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Susan Rosencrance, Ph.D. Director (Acting), Office of Lifecycle Drug Products Office of Pharmaceutical Quality FDA Center for Drug Evaluation and Research

Evolution of the CMC Review - ANDAs

October 6, 2015

PQRI - 2015

Historical Perspective

Historical Perspective

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1984 – Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman Act)

• Promoted the manufacture of generic drugs – less costly versions of brand drugs with no patent protection

• Established a system of government regulations for generic drugs and authorized the FDA to accept ANDAs

A critical option to ensure all Americans have access to healthcare!

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Cheaper does not mean lower quality!!!

Same Quality Standards

• Active ingredient • Strength • Dosage Form • Route of Administration • Use of Indication • Same Batch Requirements

(identity, strength, purity, quality)

• Bioequivalent • Manufactured under cGMP

regulations

Same CMC (Quality) Review Process

• Chemistry • Manufacturing • Quality Control

Measures/Testing • Labeling • Inspection • Bioequivalence (rather than

animal, clinical, bioavailability studies)

• Pharmaceutical Equivalence (same patient expectation and experience)

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• Generic manufacturers are not required to repeat the costly clinical trials of new drugs and don’t pay advertising, marketing, and promotion costs

• Multiple generic firms are often approved to market a single product, thus creating market competition → lower costs

Past Practices in CMC Review of ANDAs

• In the past, conventional drug product manufacturing had many uncertainties

• To ensure product quality, FDA controlled every aspect through testing

• Quality by Testing (QbT) approach to CMC Review

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QbT Framework Pharmaceutical Quality = Drug Meeting Regulatory

Specifications

Excipient Testing

Drug Substance Testing

Fixed Manufacturing

Controls

In-process Material Testing

End-Product Testing

Limitations to QbT 1. The review was essentially the same for all dosage

forms 2. Little emphasis placed on linking product quality

attributes to clinical performance 3. Many problems related to specifications being too

rigid – Product failing specifications had to be discarded – Clinical performance may have been acceptable, but

no link to the patient had been established

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Limitations to QbT

4. During CMC Review little to no attention was given to how the formulation or manufacturing process was designed

5. Supplements had to be filed for nearly all changes (specification, process parameter, etc.) – Depleted FDA resources – Discouraged manufacturing process improvements,

innovation, and new technologies

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Time for Change Early 2000s – Pharmaceutical quality is redefined

– FDA’s Pharmaceutical Quality for the 21st Century Initiative

– ICH Q8, Q9, & Q10 → Quality by Design (QbD)

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“Pharmaceutical quality is a product that is free of contamination and reproducible, delivering the therapeutic benefit promised on the label to the consumer.”

Product Quality ⇔ Clinical Performance

“Quality cannot be tested into products; quality can only be built into products.”

QbT ⇒ QbD Dr. Janet Woodcock

The Impact of QbD • QbD is a systematic approach to development that begins

with predefined objectives, and emphasizes product and process understanding and process control, based on sound science and quality risk management (ICH Q8(R2))

• Under QbD pharmaceutical quality is assured by understanding and controlling the formulation and manufacturing variables

• Specifications now established based on product knowledge and process understanding; not based on empirical testing of limited batches

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The Impact of QbD

• To implement QbD principles and concepts, Question-based Review (QbR) was developed for the CMC review of ANDAs

• Today it is expected that QbD principles are applied during the development of all generic drug products

• Across the board agreement that QbD enhanced the quality of generic drugs

• Still work to be done to realize maximum benefit

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Additional Drivers for Change

• FDA committed to reducing the backlog of ANDAs and meeting goal dates – 10-month review cycle for 90% ANDAs by GDUFA Year-5 (FY-2017)

• Challenge: More ANDA receipts than expected – GDUFA Year 1 (FY-2013) – 28% more – GDUFA Year 2 (FY-2014) – 50% more

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#1 GDUFA

5-Year Program Implemented on October 1, 2012

Big Question (?) – How to enhance the efficiency and effectiveness of CMC review while ensuring patients receive quality generics.

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Formalized a Risk Management Approach - Spring 2014

• Designed specifically for the CMC review process • Risk ranking of the drug product CQAs using a

quantitative scoring algorithm; prospectively flags risk and provides a starting point for the review

• Focuses reviewers and helps allocate resources based on product risk and patient impact

• Ensures high risk areas receive appropriate scrutiny; streamlines the review of lower risk areas

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Formalized a ‘Block Review’ Approach - Summer/Fall 2014

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•Employed when multiple ANDAs reference a single RLD

•Triggered by 3 of more ANDAs • Focuses expertise, accelerating

the review process •Eliminates the need to ‘relearn’ •Promotes consistent and

improved decision making

Block Review

Grouping CMC review assignments to a single

team of reviewers

Implemented Real-Time Communication Fall 2014/Spring 2015 • Found historical communication practice to be inherently

inefficient and ineffective as it promoted review cycles (see graph)

• Recognized the need for real-time communication with industry to achieve timely ANDA approvals of ‘quality’ generics

• Maximized the use of Information Requests and T-cons while working with OGD to meet Target Action Dates (TADs)

• Driving the CMC review process towards a more efficient 1-cycle review system.

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Data from Complete Response Letters in FY-2013 and FY-2014 – Approx. 70% Information Requests

Prepared by Geoffrey Wu

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Historical Data on Cycles to ANDA Approval (AP or TA)

Prepared by Yuexia Li

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The 6-Month Impact of Real-Time Communication

Prepared by Glen Smith

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Current Status of Backlog and GDUFA Year-1 (FY-2013) and Year-2 (FY-2014) ANDAs

Prepared by Yuexia Li

• A single unit in CDER dedicated to drug product quality (new drugs, generic drugs, OTC drugs)

• Strategically organized to align review, inspection, and research functional areas

• ANDA review is matrixed across OPQ sub-offices, mainly residing in ONDP, OLDP, and OPF

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#2 Reorg

CDER’s Office of Pharmaceutical Quality

(OPQ) January 11, 2015

Reorganization

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Chemistry and Micro

(CMC)

OGD OPQ

OPS

OPQ

Office of Process and Facilities

Office of Surveillance

Office of Testing and Research

Office of Program and Regulatory Operations

Office of Lifecycle Drug Products

Immediate Office

Office of Policy for Pharmaceutical Quality

Office of New Drug Products

Office of Biotech Products

Moving Forward – The Integrated Quality Assessment

• OPQ is organized based on discipline and expertise

to keep pace with the increasing complexity of drug products and manufacturing processes

• Matrixing the ANDA review across OPQ enhances interactions, communication, and consistency

• Ensures the same quality standards are applied fairly and consistently to both brand and generic products imparting parity in the regulatory oversight

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The Integrated Quality Assessment

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The Integrated Quality Assessment • Under OPQ a team-based

approach is used to perform the quality assessment of an ANDA based on risk management principles

• Currently the integrated quality assessment approach is being used for ANDAs submitted in GDUFA Year-3 (FY-2015).

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The Integrated Quality Assessment The team consists of: • drug substance experts • drug product experts • process experts • facility experts

(including ORA investigators) • other technical advisors as needed

Application Technical Lead (ATL) - oversees the technical content Business Process Manager (BPM) - manages the process

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The Integrated Quality Assessment (IQA)

The team produces a single collaborative integrated quality assessment (IQA) that provides a recommendation on ANDA approvability to OGD

• Integrating quality review with inspection means:

Informed Decision Making

Benefits of the New Paradigm

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Facility Acceptability

Application Approvability

Benefits of the New Paradigm

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• Knowledge sharing and a comprehensive lifecycle approach to quality is emphasized – OPQ organization – Matrixing of review across sub-offices – Integrated Quality Assessment

• Knowledge about quality issues gained from review of the brand product can be appropriately applied to the review of the generic product

Drug Product Lifecycle Phases (Brand and Generic)

ONDP • Phase 1 - INDNDAsNDA • Knowledge base of quality

issues and potential risks established

OLDP • Phase 2 - sNDA • Knowledge base accumulated during NDA

post-marketing and lifecycle monitoring phase

OLDP • Phase 3 – ANDA • NDA knowledge base guides ANDA

pre-marketing quality assessment

OLDP • Phase 4 – sANDA • Knowledge base accumulates

during ANDA post-marketing and lifecycle monitoring phase

Transition Period: 1 or 3 years

Conclusion

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Quality by Testing (QbT)

Quality by Design (QbD)

-Risk-based Review

-Block Review -Real-Time

Comm.

‘If we aren’t moving forward, we’re falling behind’

- Ronald Volpe -

Integrated Quality

Assessment (IQA)

The CMC Review Continuum

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– The Agency is committed to adapting and changing its organizational structure and processes to best respond to ongoing challenges

• Increasing drug product complexity •New user fee requirements (GDUFA) • Increasing globalization of facilities •Drug Shortages •Drug Recalls

The Goal is Drug Product Quality

Thank You!

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