PROCESS VALIDATION FOR ACCELERATED / … VALIDATION FOR ACCELERATED / BREAKTHROUGH PROGRAMS Bob...

ISPE Process Validation Conference12 – 14 September 2017

Bethesda, MD

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PROCESS VALIDATION FOR ACCELERATED / BREAKTHROUGH PROGRAMSBob IeversDirector, Global Technical Operations Sterile & Validation Center of Excellence

2017 Process Validation Conference

Connecting Pharmaceutical Knowledge ispe.org

Outline

• Terminology Overview• “Standard” Process Validation Lifecycle Approach• Considerations for Accelerated/Breakthrough Programs• Case Study• Lessons Learned• Q&A


Bethesda, MD

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Fast Track - Eligible for some or all of the following:• More frequent meetings with agency to discuss the drug's development plan and ensure collection of appropriate data

needed to support drug approval• More frequent written communication from FDA (e.g., design of proposed clinical trials and use of biomarkers)• Eligibility for Accelerated Approval and Priority Review, if relevant criteria are met• Rolling Review (can submit completed sections of its Biologic License Application (BLA) or New Drug Application (NDA)

for review, rather than waiting until every section of the NDA is completed before the entire application can be reviewed).

Breakthrough Therapy - Eligible for the following:• All Fast Track designation features• Intensive guidance on an efficient drug development program, beginning as early as Phase 1• Organizational commitment involving senior managers

Priority Review - Signifies goal to take action on an application within 6 months (compared to 10 months under standard review).

Accelerated Approval - allows drugs for serious conditions that fill an unmet medical need to be approved based on a surrogate endpoint (i.e., a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit.)

Note: Analogous accelerated patient access processes exist (e.g., EMA: Conditional Marketing Authorisation, Accelerated Assessment)

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Terminology Overview (ref: https://www.fda.gov/forpatients/approvals/fast/default.htm)


There is an inherent pride within product development teams; common for teams to believe their product is important to patient well-being and may be considered in their eyes as a “breakthrough” (this is a good thing!)

However… there is an important distinction between a “novel” medicine and a “breakthrough”

One should not take liberties with a process validation approach with a “one size fits all” mentality!

• Real World Example: Future non-breakthrough therapy programs: “…but program ‘X’ did this for their process validation approach! Why can’t we?”

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Terminology Overview (Cont.)


Bethesda, MD

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“Standard” Process Validation Lifecycle Approach

Stage 1 - Process Design

• Product Profile

• Process Development (e.g. DOE studies)

• Clinical Development

• Risk Assessment

• Define CPPs /CQAs & process boundaries

• Develop Control Strategy

• Tech Transfer (define FMP)

Stage 2 - Process Qualification

• Systems Commissioning /Qualification (I/O/Q)

• Process Performance Qualification (PPQ)

Stage 3 – Continued Process Verification

• Active Process Monitoring

• Determine Process Capability

• Continuous Improvement

– Might result in cycling back to Process Design

Stage 1Process Design

Stage 2Process

Qualification

Stage 3Continued Process

Verification

Also Input to Other Programs/Products Stages

Continuous Improvement


General Considerations for Accelerated/Breakthrough Programs

What is not different?

• PV Lifecycle approach

• 3 Stages

• Application of Corrective/Preventative Actions to enable Continuous Improvement

• Quality Risk Management (QRM) Principles

Ref: ICH Q9 (Quality Risk Management) (http://www.ich.org)

• Prospective Stage 2 Validation / Statistically Based

• Robust Manufacturing Process / Control Strategy


Bethesda, MD

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General Considerations for Accelerated/Breakthrough Programs

What is different?

• Patient benefit is by definition higher than “typical”

• Therefore, risk tolerance is higher; mitigate these higher risks via application of:

• Consideration for a unique/alternative initial control strategy

• Stage 2b Process Qualification Strategy

• Stage 3a/b approach may be unique

• Obvious speed to market focus to benefit patient health; accelerates “typical” process development/process qualification timelines


Need to better leverage process experience we do have since may have less that “typical” development experience (can include similar processes already developed/commercialized)

Consider alternative testing schemes during process development trials to gain:

• more intra-batch and inter-batch variability than “normal”

• process input variability (e.g., raw material attributes)

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Stage 1 (Process Design)


Stage 2Process

Qualification

Stage 3Continued

Process Verification



Verification


Bethesda, MD

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Consider commercializing via pilot scale with intent to transfer to a more “traditional” commercial scale; some downsides/risks to this approach:

• Facility capacity impacted for other new compounds/formulations

• Filing timelines for longer-term intent

Consider alternate test schemes:

- number of batches justification

- type/level of testing/analysis based on Stage 1 risk assessment (“more”?)

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Stage 2(b) (Process Qualification)


Stage 2Process

Qualification


Verification




Capitalize on use of Stage 3 to confirm process capabilities / identify continuous improvement opportunities.

Consider Stage 2b type testing (intra-batch variability analysis) longer until variability sufficiently established

Adjust CPV Plan as knowledge is gained, confirm/refute previously assessed risks, discover new risks

• Consider conservative selection of variables initially

• Remove low risk variables once experience is gained

• Adjust reporting frequency based on knowledge over time

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Stage 3 (Continued Process Verification [CPV])


Stage 2Process

Qualification


Verification




Bethesda, MD

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CASE STUDYPROCESS VARIABILITY IDENTIFIED DURING STAGE 2 – WHAT TO DO?


Case Study – Process Variability Identified during Stage 2Background

• Non-sterile solid dosage product (tablet)

• Product Attained:

• Breakthrough therapy designation

• Priority Review

• Sufficient annual production volume, therefore did not pursue concurrent validation

• Initial Supply Chain

Drug Substance Facility

Drug Product Intermediate Facility

Drug Product Final Dosage Facility

Site ‘A’ Site ‘B’ Site ‘C’


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Connecting Pharmaceutical Knowledge ispe.org 13

Tablet Dissolution Performance – Market #1

Market #1 Specification: Q=85%, 45 min

Executed statistically based sampling plan during Stage 2; Passed Stage 2, launched product in Market #1


Tablet Dissolution Performance – Market #2

Initial Specification: Q=85%, 45 min

Specification: Q=75%, 30 minBased on Market #2 feedback (process capability centric)


Bethesda, MD

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Change of Plans…Initial Supply Chain

Drug Substance Facility

Drug Product Intermediate Facility

Drug Product Final Dosage Facility

Modified Supply Chain

Site ‘A’ Site ‘B’ Site ‘C’

Site ‘A’

Site ‘B’Site ‘C’

Site ‘BAlt’* Intermediate material characterization analysis

concluded comparable physico-chemical properties

* Executed development batch at site ‘C’ to confirm equivalency


Intermediate “BAlt” Process Qualification

Market #2 Specification: Q=75%, 30 minBased on Market #2 feedback (process capability centric)

Executed N=3 Stage 2 PPQ to qualify Site BAlt

Passed f2 similarity profile testDid not meet Stage 2 statistically based sampling planOne batch failed Release dissolution


Bethesda, MD

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Root Cause Analysis:

Thorough root cause investigation completed; concluded event result of a number of contributing factors:

• An inappropriate dissolution specification at the 30 minute timepoint (process capability based).

• A tablet hardness profile at the upper end of the acceptance range.

• A granule particle size that had a larger coarse granule mode than those seen during development and early commercial batches attributed to equipment mill screen size variability.

• Normal process variability of SDI across the two different manufacturing sites, Site B and BAlt.

Corrective Actions:

• Submit a filing variation proposing to revert back to Market #1 specification (i.e. Q=85% at 45 minutes).

• Revise in-process compression hardness controls to enable average batch hardness results more centred at target.

• Implement a revised mill screen inspection/characterisation process to ensure more repeatable PSD results.

• Replace mill screen

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Intermediate “BAlt” Process Qualification (Cont.)


Case Study – Process Variability Identified during Stage 2

Partnered with agency to agree in concept to revised specification (clinically relevant) post PPQ execution

Executed filing variation for new specification for formal approval

Closed Stage 2 Process Qualification Report for BAlt; met quality criteria for Market #1

Product release Quality controls in place to prevent relaese to market #2 until approval

Market #2 approved

Launched product in Market #2


Bethesda, MD

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Case Study – Process Variability Identified during Stage 2

Capitalize on Stage 3 Continued Process Verification (CPV)

• All batches from both intermediate sources to date:

• met all dissolution release specifications

• batches tested to date for dissolution profile comparison have met the requirements of dissolution profile F2 in comparison to the pivotal clinical batches

• Process Capability Analysis (Ppk)

• Site B: 1.67

• Site BAlt (Post CAPA Implementation): 1.51

• Recommended that the 30 minute dissolution be further monitored in future CPV reports since recognize infancy of BAlt

source (N=10 post CAPA implementation).

• Tablet Hardness Control

Revised tablet hardness control

Spec: 28-35 kP


Lessons Learned

1. Caution with use of process capability based specifications, particularly with breakthrough programs; consider alternative process signal monitoring to enable continuous improvement to the control strategy

2. Still some hesitancy to approach regulatory authorities when unanticipated events/learnings arise

3. Root cause analysis still needed to continuously learn!

4. Capitalize on CPV programs


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Lessons LearnedTrust the Process Validation Lifecycle Process!

Inevitably you will learn something new about a manufacturing process over time. Let this facilitate continuous improvement to reduce variability on a process!

Key is to react appropriately based on “new”/”unexpected” process signals (this may include continue to monitor / no control strategy modification action required so that higher risk variables can be of focus)


Stage 2Process

Qualification


Verification


QUESTIONS?


Bethesda, MD

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BACK-UP


Statistically Based Sampling Plan

PROCESS VALIDATION FOR ACCELERATED / … VALIDATION FOR ACCELERATED / BREAKTHROUGH PROGRAMS Bob...

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