

14 INFORMATION SHARE/ TRANSFER FROM DEVELOPMENT TO COMMERCIAL Document Developmental Learnings: Data Trends Stability profiles of the product at ICH conditions 25/60 30/65 30/75 Helps identify Out of Trends when evaluating commercial stability data Differences in the trending can indicate process inconsistencies or deviations

15 COMMERCIAL STABILITY PROGRAM BASICS Standard Operating Procedures Highly regulated industry that is ever changing SOPs which represent the companies standard interpretations of the regulations Can be more prescriptive than the regulations to be a more user friendly document Specifies the company s current thinking on regulatory topics

16 COMMERCIAL STABILITY PROGRAM BASICS Standard Operating Procedures NOTE: There is no one size fits all stability program, but it is imperative to follow SOPs, as they will be the documents regulatory agencies will use asses your program Deviations to the SOPs should be fully documented and based upon scientific rationale

17 COMMERCIAL STABILITY PROGRAM BASICS Environmental Chambers Different temperature and humidity conditions Must be PM/Cal and maintained on a regular basis A program should be in place to track this is completed PM should be done yearly or every 6 months, depending Cals should be done annually, biannually or every 3 years. Depending on the age of the chambers Depending on if there have been known issues

18 COMMERCIAL STABILITY PROGRAM BASICS Visibility to Production Schedule Ordering stability samples for commitment batches Ordering stability samples for routine annual lot stability Ordering stability samples when there is a change to the process that requires stability data

19 COMMERCIAL STABILITY PROGRAM BASICS Product Details Specifications For release and stability Expiry Period Based upon stability data from pivotal studies Label Storage Statement based upon stability data from pivotal studies and supplemental studies

20 COMMERCIAL STABILITY PROGRAM BASICS Markets Different requirements for different markets Sometimes different specifications Different tests, etc. Example: Dissolution tests with different timepoints to report Test to the tightest specifications

21 COMMERCIAL STABILITY Initial Stability Batches Commitment batches 3 of the first commercial batches to be placed on Long Term and accelerated ICH Timepoints First Annual batch Long Term conditions only Reduced timepoints (annually)

22 COMMERCIAL STABILITY Fill any Gaps from Development Regulatory commitments to do additional testing must be met Supplemental stability tests Bulk Photostability Excursions Period after Opening (cosmetics) In-Use testing

23 COMMERCIAL STABILITY Annual Stability Program Reduced program Long Term condition Reduction of ICH Timepoints (annually) Reduction of certain tests Such as micro (1 batch in 10) Actual Expiry Interval In addition to testing annually, it is wise to consider a timepoint that matches up to the actual expiry of the product

24 COMMERCIAL STABILITY Batches to Support Changes/ Deviations Placed on full ICH stability in most cases Packaging changes API supplier changes Manufacturing process / equipment changes

25 COMMERCIAL STABILITY FDA Inspection Guide Expiration Dating and Stability Testing for Human Drug Products it is imperative that stability studies are not limited only to initial production batches but a portion of annual production batches be the subject of an ongoing stability program Inspection Guide Oct 1985/ webpage Apr 2009

26 COMMERCIAL STABILITY WHO stability guideline: Unless otherwise justified, at least one batch per year of product manufactured in every strength and every primary packaging type, if relevant, should be included in the stability program

27 ANNUAL STABILITY PROGRAM Specific instructions or requirements for an Annual Stability program and limited. Standard Operating Procedures should govern program, which will be based upon company s current thinking and regulatory expertise. One batch per formulation per package type per year. One batch in every 50. Every n-th batch could be placed on stability. Square root of the number of batches to be produced plus 1 as the number of lots/ year for the stability program.

28 ANNUAL STABILITY PROGRAM One batch per formulation per package type per year. Every n-th batch could be placed on stability. Square root of the number of batches to be produced plus 1 as the number of lots/ year for the stability program.

29 SOURCES OF CHANGE THAT IMPACT STABILITY Once a product is launched there are many sources of change that will have to be evaluated. Often changes are considered small enough not to impact stability but there is always some degree of unknown. Consider the cumulative of those small changes. Often there are attributes of the raw materials or manufacturing processes that contribute to the stability unknowingly.

30 SOURCES OF CHANGE THAT IMPACT STABILITY Deviations Alternate/ New Suppliers Change in packaging Cost Savings Process/ Method Optimization Equipment changes Manufacturing and packaging Line Extensions Site Transfers

31 CHANGE MANAGEMENT AS IT APPLIES TO STABILITY Change Control Raw Material/ Components Process Analytical Methods Specifications Document Change Evaluate Impact Document Implementation Requirements Variations/ Amendments Consider revisiting Bulk, Photo, In Use/ PAO, Excursion and PPI Studies

32 LIFE CYCLE STAGES OF PRODUCTS Initial Product Launch Tweener - Real Time Data to Expiry on 1 st Commercial Batch(es) Senior - Established Stable Product Hospice Problematic Products of any Age

33 IMPACT OF LIFE CYCLE STAGE ON YOUR STABILITY PROGRAM - TWEENER Data up to expiry should be obtained by this point Continuing data should be generated at the site level Ongoing review of data should be at the ABOVE site level assessing all data from all sites. Differences in manufacturing site data should be investigated

34 IMPACT OF LIFE CYCLE STAGE ON YOUR STABILITY PROGRAM - TWEENER Trending shifts can show manufacture drifts Outliers can illuminate manufacturing issues Out of specification investigations Field Alerts and Product recalls Identify and address potential issues and determine significance (curable, chronic or fatal) Risk Based Approach Concepts in ICH Q9 Quality Risk Management

35 CURABLE, CHRONIC OR FATAL? Out of specification results Investigation to find cause Identifiable cause Curable? Take necessary steps to address the situation Chronic or fatal indicate a problem with the product that may or may not be overcome The Tween becomes Hospice

36 IMPACT OF LIFE CYCLE STAGE ON YOUR STABILITY PROGRAM - SENIOR Well established products are considered Senior Wealth of stability data Problems / issues rare and easily overcome Consider Possible Extension of the Expiry Reduced Stability Testing more discussion on this later

37 IMPACT OF LIFE CYCLE STAGE ON YOUR STABILITY PROGRAM - HOSPICE At any stage of the life cycle a product can become Hospice Occurs when there are chronic or fatal issues with product stability There can be compounding effects that are impacting product stability Increased monitoring of the stability program may be necessary (adding timepoints) Additional batches may be placed on stability

38 TREATMENT OF HOSPICE PRODUCTS Revisit Product attributes What is causing issues in the Stability Program and how can they be overcome? Revisit packaging Is the packaging protective enough? Addition of a desiccant in the packaging Addition of cotton for friable tablets

39 TREATMENT OF HOSPICE PRODUCTS Are the Tests and Methods appropriate? Robust method Stability Indicating Validated for the range of use Adequate replicate samples preps Intermediate testing? In-process controls?

40 TREATMENT OF HOSPICE PRODUCTS Revisit Product Specifications Specifications are sometimes set with limited amount of data on a limited amount of batches Generation of data over time will determine the appropriateness of those specifications

41 TREATMENT OF HOSPICE PRODUCTS The specification limits should be considered in conjunction with the expiry period and the label storage statement. Keeping the same specifications Different expiry for different zones Change label storage statement Tighten the internal release limit to account for the trending Widening Specifications regulatory approval

42 TREATMENT OF HOSPICE PRODUCTS When all else fails REFORMULATION!! Or removal of the product from the portfolio

43 WHEN, WHERE AND HOW TO CUT BACK ON TESTING Products with a Significant Body of Data Usually multiple batches with acceptable data up to-and even beyond approved shelf-life All supporting supplemental stability studies are acceptable Can consider reducing the amount of annual batches place on stability each year Another consideration is reducing the overall stability program. I If each strength each package type and size is taken for an annual program, bracketing or matrixing can be considered Or alternating package types per year

44 WHEN, WHERE AND HOW TO RAMP UP ON TESTING Deviations / Change controls When data/ trends are indicating something has changed Add full testing at regular intervals Add key intervals based on projections Test only expiry limiting parameter at increased frequency Place additional batches on stability

45 CONCLUSION Its easy to think of a product having a life-cycle Tween Senior Hospice Knowing the state a product is in determines the progression of the stability program for that product Tween data generating with minimal issues Senior significant amount of data obtained showing stability over the course of its shelf-life Hospice problematic products that require extra TLC

46 REFERENCES tured-articles/ stability-testing-doing- Everything-or-Doing-the-Right-Thing/ es/officeofmedicalproductsandtobacco/cder/ucm pdf

47 RESOURCES Guidance for Industry: ICH Q1A-Stability testing of new drug substances and products Guidance for Industry: ICH Q1B-Photostability testing of new drug substances and products Guidance for Industry: ICH Q1C-Stability testing for new dosage forms Guidance for Industry: ICH Q1D-Bracketing and matrixing designs for stability testing of new drug substances and drug products Guidance for Industry: ICHQ1E-Evaluation of stability data