# Presentation: 276680

## Question-based Review for Generic Drugs: An Enhanced Quality Assessment System

*GPhA* Technical Committee Meeting,  June 29, 2005

*Lawrence X. Yu, Ph.D.*
*Director for Science*
*Office of Generic Drugs*

## OGD QBR WG

- Andre Raw			Robert Lionberger
- Radhika Rajagopalan	Lai Ming Lee
- Frank Holcombe 		Rashmikant Patel
- Florence Fang		Vilayat Sayeed
- Paul Schwartz		Richard Adams
- Lawrence Yu (Chair)

- Gary Buehler, Robert West, Rita Hassall
- Brenda Arnwine, Gururaj Bykadi, James Fan, Scott Furness, Dave Gill, Shing Hou Liu, Albert Mueller, Susan Rosencrance Bing Wu, Michael Smela, Glen Smith, Ubrani Venkataram, Karen Bernard and Neeru Takiar.

- Acknowledgement

## Content

- What is QBR?
- Why is QBR necessary?
- How is QBR developed?
- What are the benefits of QBR?

## What is QBR?

## Question Based Review

- QBR is a general framework for the science and risk-based assessment of product quality
- QBR contains the important scientific and regulatory review questions
- Evaluate whether a product is of high quality
- Determine the level of risk associated with the manufacture and design of this product.
- QBR integrates scientific information to connect CMC information supplied by the sponsor to the product quality expected by the consumer

## What Does a CMC Reviewer do?

- Evaluates identity, strength, stability, purity, and quality
- Definition of Quality: the drug product is free from contamination and will reproducibly deliver the therapeutic benefit promised in the label to the consumer (Janet Woodcock)
- Determines that the generic drug product
- is appropriately designed (a pharmaceutical equivalent to the brand name product)
- can be reproducibly manufactured

## Questions to Who?

- CMC Reviewer
- Questions are designed for the reviewer to answer in the evaluation of the application
- Industry
- The Quality Overall Summary (QOS) should address the reviewers’ questions and guide them to appropriate locations in the application

## Why is QBR Necessary?

## Receipts of Original ANDAs 

## ANDA Chemistry Supplements

## Issues with Our Current CMC Review System

- Overly conservative
- “Overly conservative specifications that are sometimes irrelevant to clinical performance”
- Inordinate number of CMC supplements
- One size fits all – Risk is not systematically considered
- Too much time on low risk products
- Too little time on high risk products
- CMC risk ≠ medical risk
- Multiple (> 4) cycles on some applications
- High risk products: sponsors did not provide sufficient information when ANDAs were submitted

## cGMP Initiative “Desired State”: Manufacturing 

- Product quality and performance achieved and assured by design of effective and efficient manufacturing processes
- Product specifications based on mechanistic understanding of how formulation and process factors impact product performance
*An ability to effect continuous improvement* and continuous "real time" assurance of quality

## cGMP Initiative “Desired State”: Regulatory

- Regulatory policies and procedures tailored to recognize the level of scientific knowledge supporting product applications, process validation, and process capability
- Risk based regulatory scrutiny that relates to the level of scientific understanding of how formulation and manufacturing process factors affect product quality and performance and the capability of process control strategies to prevent or mitigate risk of producing a poor quality product

## From a “Reactive” to a “Proactive” Decision System for Pharmaceutical Quality

- Reactive (examples)
- Testing to document quality
- Repeating deviation and out of specification investigations
*Prior Approval Supplement* for process optimization and continuous improvement efforts
- Multiple CMC review cycles
- Procrustean approach for demonstrating therapeutic equivalence of generic products

- Proactive (examples)
- Quality by design and “real time release”
- Right First Time
- Process optimization and continuous improvement efforts within a facilities quality system
- Single CMC review cycle and risk-based specifications
- QbD approaches for demonstrating therapeutic equivalence of generic products

**This is a journey and not a destination!**

- Ajaz Hussain

## How is QBR Developed? 

## QBR Principles

- Quality built in by design, development, and manufacture and confirmed by testing
- Risk-based approach to maximize economy of time, effort, and resources
- Preserve the best practices of current review system and organization
- Best available science and wide consultation to ensure high quality questions

## QbD = Capable + In Control 

- A systematic process of defining optimal design specifications of a product, its manufacturing process and its quality control and assurance methods
- High degree of process understanding
- High confidence of low risk of releasing a poor quality product
- High efficiency through continuous learning and improvement

- Ajaz Hussain

## CMC Review: Pharmaceutical Development

- Product Development
- Evaluate quality by design
- Regulatory testing confirms performance of a well designed product
- Process Development
- Provide evidence of sufficient process understanding to successfully scale up production to commercial scale

## Development Report Content

- Appropriate level of development information depends on risk
- Low risk drugs
- The level of review of the manufacturing process and scale up may be lower for products such as solutions and IR solid oral products
- Complex dosage forms
- Encourage critical thinking
- A mechanistic understanding how formulation and manufacturing process affect pharmaceutical quality,
- Scientifically sound regulatory decisions

## CMC Review: Risk Assessment

- Goal of risk assessment is to allocate scarce reviewer resources to benefit the public
- More emphasis on
-  Critical dose drugs (NTI)
- “Complex” dosage forms/delivery systems
- Release mechanism; parenteral controlled release products; liposomes...
- Less emphasis on
- Solution products
- Solid Oral IR Dosage Forms
- Supplements

## Capture Best Practices

- Incorporate the best practices from the current CMC review
- The QBR will bring together rules, guidelines, experience, and best practices
- Before the QBR is finalized, every reviewer will be given an opportunity to provide detailed comments in their area of expertise.
- The development of questions provides an opportunity to ensure that OGD is asking the right questions in the most efficient manner and to critically analyze current practices

## Meetings with Stakeholders

- February 24, 2005: GPhA Technical Committee meeting
- June 8, 2005: GPhA Technical Steering Committee meeting
- June 29, 2005: GPhA Technical Meeting
- ...

## Question Based CMC Review: SMART Goal

- SMART GOAL – Specific, Measurable, Acceptable, Realistic, and Timetable
- Modern, risk-based pharmaceutical quality assessment
- Appropriate regulatory scrutiny
- Significant reduction of CMC supplements
- Timeline
- 1/2005 – 2/2005: Draft QBR
- 3/2005 – 4/2005: Chem DDs
- 5/2005 – 6/2005: Chem TLs
- 7/2005 – 8/2005: Chem Reviewers
- 9/2005 – 12/2005: Trial Period
- 1/2006 – 12/2007: Gradual Implementation

## What are the benefits of QBR?

## Benefits

- Assure drug product quality
- Enhance review quality
- Reduction in review time
- Reduced post-approval supplements

## Assure Drug Product Quality

- Capable + In Control >> Testing
- Drug X
- Good design of formulation + capable manufacturing + appropriate testing can always ensure a quality product
- Bad design of formulation + capable manufacturing + excessive testing can not always ensure a quality product  product recalls
- Blend Uniformity
- Good design (understanding) + appropriate testing can always ensure uniformity
- Bad design (poor understanding) + excessive testing can not always ensure uniformity  failed batches

***“******FDA regulates product quality. If processes are in control, ***
***then quality is under control” Janet Woodcock***

## Enhance Review Quality

- Standardized method of delivering a comprehensive CMC review
- Derive bioequivalence inferences from pharmaceutical development information and prior knowledge
- Enhance critical thinking of reviewers
- Recognize deficiencies in CMC data set

## Reduction in Review Time

- Quality overall summary (QoS)
- QBR will guide the content of the QoS in future submissions.
- A QOS will eliminate reviewers recopying information such as composition, specification, etc.
- Development Reports
- When sponsors share their pharmaceutical development experience, it promotes a mechanistic understanding and reduces cycles of deficiencies
- Transparency
- The logic by which OGD connects specifications to product quality will be transparent and not arbitrary
- QBR provides clear direction for sponsors to improve the quality of their applications and obtain first cycle approval

## Reduce Supplements

- Draw conclusions about risk that will be useful in evaluating the need for post approval supplements
- By containing a risk assessment section, it will relate regulatory scrutiny to the level of scientific understanding. It is anticipated that this will eliminate/downgrade up to 80% of CMC supplements, and thus free up scarce resources
- Allow sponsors freedom to execute manufacturing processes for which they have demonstrated process understanding
- When a sponsor submits a product development report and demonstrates product and process understanding, the reviewer may be able to classify the product as lower risk, and the sponsor will be allowed reduced supplements in the future, facilitating continuous CMC improvement and innovation.

## OGD QBR: Conclusion

- By directing reviewers to ask the right questions, it enhances critical thinking of reviewers and better enables reviewers to recognize only the “important” deficiencies in CMC information with emphasis on quality by design
- Review will may be shorter for solution and IR products

## OGD QBR: Conclusion (Continued)

- By encouraging sponsors to provide their pharmaceutical development experience, it promotes a mechanistic understanding
- How formulation and manufacturing process factors affect pharmaceutical quality
- By containing a risk assessment section, it will relate regulatory scrutiny to the level of scientific understanding. It is anticipated that this will eliminate/downgrade up to 80% of CMC supplements, and thus free up scarce resources

##              OGD QBR (Draft)The question based review (QBR) serves as a general framework for the CMC assessment of ANDAs that focuses on critical pharmaceutical attributes of product quality.  With justification, deviations or alternate approaches to this framework can be utilize, as necessary, to ensure the adequacy of the assessment of product qualityFor ease of discussion, a simple dosage form is defined as a solution or an immediate release (IR) solid oral dosage form.

## QBR: Drug Substance

- Description and Characterization
- What are the nomenclature, molecular structure, molecular formula, and molecular weight?
- What are the pKa, aqueous solubility (as function of pH), partition coefficient, polymorphism, hygroscopicity, and melting points?
- Control of Drug Substance
- Appearance and Identification
- Are the specifications for appearance and identification appropriate?
- Assay
- Is the proposed drug substance assay limit acceptable?
- Is the analytical method validated and stability-indicating?
- Impurities and Residual Solvents
- Are all the possible impurities accounted for?
- What is the justification for the impurity acceptance limits?
- Are the analytical methods validated and suitable for their intended function?
- Additional Specifications
- Based on the review of the drug product and manufacturing process are specification(s) required on particle size, solid state form, moisture content, or other properties of the drug substance and why?
- For each additional specification: What is the justification for the acceptance limit? Is it suitable for its intended function?

## QBR: Drug Product

- Description and Composition
- What are the components and composition of the final product? What is the function of each excipient?
- Do any excipients exceed IIG limits in the context of maximum daily dose and route of administration?
- If product is an NTI drug or a non-simple dosage form
- Are there significant differences between this formulation and the RLD that present potential concerns with respect to product performance?
- Control of Excipients
- What are the specifications for the inactive ingredients and are they appropriate per their intended function?

- Simple Dosage Form: Either a solution or an IR solid oral dosage form

## QBR: Drug Product (Continued)

- Manufacture
- For all products
- Does the batch formula accurately reflect the drug product composition?  If not, what are the differences and the justifications (e.g. potency adjustment, overage, excess coating solution, etc.)?
- If product is not a solution
- What are the key unit operations in the drug product manufacturing process?
- Are in-process tests identified by the sponsor appropriate?
- What is the difference in size between commercial scale and biobatch and do they use the same unit operations?
- If product is an NTI drug or a non-simple dosage form
- What are the critical steps in the manufacturing process?
- What are the in-process tests/controls that ensure each critical step is successful?
- In the proposed scale up process what operating conditions will be adjusted to ensure the product meets all in-process and final product specifications?
- Why do you believe the sponsor has demonstrated a reasonable plan to scale up the process?

## QBR: Drug Product (Continued)

- Control of Drug Product
- Identity
- Is the specification for the identity of the drug product appropriate?
- Assay and Uniformity
- Are the proposed drug assay limits acceptable?
- Is the assay method validated and stability-indicating?
- How is the content uniformity evaluated? Is it acceptable?
- Impurities/Degradation Products
- Are the degradation products and their origins adequately described?
- What is the justification for the acceptance limits on degradation products?
- Are the analytical methods validated and suitable for their intended function?
- Dissolution
- What are the dissolution methods and acceptance criteria and how were they selected?
- What is the significant role of dissolution testing for this product?
- Additional Specifications
- Are there additional specifications that are required to ensure the product will perform as labeled and why?
- For each additional specification: What is the justification for the acceptance limit? Are the analytical methods validated and suitable for their intended function?

## QBR: Drug Product (Continued)

- Reference Standard
- Are there a qualification report and COA provided for the reference standard or is this material purchased from an appropriate source?
- Container/Closure System
- Has the container/closure system been used in a previously approved product or otherwise qualified for this dosage form?
- What specific container/closure attributes are necessary to ensure product performance?
- Drug Product Stability
- Data
- What stability data has been submitted?  Has the sponsor provided stability data for the drug product packaged in the proposed container/closure?
- Acceptance limits
- Are all attributes that could change over time evaluated in the stability tests?
- What are the acceptable limits on these attributes?
-  Shelf-life recommendation
- What is the justification of shelf life?
- Is the post-approval stability protocol acceptable?

## QBR: Product Development Report

- Drug Substance
- Which properties or physical chemical characteristics of the drug substance affect drug product performance?
- Excipients
- Is there any evidence of incompatibility between the excipients and drug substance?
- Formulation
- What is the formulation intended to do?
- What mechanism does it use to accomplish this?
- Were any other formulation alternatives investigated and how did these perform?
- Were any formulation optimization or sensitivity studies carried out for variations in composition around the final formulation?  Were these studies sufficient to establish a design space for formulation composition?
- Is the formulation design consistent with the dosage form classification in the label?
- Drug Product
- What are the critical quality attributes that ensure the product will perform as labeled?

## QBR: Process Development Report

- Process Description
- Why was this manufacturing process selected for this drug product?
- Were alternative unit operations investigated by process development studies?
- Critical Steps and Scale Up
- How were the critical steps in the process identified?
- What are the critical process parameters for each critical step and how were they identified, monitored and/or controlled?
- Were process development studies that varied starting materials or operating parameters conducted? Were these studies sufficient to establish a design space for process?
- In process tests
*Why is each in process test required?*
*How were the acceptance limits chosen? *
*Why were the in-process tests identified as critical to product quality?*
- What scale-up experience does the sponsor have with the unit operations in this process?

## QBR: Risk Summary

- NTI drug
- Classified as a on-NTI drug, risk score = + 0
- Classified as an NTI drug, risk score = +1
- Dosage Form
- Simple Dosage Form, risk score = + 0
- Other Dosage Forms and NTI drugs, risk score = + 1
- Development Report
- If the sponsor submits a development report that addresses the FDA’s questions: Risk score = + 0
*Solution and IR Products:  Product Development Report*
*Other Dosage Forms:  Product and Process Development Reports*
- Insufficient or missing development report, risk score = + 1
- If the application is of high overall quality
-  Less than or equal to 2 cycles, risk score = + 0.
-  Greater than 2 cycles, risk score = + 1

## QBR: Risk-Based Conclusion

- Should the application be approved?
- What post-approval waivers/commitments are appropriate for this product?
- If the total risk score is less than or equal to 1
*All CBE0 and CBE30 changes may be in annual reports*
*PAS to CBE 30*
*Domestic manufacturing site changes to domestic manufacturing site that has not been cGMP inspected*
*A change to an alternate drug substance supplier that is used in preexisting FDA approved drug product*
*A change to the stability protocol that is within the scope of FDA guidances*
- If the total risk score is greater than 1
*All supplements should be submitted as usual*

## QBR: An Enhanced Quality Assessment System

- Knowledge Base