Pfizer4444th th International SFSTP ConferenceInternational SFSTP Conference

June 6June 6--7 20127 2012

Science and Risk based Strategies for Stability and Regulatory uses throughout the Product Lifecycle

44th International SFSTP Conference – June 6 and 7 2012FROM SCIENTIFIC UNDERSTANDING TOWARDS PRODUCT FROM SCIENTIFIC UNDERSTANDING TOWARDS PRODUCT

QUALITY (by Design) QUALITY (by Design)

KEVIN RYAN – Associate Research Fellow

Team Leader, Analytical Research and Development , Sandwich, UK

Pfizer4444th th International SFSTP ConferenceInternational SFSTP Conference

June 6June 6--7 20127 2012

Science and Risk based Strategies for Stability and Regulatory uses Throughout the Product Lifecycle

Summary of Content

Stability Life Cycle and Opportunity LandscapeStability Knowledge SpaceLean StabilityAccelerated Stability Assessment Protocol (ASAP)Stability Risk Assessment (SRA)

Definitions• API = Active Pharmaceutical Ingredient• DP = Drug Product• SLLA= Shelf Life Limiting Attribute• SA= Stability Related Quality Attribute

Pfizer4444th th International SFSTP ConferenceInternational SFSTP Conference

June 6June 6--7 20127 2012

The Stability Life Cycle and Opportunity Landscape

The development of safe drug products require significant resource and experimental data, much of which may be considered as “non value” adding to product understanding nor mitigating risk of stability issues which may impact clinical and commercial products.

Good scientific understanding of stability, stability knowledge space based strategies, use of scientific tools, risk based assessments and lean approaches facilitate value adding key information being generated at the right time, which mitigates potential stability related issues and allows leaner development programmes for drug products with well understood stability profiles and improved control strategies

Pfizer4444th th International SFSTP ConferenceInternational SFSTP Conference

June 6June 6--7 20127 2012

Early/ Exploratory Dev.

Full Dev.

The Stability Life Cycle and Opportunity Landscape

Phase I Phase IIa------ b Phase IIIDiscovery Post Marketing

“Enabling”Formulations

“Commercial”Formulations

“Clinical“ Formulations

Early Generic/ Orth analytical methods

Evolving fit for purpose QbD analytical methods

Final QbD ICH Analytical methods

First In Human

Proof of Concept

Filing LaunchCommercial Dose selection

API & DP Registration Manufacture

Dev. Commercial API solid form (Salt, polymorph,

crystallisation, particle size)

API & DP Design Space optimisation

Dev. Commercial DP - design & manufacturing Process)

Early Fit for purpose API

Commercial

Application of Lean Science Based Strategies, Stability Knowledge Space Understanding,

Scientific Tools and Risk Based Assessments generating value adding information

API/ DP Process Improvements

Variations

Variations and New Products

Post approval Stability Commitment ,

Annual Site Stability

Pfizer4444th th International SFSTP ConferenceInternational SFSTP Conference

June 6June 6--7 20127 2012

Science Based Approaches

Scientific understanding of Stability

“The Stability Knowledge Space”

Pfizer4444th th International SFSTP ConferenceInternational SFSTP Conference

June 6June 6--7 20127 2012

Science based approach-Terminology to Consider

Stability Related Quality Attribute (SA): may/ will influence API or DP shelf life when stored at fixed conditions (There are many…) and may/ may not be measured on stability). SAs are a subset of Quality Attributes

Shelf Life Limiting Attribute (SLLA): An attribute which will breach its limit when stored at fixed conditions at a point pre-determined by a subset of the SA(s) (e.g. degradation product) and would be measured on stability

Stability Knowledge Space (SKS): Is part of the API or DP “release requirements”, a well understood space built through development knowledge, understanding of SAs and verified by SLLAs that, allows confident shelf life assignment for a given API or DP, independent of scale, site, process and route.

Development knowledge

Pfizer4444th th International SFSTP ConferenceInternational SFSTP Conference

June 6June 6--7 20127 2012

The Stability Knowledge Space can be built using development knowledge:

In-silico modelling/ chemistry knowledge Literature/ knowledge gained on other compounds/ generic understandingExcipient compatibility studiesAccelerated Stability Assessment Protocol (ASAP)*Development/ clinical stability studiesMicro-calorimetryPackage selection: MVTR/ moisture isotherms

Determine what needs closer study (SRA) & what needs no further study

*K. C. Waterman, A. J. Carella, M. J. Gumkowski, P. Lukulay , B. C. Macdonald, M. C. Roy, S. L. Shamblin. Improved protocol and data analysis for accelerated shelf-life estimation of solid dosage forms. Pharm. Res. 24 (4):780-790 (2007).

Developing a Stability Knowledge Space (API)

Pfizer4444th th International SFSTP ConferenceInternational SFSTP Conference

June 6June 6--7 20127 2012

Salt StoichometryMoisture

Solvent Content

Impurities*

Crystal Habit Particle Size

Amorphous Content

Polymorph/ solvate/hydrate

Science based approach-

Stability Attributes (API)

For a fixed storage condition/ use-by date/ packaging:

Scale, process, synthetic route and site are potential influencing factors on the attributes of an API batch but are not SAs themselves; it is the SAs that need to be considered for the ‘Stability Knowledge Space’

* Depending on the primary degradation route, for the shelf-life limiting degradant, catalytic impurity levels (e.g. acids/ bases) may be important. For significant changes in impurity profile, check effect on melt point for low mp APIs

SKS

M

SC Po

PS

AC

CH

I

S

PS

The SKS is in effect the release requirements for SAs, to ensure appropriate stability

Pfizer4444th th International SFSTP ConferenceInternational SFSTP Conference

June 6June 6--7 20127 2012

Science and Risk-Based Approaches

Science & Risk based

“Lean Stability”

Pfizer4444th th International SFSTP ConferenceInternational SFSTP Conference

June 6June 6--7 20127 2012

API Review/ Retest Period (During development)

Initial retest period assignment of 18M based on Purposeful degradation studies, in silico modeling or stressed conditions (70⁰C/75%RH)Stability on 1st GMP batch set up prior to release, at accelerated, long term and 1 condition below long term for trending across temperatures. Reduced testing employed - Initial, 3M 12M, 24M, 36M. (no testing at 6W, 6M, 9M or 18M)No assay testing on API stability if the lot on stability is the same as that used for the reference standard

Assay tests the API against itself and variability in assay values is reflective of method accuracy rather than degradation. Ref. stds are generally stored under the same conditions as clinical supplies. HPLC methodology developed to ensure all known degradation products are resolved from main band.

For route changesIf scientific justification has deemed the data from the initial lot to be representative, then the new batch(es) are not placed on stabilityOtherwise, minimal and/ or reduced testing is done to justify the API review/ retest period assignment

Application/ Success of Lean Stability

Pfizer4444th th International SFSTP ConferenceInternational SFSTP Conference

June 6June 6--7 20127 2012

Drug Product Use Period (During development)

ASAP employed to set initial use period of 12M , with commitment to a reduced formal stability protocolFor change

Science based risk assessment to determine if DP must be set up on stability because of, e.g. a new packaging configuration, substantial change in API route, formulation change, etc

Reduced testing from FIH to Phase II/III3M, 6M, 12M, 24M, 36M30°C/75%RH as default condition to provide data for Zone IV climatic regions and late development (e.g. registration stability where composition of dosage form is similar to commercial). 5°C Contingency onlyDesigns provide stability knowledge prior to ICH studies while minimizing risk to clinical programs. 30°C/65%RH or 30°C/75%RH selected based on SRA & ASAP as long term condition, in lieu of 25°C/60%RH

Reference API stability results if applicable, e.g. extemporaneously prepared powder in a capsule

Application/ Success of Lean Stability

Pfizer4444th th International SFSTP ConferenceInternational SFSTP Conference

June 6June 6--7 20127 2012

Science Based Approaches

Scientific understanding of Stability

“Accelerated Stability Assessment Protocol (ASAP)”

Pfizer4444th th International SFSTP ConferenceInternational SFSTP Conference

June 6June 6--7 20127 2012

Humidity Corrected Arrhenius Equation

Ln k = Ln A - Ea/(RT) + B(%RH)

Measured (calculated from % degradation results)

Selected by user, at least 3 combinations required

3 parameters need to be determined (using multilinear regression) for each degradation reaction

The effect of temperature and relative humidity on reaction rates for solid pharmaceuticals can be expressed by the following equation:

k = Rate constantA = Collision frequencyEa = Activation EnergyR = Gas ConstantT = Absolute TempB = Humidity Term: (Equilibrium RH)K. C. Waterman, A. J. Carella, M. J. Gumkowski, P. Lukulay , B. C. Macdonald, M. C.

Roy, S. L. Shamblin. Improved protocol and data analysis for accelerated shelf-life estimation of solid dosage forms. Pharm. Res. 24 (4):780-790 (2007).

Pfizer4444th th International SFSTP ConferenceInternational SFSTP Conference

June 6June 6--7 20127 2012

Product “Y” in 50 count Bottle (25C/60% RH)

0.6

0.4

0.2

0.0

% Im

purit

y X

XX

monthASAP Long Term

StabilityPack Selection

Tool

Protective packaging

needed

No packaging concerns

Sensitive to

packaging

(years)

ASAP Defined Product Stability Landscape

2 tablets

15 tablets

15 tablets +desiccant

open bottle

“Product X” in 60-cc HDPE Bottles (40ºC/75%RH)

Application/ Success of ASAP

Pfizer4444th th International SFSTP ConferenceInternational SFSTP Conference

June 6June 6--7 20127 2012

Application/ Success of ASAP

ICH Q1A based development stability programs typically use long-term and accelerated conditions that are lengthy and not always predictive of actual degradation levels and impact of change. Within Pfizer, ASAP has delivered:

Greater Speed and reliability than conventional stability approachesPhase I/ IIa - For IMPD’s, standard practice is to submit ASAP to define risk and allow proposed initial use-by-dates without a formal stab protocol and data (we do commit to a protocol). We typically save 6-8 wks development time

Rapidly Determine impact of change during development (Manufacturing process, Formulation, Packaging) and post approval

(product X changed excipient – ASAP used to predict impact & showed no risk)

Greater Predictive Power in management of riskHow will my Zone 2 approved product perform in zone 4b

To consider- Should proven science based predictive tools such as ASAP be an option as part of regulatory guidance?

Pfizer4444th th International SFSTP ConferenceInternational SFSTP Conference

June 6June 6--7 20127 2012

Risk-Based Approaches

Understanding Risk

“Stability Risk Assessment (SRA)”

Pfizer4444th th International SFSTP ConferenceInternational SFSTP Conference

June 6June 6--7 20127 2012

Stability Risk Assessment (SRA)

A efficient process to utilise and structure development (product and formulation development) information, identifying and prioritise both physical and chemical stability risks and concentrating attention on high risk areasA comprehensive scientific (not regulatory) assessment targeted at preemptivelyidentifying attributes that could limit (put at risk) the shelf life of both API & DP (facilitates “stability knowledge space understanding” & “lean stability”)Involves the ranking of the relative importance of factors (input variables) which could influence those attributesIncludes a repository for stability knowledge, facilitates application of scientific understanding of stability and knowledge across a diverse global portfolio

Prompts the development of a more focused stability mitigation strategy (modify the formulation or process; add controls to the product or process; utilise appropriate packaging options) to increase product robustnessProvides scientific justification for optimized and value added stability designsEnables informed decisions to be made (with this captured stability knowledge) including the potential impact of changes during development

Pfizer4444th th International SFSTP ConferenceInternational SFSTP Conference

June 6June 6--7 20127 2012

Stability Risk Assessment Context

“Stability Knowledge for a Stable Outcome”SRA- Process

Pfizer4444th th International SFSTP ConferenceInternational SFSTP Conference

June 6June 6--7 20127 2012

SRA- Process

Pfizer4444th th International SFSTP ConferenceInternational SFSTP Conference

June 6June 6--7 20127 2012

Potential SLLA’s - WHOExamples of Potential Shelf Life limiting AttributesList of test is not intended to be exhaustive, nor is it expected that every test be evaluated.

API Tablets Hard gelatin Capsules Soft gelatin capsules Oral solutions Suspensions EmulsionsAppearance Appearance Appearance Appearance Appearance Appearance AppearanceAssay Assay Assay Assay Assay Assay AssayDegradation products Degradation products Degradation products Degradation products Degradation products Degradation products Degradation productsMicrobiological limits Microbiological limits Microbiological limits Microbiological limits Microbiological limits Microbiological limits Microbiological limits

Dissolution Dissolution Dissolution Precipitate formation Precipitate formation Precipitate formationDisintegration Disintegration Disintegration Viscosity Viscosity ViscosityWater content Water content pH pH pH pH Hardness Brittleness Leakage Viscosity Extractables Extractables

Pellicle formation Extractables Dispersibility Phase Separation

Clarity Rheological propertiesMean size and distribution of dispersed globules

Mean size and distribution of particlesPolymorphic conversion

Powders and granulesfor oral solution or

suspensions Topicals Ophthalmics Suppositories Parenterals Transdermal PatchesAppearance Appearance Appearance Appearance Appearance AppearanceAssay Assay Assay Assay Assay AssayDegradation products Degradation products Degradation products Degradation products Degradation products Degradation productsMicrobiological limits Microbiological limits Microbiological limits Microbiological limits Microbiological limits Microbiological limitsWater Content Clarity Sterility Softening range Colour In vitro release ratesReconstitution times pH Particlulate Matter Disintegration Clarity Leakage

Viscosity Extractable volume Dissolution Particlulate Matter Adhesive forceConsistency pHParticle size distribution Sterility

EndotoxinsWater contentReconstituition time

Reference:Stability testing of active pharmaceutical ingredients and finished pharmaceutical products: Annex 2 WHO Technical report NO 953, 2009

Pfizer4444th th International SFSTP ConferenceInternational SFSTP Conference

June 6June 6--7 20127 2012

An Example Product SRA

Pfizer4444th th International SFSTP ConferenceInternational SFSTP Conference

June 6June 6--7 20127 2012

Application/ Success of SRA and Lean Approaches

SRA and product understanding built built into CTD has given us regulatory relief in both established and Emerging markets

API for a stable product X (oncology) –, Filed with 6M data, 24M shelf life given.Appearance and Purity were the only tests on both Post approval and annual stability commitment protocols.First checkpoint was 12M, then 24M and 36M, only condition was 25⁰C/60%RH.Successfully achieved in US, EU, Switzerland, Japan, Canada, Korea, Mexico, SingaporeDP- able to remove the test for water and have fewer checkpoints; 30⁰C/75%RH (0, 6 & 12M, 24M & 36M) and 40⁰C/75%RH (0 & 6M). Successfully achieved, except for US

Current Pfizer lean stability strategy, based on SRA and enhanced product understanding (stable products), is for targeted post approval stability commitment proposals

API- Reduced test points (0, 12, 24 & 36M), appearance & impurity testingDP- Reduced test points (0, 12, 24 & 36M), appearance, degradation products and dissolution

“monitor those attributes that change on stability, ideally, only SLLAs”

Pfizer4444th th International SFSTP ConferenceInternational SFSTP Conference

June 6June 6--7 20127 2012

Pfizer Colleagues To Acknowledge

Robert Timpano (Groton, US)

Garry Scrivens (Sandwich, UK)

Stephen Colgan (Groton, US)

Jon Beaman (Sandwich, UK)Roger Weaver (Sandwich, UK)