Implementationof Quality-by-Design:

ONDQA Initiatives

Advisory Committee for Pharmaceutical Science October 5, 2006

Chi-wan Chen, Ph.D.Deputy Director

Office of New Drug Quality Assessment

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Outline

Implementation of QbD in ONDQA Reorganization Pharmaceutical Quality Assessment

System CMC Pilot Program

Objectives, goal/status, process, criteria, observation to date, benefits/challenges

Public meetings Internal trainings

Next steps

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Reorganization

ONDC was reorganized to Office of New Drug Quality Assessment (ONDQA) in November 2005

Objective: To implement PQAS Separation of pre-marketing (INDs/NDAs) from

post-marketing (supplements/annual reports) review activities to better utilize limited resources

Establishment of Manufacturing Science Branch and recruitment of pharmaceutical scientists, chemical engineers, and industrial pharmacists to complement current review staff

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Reorganization (cont’d)

Pharmaceutical Assessment Lead (PAL) in Pre-Marketing Division

Serves as liaison to clinical division Performs an Initial Quality Assessment (IQA), a “big-picture”

assessment protocol focusing on critical CMC issues, and a timeline for completing the review

PAL in Post-Marketing Division Performs a risk assessment to determine the extent of

review needed Where in-depth review is needed, performs an IQA focusing

on critical CMC issues

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Pharmaceutical Quality Assessment System

PQAS is ONDQA’s new science- and risk-based approach to CMC review that Emphasizes submissions rich in scientific

information demonstrating product knowledge and process understanding

Focuses on critical pharmaceutical quality attributes and their relevance to safety and effectiveness

Enables FDA to provide regulatory flexibility for specification setting and post-approval changes

Facilitates innovation and continuous improvement throughout product lifecycle

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CMC Pilot Program - Objectives

To provide participating firms an opportunity to submit CMC information demonstrating

application of quality-by-design (QbD) principles product knowledge and process understanding

To enable FDA to evaluate CQOS; new concepts and approaches (e.g., QbD,

design space, real-time release) in Q8, Q9, Q10, and PAT Guidance; CMC Agreement; team review

To enable FDA to seek public input in developing a guidance on the new PQAS

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CMC Pilot – Timeline/Goal/Status

Program timeline FR Notice re CMC Pilot: July 14, 2005 Deadline to request for participation: March 31, 2006 Deadline to submit NDA or supplement: March 31, 2007

Goal: 12 original NDAs and supplements Status

11 original and supplemental NDAs accepted 4 submitted to date One approved; 3 under reivew Others are to be submitted within a year

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CMC Pilot - Submission Criteria

An expanded Pharmaceutical Development (P.2) More relevant scientific information

Demonstrating QbD, product knowledge, and process understanding

Identifying critical quality attributes (CQAs) and how they relate to safety and effectiveness

Linking material attributes and process parameters (CPPs) to quality attributes

Identifying possible sources of variability and how associated risks can be mitigated

Describing process controls and quality assurance strategies A comprehensive Quality Overall Summary (CQOS)

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CMC Pilot - Review Process

CMC assessment performed by a team of experienced reviewers with good understanding of the new PQAS, and strong background in pharmaceutical and

manufacturing sciences Process managed and overseen by ONDQA

IO with PM support Integrated review/inspection team Frequent meetings with applicant before

submission, during review, and after approval

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CMC Pilot - Expanded P.2

All pilot NDAs to date provided more scientific information than typical NDAs regarding

Formulation and product development Process understanding and optimization

Most demonstrated process reproducibility, but not necessarily process robustness

The more relevant scientific information is useful in facilitating CMC review and justifying proposed regulatory flexibility

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CMC Pilot - Application of QbD

All pilot NDAs to date contained some elements of QbD: Critical quality attributes (CQAs) Formulation development Risk assessment; design of experiments Impact of DS/excipient attributes on DP manufacturability

and/or CQAs Process development; impact of process parameters on CQAs Design space for critical DS/excipient attributes and CPPs

Other observations: Process reproducibility, but not necessarily process

robustness, demonstrated Process analyzers used to collect data in development, but not

for commercial production

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CMC Pilot - Design Space

Issues raised: How were design space and control space

established for each unit operation? Is the design space for each unit operation

independent of equipment design and batch size? How does control space relate to design space? How does control space relate to operational

ranges in the Master Batch Record?

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CMC Pilot - Regulatory Flexibility

Examples of proposed regulatory flexibility: In-process testing in lieu of end-product testing, e.g.,

blend uniformity in lieu of content uniformity Real-time release in lieu of end-product testing Annual report for post-approval changes within

established design space Degree of flexibility granted would depend on level

of knowledge and understanding demonstrated

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CMC Pilot - Regulatory Agreement(under consideration)

An agreement between FDA and applicant on critical CMC issues which could potentially

Enable applicant to share QbD information without concerns about regulatory implications

Identify CQAs and CPPs, their ranges and interrelationship

Describe design space for excipient attributes and process parameters

Describe control strategy Describe change control protocols for assessing post-

approval changes to CQAs, CPPs, process, equipment, scale, etc., and associated regulatory mechanisms

Describe how design space will be reassessed, verified, or redefined

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CMC Pilot - Benefits

Pilot enables industry and FDA to Explore ways to implement Q8, Q9, PAT, and PQAS

Pilot enables FDA to Better define what constitutes a QbD-based submission Better establish what constitutes a science-based risk

assessment Use experience gained to develop a guidance on QbD

and PQAS Good science leads to better quality product,

fewer product rejects/recalls, and enhanced public health protection

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CMC Pilot - Challenges

Level of detail in submission demonstrating product knowledge and process understanding

Expectations for a QbD-based submission while addressing traditional requirements

Providing regulatory flexibility while assuring product quality

Industry’s continuous apprehension in sharing information, including failed experiments, with FDA

Cultural changes needed in industry and FDA More resources needed initially for industry & FDA

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CMC Pilot - Summary

Pilot Program got off to a good start in meeting its initial goal for industry participation

Aspects of QbD were included in Pilot NDAs, and expanded PD is useful

CQOS needs further development Scientific approaches to CQAs, CPPs, & design

space need further development Regulatory flexibility is being proposed CMC Regulatory Agreement is being explored Program benefits FDA in developing guidance

to implement QbD and PQAS Challenges remain for industry and FDA

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Public Meetings

CMC Workshop, October 2005 ACPS, October 2005 CMC-GMP Track, DIA Meeting, June 2006 PDA-FDA Meeting, September 2006 ACPS, October 2006 AAPS Meeting, October 2006 ISPE/PDA Q8/Q9 Workshop, December 2006 FDA Quality Initiatives Workshop, February 2007

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Internal Trainings

Hands-on training through team review NDA Peer Review Forum twice a month ONDQA Focus Groups

Biotech; Dissolution; Drug Eluting Devices; Excipients; Fermentation Products; Inhalation Products; Manufacturing Science; Oral Dosage Form Formulation; Quality by Design; Topical Products; Transdermal Delivery System

ONDQA Science Forum once a year ONDQA Seminar Series by outside experts Other subject matter trainings on an ad hoc basis

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Next Steps

Sharing of lessons learned with each applicant under CMC Pilot Program

Sharing of lessons learned from CMC Pilot Program within FDA and with industry

Evaluate need for new guidances on PQAS QbD CQOS CMC Regulatory Agreement