Dr. Earl Dye CMC/GMP Considerations for Expedited Development Programs

Earl Dye is Director of Technical Regulatory Policy in Genentech’s

Washington, DC Regulatory Affairs Office, and is the FDA Liaison for a

Roche Global Technical Regulatory Policy Group. He has been at Genentech

for ten years and is responsible for evaluating proposed biotechnology/biologic

CMC regulations, guidelines, policies and practices of US FDA and other federal

government agencies. Prior to joining Genentech Dr. Dye was the Director of the

Division of Application Review and Policy in CDER’s ODE 6, and was responsible

for managing the review of BLA’s, supplements, and IND’s for therapeutic biologic

proteins. He joined the FDA in 1992, and became a regulatory expert for

therapeutic biologics, participated in foreign and domestic inspections of

licensed manufacturers, and was actively involved in developing policy for

review of therapeutic proteins. Dr. Dye graduated from Ohio State University

with a PhD in Medical Microbiology in 1978, and was a staff scientist at the

Trudeau Institute where he directed a laboratory investigating cellular

mechanisms of antitumor resistance.

CMC/GMP Considerations for Expedited

Development Programs

Earl S. Dye, PhD

2015 AAPS Annual Meeting

October 27, 2015

Outline

• Expedited Development Programs

– US FDA

– Other Countries

– Changes in Clinical Development Paradigms

• Compressed Clinical Timelines will put CMC/GMP Issues on Critical Path

– CMC/GMP Strategy for Breakthrough Therapy Programs

• CMC/GMP Considerations for Developing Breakthrough Products

• Balancing Risk of Less CMC Data at Time of Filing vs Patient Benefit

• Summary and Conclusion

Expedited Programs for Serious Conditions

US FDA

• FDA final guidance issued in March

2014 defines each program,

requirements, and benefits

– Accelerated Approval

– Fast Track

– Priority Review

– Breakthrough Therapy

Accelerated Approval Fast-track Designation Priority Review

When Appropriate

Drugs with the potential to fill an unmet need for serious or life-threatening diseases, and whose activity can be assessed using a qualified surrogate endpoint

Drugs intended to fill an unmet need for serious diseases

Drugs with potential to provide major advance over existing therapies

How it Helps Makes potentially useful new agents rapidly available to patients

Enables more efficient development through frequent communication between FDA and sponsor

Shortens FDA review time by 4 months

Limitations Requires additional randomization of patients in confirmatory trials

Does not condense or abbreviate clinical development

Does not condense or abbreviate clinical development

FDA’s Expedited Pathways

Breakthrough Therapy Program in US

• Advancing Breakthrough Therapies for Patients Act, 2012: Specifies that a new drug

may be designated as a Breakthrough Therapy if it is intended to treat a serious or life-

threatening disease, and preliminary clinical evidence suggests that it provides a

substantial improvement over existing therapies

• As of Oct 2015, FDA has rendered decisions on 337 BTDRs since the programs

inception, granting 104 requests mostly through CDER

– CDER received 282 requests and granted 89 (31%)

– CBER received 55 requests and granted 15 (27%)

• 16 BT designated projects have been approved with an average of 5.7 months from

submission of the BLA/NDA

• This year 4 Breakthrough Therapy Designations (BTD) rescinded because they no

longer met criteria of substantial benefit over existing therapies

Medicines Adaptive Pathways to Patients Initiative

(MAPPs) in EU

• EMA and CHMP have been discussing “Progressive License” approach

– Announced a Pilot Phase of “adaptive licensing” in March 2014

– Since renamed “pathways” and referred to as Medicines Adaptive Pathways for

Patients (MAPPs)

• The aim of the pilot phase is to discuss with various stakeholders the earliest possible

point at which patients can be given access to innovative medicines

– Initial approval may be on a small sub-set of population

– Further submission and expansion of populations thereafter

• Gain experience in a “safe harbour” context with regulatory authorities and experts,

health technology assessment bodies, and patient groups in discussion of specific

requirements for the benefit-risk assessment in early authorizations of these medicines

• Several companies have already initiated pilot projects; a recent EMA report indicated

that 58 products have been submitted to the pilot, and 16 accepted

SAKIGAKE Process in Japan

• Principles are broadly similar to US FDA Breakthrough Designation Process

– Speed review of innovative new drugs

• Sakigake products receive priority review with a target of six months from

submission to approval (versus 12 month review for standard products)

• Waiting time for consultations with the regulator before the start of clinical

trials cut from the standard 2 months to one month

• PMDA will assign a consistent “concierge” contact to shepherd Sakigake

products through the regulatory process from consultations to approval

• Rolling submissions allowed to start reviews on available data before full

submission of pivotal clinical results; may result in enhanced requirements for

post-marketing surveillance and lengthened re-examination period

New Approaches to Clinical Development Compress

Timelines by Combining Phases

Registrational FIH POC

Alternative Development Paradigms: 3-5 years

Registrational FIH=POC

POC=Registrational FIH

FIH=POC=Registrational

Standard Drug Development Paradigm: 8-10 years

• Clinical development timelines may be reduced from 7-10 years to 3-5 years necessitating new

approaches to product & process development, commercial readiness, launch and regulatory

filings

– Will need effective interface with clinical to identify potential candidates early

– Resource intensive; will need to be selective

– Requires collaborative cross functional approach between development, commercial and

regulatory operations

• Does not mean you can do less, will need to start some activities sooner

– Focus on reliable supply of quality product at launch, not process optimization

– Front-load critical product and process characterization activities earlier

• Develop manufacturing readiness plan to address timeline for development of the manufacturing

capabilities with goals aligned to clinical development program

• Perform risk assessment regarding availability of less CMC information at the time of filing and

product launch versus patient benefit; discuss mitigation approaches with Health Authorities

– Ensure adequate supply of safe and effective product at time of launch

Expedited Clinical Development Programs will put

CMC/GMP Issues on Critical Path

Modeling CMC Development Timelines for

Breakthrough Products

• Cross functional technical team modeled accelerated timelines for large and small

molecule products based on traditional phase dependent CMC/GMP activities

• Assumed 5 year clinical development program from initiation of phase l to launch

based on:

– Breakthrough designation granted after phase l studies, with pivotal study becoming

expanded phase lb or ll

– 1-2 years for sufficient preliminary clinical data to qualify for breakthrough therapy

designation

– 2-3 years to complete the pivotal study, file an application and launch the product

• Under this scenario some phase lll activities will be on critical path and need to be

accelerated; sufficient time to complete PC/PV activities available unless phase lll

timelines reduced

• Each breakthrough development programs will vary depending on: complexity of the

product; timing of designation; how soon accelerated CMC development activities

begin; availability of platform technology and relevant prior knowledge

Perspective on Breakthrough Process

Chemistry, Manufacturing and Control--Typical

Define

TPP

pCQAs

Stability studies

Product & Process

Monitoring

0 1 2 3 4 5 6 Clinical Timeline

Cell Line

Selection Commercial Site

Non-

Clinical Phase 1 R&D

Process Characterization

& Validation

Phase 2

Clinical Studies Clinical Studies

Product Release w

Validated Methods

Commercial Method

Transfer & Validation

Product Release w

Qualified Methods

Commercial Method

Transfer & Validation

Product Release w

Qualified Methods

Product Release w

Validated Methods

Clinical Site Cell Line

Selection Commercial Site

Non-clinical Studies Non-clinical Studies

Establish Analytical

Profile & Methods

Establish Analytical Profile & Methods

BTD

CMC on Critical Path to BTD Launch

DS/DP

Qual

Lots

Clinical Site Commercial Site Cell Line

Selection

DS/DP

Qual

Lots

Compress CMC Ph 3 Activities

Life Cycle

Management Phase 3

File

Approve

Interim

Data

Life Cycle

Management

File

Approve

Breakthrough Therapy

CMC/GMP Considerations for Developing

Breakthrough Products

General Manufacturing Considerations

• Leverage prior knowledge, platform data, and use of comparability protocols

• Prioritize development efforts on process reliability over yield and cost of

goods. Optimize process and formulation post-approval, if no impact on

patient safety or product availability

• Ensure fit of candidate molecules into manufacturer’s platform for DS and DP

and related processes to improve speed and robustness

• Front load activities to address non-platform behavior and / or unusual

product and process characteristics

• Assess CQAs earlier and front load method validation for them

• Identify launch sites for drug substance (DS) and drug product (DP) early

Process and Formulation Development

Considerations

• In general:

– Phase lll and commercial process and formulation optimization could be truncated due to

accelerated clinical development timelines.

– Prioritize development efforts on process reliability over yield and cost of goods.

– Optimize process and formulation post-approval, if no impact on patient safety or product

availability

– Consider straight through processing and scheduling of intermediates to avoid need for

intermediate hold time studies

• Biologic drugs focus on:

– Cell line lock at Phase I

– Launch with Phase I/II formulation and optimize post-approval

• Small molecule drugs focus on:

– API and excipient attributes impacting formulation and DP manufacturability

– DP process impacting PK and patient safety

– If possible, lock clinical formulation to avoid BE studies prior to launch

Process Validation Considerations

• Likely to have limited manufacturing experience at commercial scale

• Leverage process and product platform knowledge (e.g., for monoclonal antibodies)

with appropriate justification to speed development

• Consider whether clinical DS could be used to validate commercial DP process

• Consider life-cycle validation principles, “continued verification”

– Use development experience/smaller scale batches in PPQ strategy

– Some PC/PV studies could be deferred, such as linkage studies

• Consider concurrent validation approach to allow for product distribution concurrent

with release of each conformance batch (batch specific release option).

– Dependent on ability to demonstrate manufacturing consistency of clinical process material

– Provide validation protocol and at least one executed batch record at time of filing

– Robust Quality Systems able to identify deviations and correct

• PC/PV studies impacting patient safety must be complete prior to filing

Analytical Development Considerations

• Analytical method development

– Partial or complete front-loading of analytical understanding to balance more

limited process robustness and support future comparability exercises

– Focus on high priority assays early, such as potency for biologics; and content,

impurities and dissolution for small molecules to ensure suitability for control

system

– Involve commercial QC in assay design during development and co-validate if

possible

– Use partially validated methods for internal release and stability testing of

qualification lots and complete validation before commercial release

• This approach presents a business risk if problems arise in validating a

method and should be accompanied with a backup plan requiring retesting

lots and or implementing alternative methods.

– Launch from clinical site and transfer to commercial site post-launch

Control Strategy Considerations

• Control strategy based on limited manufacturing experience but ensuring patient

safety and efficacy.

• Launch with provisional control system that ensures consistent product, and upgrade

the control system post-approval after more manufacturing experience and completion

of process validation, i.e.,

– Filing with an expanded monitoring program with more tests initially, more assay controls,

and justify elimination of some tests post-approval as more knowledge is accumulated

– Filing with broader IPC and product specification acceptance criteria at launch and re-

evaluating post-approval for specifications that are linked to process consistency

– Filing with preliminary CPPs and CQAs

• Utilize enhanced modeling techniques where possible to support conclusions

• Manage second generation processes through a life-cycle approach in post-approval

lifecycle management plan

Manufacturing Scale and Launch Site

Considerations

• In general:

– Determine as soon as possible launch sites for DS and DP (clinical vs commercial)

– Clinical manufacturing facilities used for launch would need to meet the same quality

expectations as commercial manufacturing facilities.

• Key differences for consideration are:

– Cleaning verification versus cleaning validation

– Multi-product manufacturing, including investigational compounds with limited

safety data

– Use of dedicated product contact equipment and or use of disposables to assist in cleaning

validation issues

– If using a contract manufacturing organization (CMO) for DS/DP need to ensure that they

have the capacity for rapid scale up to support commercial volumes

• For Biologic drugs:

– Pivotal clinical studies could be performed with material from different scale and/or site than

is intended for long term commercial production (e.g., Phase II study becomes pivotal)

– Scale-up Phase lll clinical lots to commercial scale for launch with bridging comparability

study

Stability Data Considerations

• Accelerated development timelines will limit availability of real time stability

data

• Launch with reduced real time stability for commercial material

– Leverage stability from early development and clinical batches when

formulation remains unchanged and product comparability demonstrated

– Use forced degradation and stress studies to provide additional

supporting and comparability data

– Provide stability protocol for commercial material

– Gain Health Authority concurrence and commit to provide more real time

confirmatory data during review and post-approval

Ensure PQS Alignment with Acceleration and

Deferral of CMC Activities

• PQS must provide flexibility to accommodate accelerated activities for BT product

development and potential need to defer certain activities as documented in a

manufacturing readiness plan

• The accelerated development PQS strategy for each product will be dependent on

timing of BT designation, and available product and platform knowledge for the

product

– Only PQS activities with no impact to patient safety or product supply can be deferred.

– A quality risk assessment must be applied to all activities that will be deferred, and the

rationale, and controls needed to ensure deferred activities are completed documented

– All deferred activities must be addressed in comparability/bridging protocols and

incorporated in a post approval lifecycle management (PALM) plan

• The manufacturing readiness plan can be used for developing internal filing and

inspection readiness checklists to ensure all deferred activities are completed or

addressed in a PALM; and serve as roadmap for discussions with FDA

Breakthrough Therapy

Balancing Risk of Less CMC data at Time of

Filing vs Patient Benefit

Addressing Technical Risks vs Patient Benefit

(1/2)

• In spite of front-loading certain critical product and process characterization

activities it may not be possible to complete all CMC/GMP activities at the

time of filing and launch of a breakthrough product.

• Manufacturers should develop a manufacturing readiness plan which aligns

the timeline for completing the manufacturing activities with those of the

clinical development program. Plan should address:

– All manufacturing sites readiness to launch the breakthrough product;

– Status of critical characterization tools;

– Validation approach for process and methods;

– Stability data to support adequate expiration dating for the product;

Addressing Technical Risks vs Benefit to Patients

(2/2)

• Where gaps exist in completing certain activities a risk assessment should be

performed addressing the availability of less CMC information at the time of

filing and product launch versus patient benefit.

• This should be coupled with a risk mitigation plan to address these risks either

prior to launch or through the use of a post approval life-cycle management

plan.

• This manufacturing readiness plan and risk assessment should form the basis

for discussion and agreement with FDA prior to filing the marketing

application.

CMC Activities that May be Incomplete at Launch

Cannot Compromise Patient Safety or Product Supply

• Process validation (fewer than the standard number of full-scale manufacturing runs)

• Process characterization (e.g. long duration elements like resin reuse, validation of

intermediate process hold times, or extending limit of in vitro cell age for lifecycle

management of a biologic product)

• Available real time stability data on commercial product

• Validated transfer to commercial manufacturing site/scale,

• Provisional control system that ensures consistent product with need to upgrade post-

approval

• Reliable process capable of meeting initial product demand with need to optimize

process yield and performance post-approval

• Phase I-II formulation for launch with potential need to optimize post-approval

Risk Mitigation Approach for Less CMC Data

• PMCs & PMRs

• Well designed comparability protocols

• Post-approval lifecycle management plan

– Include as part of the filing to support completion of deferred CMC activities post-

approval

– Provide detailed timelines, deliverables, and types of regulatory filings to

complete activities

• Ensure appropriate flexibility in the Pharmaceutical Quality System to enable

acceleration or deferral of certain manufacturing development activities for

breakthrough drug development

– QC reviewed and approved

– Ensure PAI readiness

FDA Standards for Marketing Approval

• Substantial evidence of effectiveness, safety and product quality

– Expectation for pharmaceutical quality is the same for all drugs

• FDA regulations for orphan drugs allow for flexibility and scientific judgment in applying

approval standards, in terms of

– Kind of data needed, and

– Amount needed for a particular drug to meet the statutory standards

• FDA final guidance on Expedited Programs for Serious Diseases:

– “FDA may exercise some flexibility on the type and extent of manufacturing

information that is expected at the time of submission and approval for certain

components (e.g., stability updates, validation strategies, inspection planning,

manufacturing scale-up).”

• Need open and transparent discussions with FDA on balancing risk of less CMC

information at the time of filing vs patient benefit; and means to mitigate risk

Summary

• Breakthrough Therapies offer significant patient benefits, but the reduced timelines

introduce significant CMC challenges for product development

• Each case will have different risks and constraints so the specific CMC approaches will

vary by product

• Key areas of opportunity include:

– Leveraging prior knowledge and platform data,

– Use of comparability protocols

– Use of initial product supply from a clinical process or site;

– Delaying certain process validation requirements not directly related to patient

safety

• Expect these programs to generate significant post-approval CMC efforts and Phase IV

commitments

• Key to success is open and transparent discussions with FDA

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