applying science-and risk-based stability strategies ......leverage pre-established control...

1Biogen | Confidential and Proprietary

Applying Science- and Risk-Based Stability Strategies Globally:An Industry Case Study1

Donnie Pulliam, MBAManager, Global Regulatory Affairs-CMCBiogen, Research Triangle Park, North Carolina, USA

1Content previously presented at AAPS PharmSci360 conference in Washington, DC, USA on November 4, 2018.


Outline

• Background / Problem Statement

• Case Study: Post-approval commitment success story

• Path Forward


ICH (est. 1990) has facilitated the harmonization of guidelines for global pharmaceutical development and regulationInitially comprised of representatives of regulatory agencies and industry associations of Europe, Japan, and United States; today, includes 10 regulatory agency members and 13 regulatory agency observers.

Guidelines Relevant to Stability Strategies:ICH Guideline Topic(s) Implementation Year

Q1A(R2) Stability Testing of New Drug Substances and Products 2003Q5C Stability Testing of Biotechnological/Biological Products 1995

Q1D Bracketing and Matrixing Designs for Stability Testing 2002

Q1E Evaluation of Stability Data 2003

Also: Q1B, Q1C, Q1F, Q5E, Q6A, Q6B, Q12

Stability Testing, Comparability, Specifications, Life Cycle Mgmt Multiple; visit www.ich.org

Background / Problem Statement


Regulatory guidance on the permissibility of science- and risk- based stability strategies - whether it be investigational, registration or post-approval –indicates receptivity when a technical justification is provided.

Source Statement(s)

ICH Q1A “Reduced designs, i.e., matrixing or bracketing, where the testing frequency is reduced or certain factor combinations are not tested at all, can be applied, if justified.”

“The stability protocol used for studies on commitment batches should be the same as that for the primary batches, unless otherwise scientifically justified.” (applicable to both drug substance and drug product)

ICH Q5C “[R]educed testing may be appropriate … Where data exist that indicate the stability of a product is not compromised, the applicant is encouraged to submit a protocol which supports elimination of specific test intervals (e.g. 9 month testing) for post-approval/post-licensure, long-term studies.”




Current State does not reflect the harmonization the ICH guidelines were intended to enable• Regulatory acceptance of science and risk based (“lean”) stability strategies

varies between agencies.• Regulatory positions “at the podium” are not always aligned with regulatory

feedback/queries received on regulatory filings within the same agency. There appears to be agreement “at the top” – but not with all reviewers.

• Industry spends unnecessary resources initiating and maintaining long term stability protocols that include non-stability indicating tests and low-value timepoints throughout the material’s lifecycle.


IQ Consortium “Lean Stability” Working Group was proposed and endorsed in June 2016 with these goals:

• Align industry on how to pursue lean stability strategies• Drive greater global regulatory consensus• Enable speed to clinic, registration, and post-approval changes through lean

strategies• Gain understanding of complex regulatory landscape • Remove redundant and/or non-stability related testing from stability protocols



Lean Stability Working Group Mission and Composition

• To drive industry use of stability knowledge and understanding to derive stability protocols and reduce routine non-value added stability testing.

• To further drive regulatory acceptance of science- and risk-based protocol strategies.

Company Team MemberPfizer Megan McMahonBaxter Angela CoonEli Lilly Cherokee Hoaglund-HyzerBiogen Donnie PulliamBoehringer-Ingelheim Fenghe QiuPfizer Rob TimpanoNovartis Patrick ForenzoMerck Chait WannereAbbvie Michael Lesslie

Company Team MemberMerck Ping ZhuangSunovion Mingkun FuPfizer Chi-wan ChenRoche Joachim LutzAmgen Jessica TanAmgen Peter ZhouBaxter Cheryl MartinAbbvie Debra Webb

Company Team MemberMerck Brian ReglerEli Lilly Eric Adamec

BaxterKarina Szymulanska-Ramamurthy

Pfizer Rob TimpanoNovartis Patrick ForenzoGenentech Jin WangAstra Zeneca Susan SmithEli Lilly Allison DillEli Lilly Liza Babayan Special thanks also to Jeff Hofer.


Definitions / Terminology

• Science- and risk-based strategies utilize all product knowledge and understanding to develop the right stability plan for a given product.

• This may result in application of a ‘lean’ protocol or an enhanced protocol. It depends on the product, what we know (or don’t know) and what the program data is being used for.

• Note that stability knowledge is gained throughout development (not just during registration stability studies) and through different types of studies … long-term clinical, purposeful degradation studies, short term confirmatory, etc.

• As stability knowledge increases, the potential for reducing stability testing to the most meaningful tests and time points increases.

What is Science and Risk Based

Stability?


Post-Approval Commitment Success Story

• Background

• Registration Stability Data Package

• Reduced Testing Annual Commitments

• Considerations for Pursuing Reduced Post-approval Stability Testing

• Conclusion


Background (Established Guidance)

ICH Q5C prescribes recommended stability study design for biologic/biotech products

from Section 7. Testing Frequency: (emphases added)

• For products with proposed shelf-lives of greater than 1 year, the studies should be conducted every 3 monthsduring the first year of storage, every 6 months during the second year, and annually thereafter. While the testing intervals listed above may be appropriate in the pre-approval or pre-license stage…

• [R]educed testing may be appropriate after approval or licensure where data are available that demonstrateadequate stability. Where data exist that indicate the stability of a product is not compromised, the applicant is encouraged to submit a protocol which supports elimination of specific test intervals (e.g., 9month testing) for post-approval/post-licensure, long-term studies.


Background (Pre-Licensure Understanding)

Drug Substance (DS)• Frozen liquid

• Monitored at: -70±10°C; 5±3°C; 25±2°C/60±5%RH

Drug Product (DP)• Refrigerated liquid, prefilled syringe

• Monitored at: 5±3°C; 25±2°C/60±5%RH

• Multiple strengths (ICH Q1D bracketing approach)

Stability profile• Monitored attributes: 8 for DS, 12 for DP

• Three stability-indicating analytical methods


Registration Stability Data PackageDrug Substance

* no statistically significant trends in monitored attributes

Drug Product

Representative Batches

-70±10°C Available Data

5±3°C Available Data

25±2°C/60±5%RHAvailable Data

5 Up to 60 Mo* 6 Mo* 6 Mo

Strength RepresentativeLots

5±3°C Available Data

25±2°C/60±5%RHAvailable Data

A (Maximum) 3 Up to 36 Mo 6 MoB (Intermediate) 1 18 Mo 6 MoC (Minimum) 3 Up to 36 Mo 6 Mo


It’s all about consistency….Process-validation (PV) batch/lot product quality

• Conformed to specifications at release/through expiry• Comparability to clinical batch quality/characterization

Registration stability studies aligned to Q5C, Q1D

• Batch enrollment, testing frequency, recommended tests

Consistent stability profile across strengths

• ICH Q1E poolability requirement was met in some cases


Reduced Testing Annual Commitment (DS)

Long-term condition only, at annual intervals only• All attributes monitored, as in PV batch studies

Recovery per DS batch enrolled:• QC Workload Savings: 4 time points• Material: reduced stability inventory provides for an

additional 720 DP doses at maximum strength per DS batch enrolled on stability


Reduced Testing Annual Commitment (DP)

Long-term condition: No testing at 3Mo & 9Mo• All attributes monitored, as in PV lot studies

• Enrollment of only one strength per year

Recovery (est.) across all strengths per year• QC Workload Savings: 22 time points• Material: reduced stability inventory provides for an additional 4000 DP doses

across all potential DP lot strengths that otherwise would be enrolled on stability


Considerations for Pursuing ReducedPost-approval Stability Testing

Leverage pre-established control mechanisms • For example, reduction of tests in DS stability monitoring via DP release

testing of same attributes

Leverage understanding of product quality attribute criticality• Those attributes not assessed to be critical or highlighted in Q1A/Q5C should

be considered for reduced testing frequency.


Considerations for Pursuing ReducedPost-approval Stability TestingLeverage understanding of stability profile• Attributes which demonstrate no statistically significant trends or have

consistent stability signature from lot to lot should be considered for reduced testing frequency.

Expect regulatory agency feedback re: requests to further reduce testing frequency for attributes already highlighted in ICH guidancesfor annual monitoring• For example, container closure integrity


Case Study ConclusionReduced post-licensure stability monitoring has been achieved, as suggested by ICH Q5C

A robust registration package is essential• Comparable product characteristics to clinical experience

• Stability data package aligned with Q5C, Q1B, -D, -E

• Consistent release and stability profiles among lots

Significant benefits to industry and to the patients we serve• Reduced QC testing workload

• More inventory allocation to the commercial supply chain


Path Forward

• Publication(s) related to industry survey results and case study experiences in 2019

• Internal industry alignment on phase-appropriate lean stability approaches

• Continued interactions between industry and global regulatory agencies to facilitate more receptivity to appropriate science- and risk-based approaches and to drive harmonization further


Acknowledgments

Biogen: ANVISACathy AndersonNeha FrantzLivia Partika IQ Consortium Lean StabilityMatthew Sampson Working Group MembersAndy SeipelKimberly Wolfram


Thank you!

applying science-and risk-based stability strategies ......leverage pre-established control...

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