Performance Based Regulatory Assessment

Leveraging the Depth of Industry Knowledge with the Breadth of

Regulator Knowledge FDA/PQRI Conference

6 October 2015 Bethesda, MD

roger nosal

Vice President & Head of Global CMC

Disclaimer

The views & opinions expressed are those of the individual presenter. The content is the intellectual property of the

individual presenter & protected under the copyright laws of the United States of America and other countries.

Used by permission.

All rights reserved.

Pharmaceutical Quality Research Institute & PQRI are registered trademarks.

All other trademarks are the property of respective owners.

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PQRI Workshop Objective

To communicate, exchange & devise a harmonized and value added path

forward towards global quality.

To communicate, exchange and devise a globally harmonized and value added path forward towards

quality through the product lifecycle.

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1. What is the Desired State?

2. What is the Current State?

3. What is the Path to Desired State?

4. What are Barriers & Next Steps?

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Content Performance-Based Regulatory Assessment

Risk Performance Quality Expectations

Risk-Based Regulatory Review

What is the Desired State?

Performance-Based Regulation

“A regulatory approach that focuses on desired, measurable outcomes, rather than prescriptive

processes, techniques, or procedures.

Performance-based regulation leads to defined results without specific direction regarding how

those results are obtained…..

Performance-based regulatory actions focus on identifying performance measures that ensure an adequate safety margin and offer incentives for

companies to improve safety without formal regulatory intervention by the agency.”

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Translating Risk into Performance

RISK PERFORMANCE • Transparency • Uncertainty • Robustness

– Control strategy – QRM

• Consistency • Balance (Benefit:Risk)

• Reliability • Sustainability • Continual Improvement

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Desired State: Quality Expectations

• Patients expect their medicines: – Are safe, efficacious & have correct identity – Deliver the performance described on the label – Perform consistently over their shelf-lives – Are made in a manner that ensures quality – Are available when needed

• Industry provides appropriate transparency regarding risk (QRM) such that regulators have confidence a control strategy is appropriately established & maintained through the product lifecycle

FDA & Industry are generally aligned . . .

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What Constitutes Good Risk-based Regulatory Review?

• Increase use of Annual Reports & control w/in PQS

• Integrate regulatory review w/inspection to transparently link the relationship of PQS to Established Conditions

• Delineate level of risk according to product type & product categories, i.e., complex vs. simple dosage forms

• Identify & communicate quality risks relevant to patient safety & efficacy

• Do not penalize firms for transparently sharing risk assessments & additional development data

— Appropriate level of detail in regulatory submissions

• Reduce post approval supplements • Establish unified approach & expectations across industry

globally

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Characterization of Risks

What is the Current State?

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Current State: • FDA concerns:

– Lack of detailed transparency in risk assessments – Absence of coherent & complete description & rationale

of a product control strategy – Uncertainty in lifecycle & Management

• Industry concerns: – Inconsistency in regulatory assessments – Integration between inspections & assessments is clunky

• Overlap of IR queries w/inspection observations • Increased scrutiny of development studies

– Absence of incentives for flexible regulatory approaches for post-approval changes, i.e., w/in PQS

– Inconsistency in assessment of individual CQA controls – Global divergence

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Concerns We’ve Heard About Risk

• Regulators want to understand how & when industry performs risk assessments – What is the level of expertise & process to establish a

product control strategy & manage changes through development & after commercialization?

– How are manufacturing process changes managed? – Are formal risk assessment approaches used to

evaluate changes? – Are changes systematically managed under a QRM

paradigm & robust change management system? – Who participates in risk assessment exercises? – How is knowledge/experience captured & transferred?

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Risk

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• Companies perform risk assessments to: – Understand the product quality attributes – Establish appropriate control strategies – Establish a baseline for subsequent process improvements

• Evaluate impact of process trending & adjustments • Evaluate process optimization proposals

– Distinguish risk & characterize uncertainty – Determine & confirm predictability

• Regulators evaluate risk assessments – To ensure appropriate control strategy is established – To ensure robustness of RA approach – NOT to repeat risk assessments

Value of Risk Assessments Component Sub-component Response Observed or Predicted Score

0 - <20% 120-40% change to activity 5>40 - 100% change to activity 100 to < 20% 120 – 50% 5> 50% change 10None detected 1Potential for immunogenicity based on literature and other product knowledge 5

Detected and limits therapeutic efficacy or safety 10

No known adverse events 1Reversible adverse event 5Irreversible adverse events 10Impact of specific isoform established in clinical study 1

In-vivo non-clinical 3in-vitro data 5Platform data, Relevant Literature 7No information 10

Uncertainty Prior Knowledge

CQA Scoring (RPN #)Severity (highest) x Uncertainty = RPN [≤ 5, non-CQA]; [> 5, CQA]

Severity

Biological activity (CB ELISA)

Pharmacokinetics

Immunogenicity

Safety

Can Risk Assessments be validated?

Do Risk Assessments adequately

predict whether a control reliably mitigates a risk?

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Leveraging Knowledge & Experience Emphasis on Control Strategy

What is the Path to Desired State?

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Opportunity for Alignment?

• Leverage Industry/Regulator Knowledge Interface: – Evaluate the combination of registration content & the

Pharmaceutical Quality System • Is Quality Risk Management robust? • Does the product control strategy assure quality, safety,

efficacy & supply reliability? • Will & management provide assurance of requisite quality

through the product lifecycle?

• Performance-based regulatory assessment should: – Focus on relevant risks – Appropriately address uncertainty – Ensure Established Conditions are scientifically

justified, not arbitrarily contrived

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Regulatory Authorities

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Indu

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Regulatory Authorities possesses a breadth of knowledge. Pharmaceutical Industry possesses a depth of knowledge.

Leveraging Knowledge & Experience

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Control Strategy by Design • Start with the Patient Understand patient needs – TARGET PRODUCT PROFILE Understand the process – Does it deliver what the patient needs? What needs to be controlled to assure quality for the patient?

• Develop analytical method(s) to monitor quality risks • Assess materials & process risks to quality Understand criteria (CQAs) needed to assure product quality Process understanding (Not all ‘critical parameters’ carry equal risk) Differentiate CPP/change management based on residual risk

• Determine which risks to quality require a test How does process deal with risks to quality – ENHANCED knowledge?

• Determine where optimal control is positioned Control on inputs, parameters, IPCs, outputs OR a mix

• Establish specification for all critical controls Test method + acceptance criterion OR Rationale for how CQA is controlled w/o testing

• Can Control Strategy provide a measure of product performance? 18

Risk-Based Regulatory Review of Control Strategy

• A robust control strategy in conjunction w/robust & management will demonstrate quality through the product lifecycle. Evaluate control strategy relative to the quality of the risk

assessments used to establish it.

Review & assess & management processes & systems at inspection.

Focus on functional relationships that are relevant to product CQAs.

Reduce &/or eliminate focus on unnecessary low risk issues.

Assess control strategy relative to consistency, supply reliability & sustainability through the product lifecycle.

Control Strategy Performance

Quality Assurance & Risk Mitigation =?

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Functional Relationship of Product CQAs to CPPs

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Barriers What is Lost w/o Risk-Based Regulatory Review?

Next Steps

What are Barriers & Next Steps?

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Barriers to Risk-Based Regulatory Review

• Lack of transparency Omission of risks in regulatory submissions Regulatory expectations & queries

• Discontinuity in & management thru lifecycle • Unaccommodating submission format: How to effectively present risk assessments & QRM

approach? How to holistically convey product control strategy? How can industry align content with IQA template? QOS?

• Increasing global regulatory divergence 22

What is Lost w/o Risk-Based Regulatory Review?

• Opportunities to . . . Improve confidence in quality Expedite regulatory reviews & approvals Reduce post approval change submissions Reconcile risk with performance Embrace continual improvement Increase mutual trust Align global regulatory expectations Enhance efficiency

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Next Steps • Joint industry & regulator QRM workshop • Pilot alternative regulatory submission

options Repurpose CTD-QOS Emphasize product control strategy as a

reflection of quality performance Reconcile integrated submission & inspection

criteria

• Collaborate on ICH development & expansion ICH Q12 Mutual Recognition & transparency

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Acknowledgements

• Mary Oates

• Ron Ogilvie

• Lynne Krummen

• Ann Subashi

• PhRMA LDKIT - RbRR

• Sarah Pope Miksinski

• John Lepore

• Moheb Nasr

• Graham Cook

• Jean-Louis Robert

• Christine Moore

• Øyvind Holte

• G. K. Raju

• Mark Rosolowsky

• Diane Zezza

• Jeff Baker

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