# Presentation: 906353

## Risk-Based CMC Review 

- Moheb M. Nasr, Ph.D.
-   Office of New Drug Chemistry (ONDC)
-  OPS, CDER, FDA
- DIA Annual Conference 2004
- Washington, D.C.
- June 16, 2004

## Risk-Based CMC Review

- Current Review Practices and Challenges
- Risk-Based CMC Review Initiative – An Update
- Pharmaceutical Quality ?
- New Vision – The Desired State
- A Product Quality System for the 21st Century
- The New Quality Assessment Paradigm
- CMC Supplement Review
- Pilot on Streamlining CMC Review of Resubmitted NDAs and Supplements

##  CMC Review

**To assure the identity, purity, quality, and strength/potency, as related to the safety and efficacy of new drugs throughout their life cycle**** **
**	****IND           ****	****  NDA ****	****	****      ****	****Post Approval**
** **

## ONDC WORKLOAD

- _Completed CMC Reviews in FY 2003_
- 159 NDAs (103 original and 56 resubmitted)
- 	342 Commercial INDs
- 	507 Research INDs
- 	1858  CMC Supplements (820 PAS), not including efficacy and labeling
- 1132 Annual reports

## Current CMC Review Practices

- Highest Quality Review conducted by competent and dedicated staff
- Evaluation of “ALL” CMC information in submitted applications
- Adherence to FDA and ICH guidances
- Tight/appropriate specification to assure consistency of manufacturing processes
- Attempts made to provide regulatory relief to industry resulting, at times, in an increased workload of ONDC reviewers
- Late and voluminous CMC submissions often leading to delayed CMC review
- Regulatory decisions made based on submitted data and individuals’ experience with products and processes
- Absence of critical information on pharmaceutical development prevents full utilization of risk-based assessment in CMC review

## Challenges

- Product Quality System for the 21st Century – A new Paradigm for the regulation of Pharmaceutical Quality
- First Cycle Approval
- Work Load
- Consistency among 19 Chemistry Teams across CDER 15 clinical divisions
- Guidance and policy development
- Lack of expertise in some critical CMC areas
- Novel dosage forms and combination drug products
- New technologies

## Risk-Based CMC Initiative – An Update

- Intended to provide regulatory relief by incorporating science-based risk assessment to CMC review
- Risk-Based CMC Initiative:
- Evolved over the last few years
- Multi-Tiered (establish attributes, propose and finalize a drug list before determining eligibility for regulatory relief)
- Product Specific
- Synthetic Drug Substances only
- Characterization achieved by traditional analytical techniques
- IR oral solids, oral solutions, non-sterile topical solutions and sterile solutions of simple salts
- Relevance in the new pharmaceutical quality paradigm?
- A Progressive and Expanded Approach will focus on quality assessment in entirety and associated regulatory processes

## Pharmaceutical Quality

**Quality:  A product that meets customer’s needs**
**Old Paradigm **
- Establishment and enforcement of public/private standards to assure the integrity of interstate commerce (adulteration, counterfeit, etc.)
- Relevance to safety and efficacy?
**New Paradigm (JW, September 17, 2003)**
- FDA *stands in for the customer to* establish & enforce quality standards generally in the realm of clinical performance (ultimate metric!)

## Pharmaceutical QualityThe New Paradigm (JW)

- Clinical performance = delivery of efficacy and safety as described in the label and derived from the clinical trials
- Fitness for use is a surrogate for clinical performance
- A product that is “fit for use” meets established quality attributes (Purity, Potency/strength, Identity, Bioavailability/delivery, Labeling/packaging, Physical performance, etc.)
- Products must be made in compliance with cGMP

## Pharmaceutical QualityThe New Paradigm (JW)

- Need to examine and evaluate linkages between:
- Quality attributes and clinical performance?
- Values/specifications and safety and effectiveness?
- cGMP compliance/inspection and safety and efficacy?
- Ultimate Goal: _The availability to the patient of high quality safe and effective drugs at reasonable cost_

## The Desired State  

- Product quality and performance are ensured through the design of effective and efficient manufacturing processes
- Product and process specifications are based on a mechanistic understanding of how formulation and process factors affect product quality and performance
- Continuous product and process improvement
- Relevant regulatory policies and procedures are tailored to reflect current level of scientific knowledge and associated risk
- Risk-based regulatory approaches recognize:
- the level of scientific understanding of how formulation and manufacturing process factors affect product quality and performance
- the capability of process control strategies to prevent or mitigate the risk of producing a poor quality product

## A Product Quality System for the 21st Century 

- Initiative focus on product quality and not just cGMP
- Major changes in pharmaceutical business over the years:
- Greater dependence on medicine in health care
- Advances in pharmaceutical and manufacturing sciences
- Applications of biotechnology
- Globalization of industry
- Minor regulatory adjustments over the years:
- 1978 cGMP Revision
- CDER-ORA agreement in early 90’s
- SUPAC, BACPAC, FDAMA in late 90’s
- Team Biologics

## Problems and Issues in Current System

- For FDA:
- Resource intensive
- Expensive and time-consuming litigation and legal actions
- Dealing with recalls and drug shortages
- For Industry:
- Continuous improvement discouraged
- Regulatory burden, not value added
- Consequences of non-compliance
- For Public:
- High cost of drugs
- Hostility, at times, towards industry and regulators

## A Product Quality System for the 21st Century - Fundamental Principles

- Risk Management (priorities, resource allocation and setting regulatory requirements)
- Science-based regulatory approaches (conduct scientific risk assessment and facilitate technological advances)
- Strong public health focus
- International cooperation
- Assessment and implementation of appropriate quality management systems
- Integrated product quality regulatory practice (review and inspection processes)

## Risk-Based CMC Review

- Benefits of a Risk-Based System*
- Patients
- Increased availability
- Faster approval of new products
- Continue to receive quality products
-  FDA
- More product and process knowledge shared by industry
- More efficient resource allocation for review and inspection
- Increased trust and understanding of industry decision making
- * *FDA/PQRI Workshop, April 2003, Washington, D.C.*

## Risk-Based CMC Review

- Benefits of a Risk-Based System*
- Industry
- More efficient, science-based inspections resulting in increased consistency
- Faster, more consistent reviews
- Potential for reduced regulatory burden
- Manage changes and nonconformance with less FDA oversight
- Focuses resources on critical issues
- Flexibility to focus on what should be done, not what can be done
- Improves communication with FDA
- * *FDA/PQRI Workshop, April 2003, Washington, D.C.*

## Risk-Based CMC Review

- This is not a single initiative to address one dimension of a multi-dimensional, often complex, quality assessment process (not just streamlining or reducing CMC supplements, etc.)
- It is the new paradigm in quality assessment of new drug applications (entire pre and post marketing activities)

##  The New Quality Assessment Paradigm

**Chemistry Review vs. Quality Assessment**
**Chemistry Review**
- Review conducted by chemists
- Focus on chemistry issues (drug substance synthesis, analytical methods and specifications)
- Data review  to generate necessary knowledge to identify CMC issues
- Strict adherence to FDA and ICH guidances
**Quality Assessment**
- Assessment conducted by interdisciplinary scientists (chemists, pharmacists, engineers and others as needed)
- Focus on critical quality attributes and their relevance to safety and efficacy (chemistry, formulations, manufacturing processes, dosage forms, product performance, etc.)
- Knowledge Assessment
- Utilization of Risk-based analysis

##  The New Quality Assessment Paradigm

**ONDC Vision:** ONDC is a strong scientific organization that serves CDER, FDA, and the public through leadership in innovation and international collaboration
**ONDC Mission:** ONDC assesses the critical quality attributes and manufacturing processes of new drugs, establishes quality standards to assure safety and efficacy, and facilitates new drug development

## The New Quality Assessment Paradigm

- CMC specifications to be based on:
- Risk-based assessment
- Clinical Relevance
- Safety Considerations
- Process Capabilities
- Knowledge gained from Pharmaceutical Development Reports
- Better utilization of modern statistical methodologies
- Assessment starts with a comprehensive Quality Overall Summary (QOS)
- Review practices based on good scientific principles (“GSP”)
- Increased emphasis on manufacturing science
- Peer/critical review of CMC evaluation by FDA scientists
- Integration of review and inspection (ICH Q 8, 9 & 10 ?)

## The New Quality Assessment Paradigm

- Regulatory relief based on:
- Process understanding and control (pharmaceutical development reports)
- Quality systems throughout manufacturing processes
- Continuous improvement
- Pharmaceutical Development Reports may facilitate:
- Meeting first cycle approval goal
- Science–based specifications
- Risk-based GMP inspection

## The New Quality Assessment Paradigm

- The new ONDC organization will be structured to facilitate the implementation of the new quality assessment paradigm
- The new ONDC organization will provide a better work environment to staff to facilitate superior performance and job satisfaction
- Consideration given to establish an FDA CMC Scientific Advisory Board
- Provide scientific consultation when needed
- Oversee ONDC regulatory research program
- Restructure and modernize ONDC training program
- Develop a seminar series

## The New Quality Assessment Paradigm

- We developed new strategies to recruit, hire and train pharmaceutical quality assessors with expertise in drug discovery, analytical chemistry, pharmaceutical development/formulation and pharmaceutical engineering **(HELP??)**
- We will build a strong and independent scientific organization to better serve the public and all internal (New Drugs, Compliance, Generic Drugs) and external (industry, scientific organizations and academic institutes) stakeholders
- We will reengineer the CMC review process at ONDC to:
- Address problems identified by FDA, Public and Industry
- Meet expectations of the new paradigm and to achieve the desired state
- Establish a modern quality system with appropriate metrics to measure quality of CMC review and performance

## Proposed ICH Q 10“Life Cycle Management Systems”

- Systems for monitoring processes to demonstrate control and/or identify trends
- Systems for managing and rectifying undesirable occurrences
- Systems to facilitate process improvements
- Systems to manage change and to monitor the effect of change

## CMC Supplement Review	

- Facilitate and encourage continuous improvements resulting in down-regulation and elimination of some CMC Supplements
- Comparability Protocols
- Provides an opportunity to bridge current system with future paradigm
- Quality by Design (QbD) Principles
- Continuous Improvements
- Expecting, understanding and managing changes
- Evaluation of impact of proposed changes and developing strategies to address impact
- Critical vs. non-critical changes
- A Great Potential to down-regulate CMC supplements
- Future ONDC Organization to manage CMC supplement review more efficiently to facilitate continuous post-marketing product improvement

## Pilot on Streamlining CMC Review of Resubmitted NDAs and Supplements

- Initial assessment by a senior CMC reviewer
- Complete preliminary assessment within 14 days
- Order referenced DMFs (not a trivial process) Prioritize issues by impact to approvability
- Development of an assessment protocol
- Forward initial assessment and protocol to primary reviewer
- Primary reviewer
- Review, identify, communicate, and resolve CMC approvability issues in a timely manner
- Streamlining resubmission and supplements review to provide adequate resources for new NDAs

## CMC Review of NDAs 

- There is _***no substitute***_ for a quality
- submission, including a Comprehensive
- Quality Overall Summary, which
- anticipates and addresses all approvability issues

## Acknowledgments	

- Janet Woodcock (CDER) and the GMP Steering Committee
- Helen Winkle (OPS)
- Ajaz Hussain (OPS)
- Chi-Wan Chen (ONDC)
- Guirag Poochikian (ONDC)