# Presentation: 243260

## FDA CDER Compliance Initiatives

**DIA 42****nd**** Annual Meeting**
**June 22, 2006**

**Joseph C. Famulare**
**Acting Deputy Director**
**Office of Compliance ****Center for Drug Evaluation and Research**

## CDER Risk-Based ModelsGoal

**Assure Public Health by Strategically Monitoring Drug Product Quality**

## Why Risk-Based Approach?

**Adjust the level of regulatory scrutiny commensurate with public health risk**
**Implement a nationally consistent approach to the regulatory inspection processes**
**Dramatic decrease in FDA capacity for inspections, sample collections, and sample analyses due to**
**increase in number of facilities, especially foreign**
**increase in number, diversity, and complexity of drugs and processes as pharmaceutical science advances**

## CDER Risk-Based Models Applied to

**- Regulatory Current Good Manufacturing ****	****Practice (CGMP) Inspections****- Post marketing Adverse Event (ADE) ****	****Inspections****- Drug Product Survey Sample Collections ****	****and Sample Analyses**

## FY2006 cGMP Inspection Site Selection 

**   ****Establishment Type**
**   ****Last 3 District Decisions**
**   ****Field Alert History**

**   ****RX/OTC Products **
**   ****Sterility/Non Sterile **
**   ****Therapeutic Category**

**   ****Process Control**
**   ****Contamination Potential**

**Facility**
**Risk**

**Product**
**Risk**

**Manufacturing Process Risk**

**Total Score**

**Year of Last cGMP Inspection**

**FY2006 cGMP Inspection Site Selection **
**Risk Factors and Model – Mathematical Model**

## ADE Inspection Site Selection Risk Model- Semi Quantitative Model

**Total Score**

**ADE Inspection Site Selection Risk Model****- Semi Quantitative Model**

## FY2006 CGMP Inspection 

**Site Selection Model**

## Model Component Factors

**Select factors for Product, Process, and Facility components**
**Factors selected on the basis of**** **
**Relevance to product quality risks**
**Availability of data sources**
**Assign weights**** **
**Empirically derived**
**Expert judgment**
**Current policy emphasis**
**Develop logical algorithm to combine factors to calculate ****site risk score – *****The Model***** **
**The Model is not:**
**A predictor of ‘good’ or ‘bad’ sites, or of OAI outcome**
**Meant to replace all local FDA discretion**
**The Model is:**
**Evolving**
**The Model directs about half of ORA CGMP inspections**

## Process Score

- Product Placed in
- Profile Category

## Distribution of FY2006 Site Risk Scores

**Tier 1**

## Future Directions

**Continuing CDER refinement of all ****risk-based models**
**The risk-based approach increasingly underlies prioritization of our regulatory activities **
**Risk-based models provide enhanced focus on improving public health outcomes of our regulatory activities**

## Pharmaceutical Inspectorate

- First Class in the process of achieving Level III Certification
- Second Class to Convene in August 2006
- Training includes Classroom and Practical exercises
- Training will include 21st Century Philosophy -Risk- Science and Latest Advantages in Technology, Quality by Design Principles, Quality Systems
- Good Example of PI Utilization
- Active Participation in the ONDQA pilot with the Office of Compliance

## The Current State of Pharmaceutical Manufacturing

- Inability to predict effects of scale-up
- Lack of agility – usually takes years to bring up a new production site
- Operations fragmented around globe
- Inability to understand reasons for manufacturing failures

- J.Woodcock, Oct. 2005

## Quality by Design (QbD)

- Quality by design (QbD)
- Not a new concept
- a.k.a., “Building Quality in” or “designing for quality”
- Is fundamental part of CGMP
- “design” is found 18 times in the 211 regulations

## Quality by Design (QbD) examples:

- “_**equipment**_ used in manufacture, processing or holding of a drug product shall be of appropriate design...” (211.63)
- “Any _**building or buildings**_ use din the manufacture, processing, packing, or holding of a drug product shall be of suitable size, construction and location to facilitate cleaning, maintenance, and proper operations.” (211.42)
- “There shall be written procedures for production and _**process **_control designed to assure the drug products have the identity, strength, quality and purity they purport or are represented to possess.” (211.100)

## Quality by Design (QBD) Industry

- Develop scientific understanding of critical process and product attributes
- Design controls and testing based on the limits of scientific understanding at development stage
- Utilize knowledge gained over the product’s lifecycle to operate in an environment of continuous improvement

- J.Woodcock, Oct. 2005

## How do We Operationalize the Desired State? Two Key Concepts

- Quality by design and the design space concept: adoption by industry and FDA
- Quality system approach: adoption by industry and FDA

- J.Woodcock, Oct. 2005

## Characteristics of Desired State

**Manufacturers have extensive knowledge about critical product and process parameters and quality attributes**
**Manufacturers strive for continuous improvement**
**FDA role: Initial verification, subsequent audit**
**No manufacturing supplements needed**

- J.Woodcock, Oct. 2005

## Quality System: Industry

- Modern quality system implements adequate change control process
- Design, controls, and validation are refined over lifecycle
- Industry, not government, charged with maintaining quality, including during process changes

- J.Woodcock, Oct. 2005

## Quality System: Regulators

- Establish minimum (e.g., “floor”) parameters for quality management system
- Inspections are audit of quality system implementation
- Ensure that adequate quality system is in place

- J.Woodcock, Oct. 2005

## Quality System Guidance Development 

*cGMP Initiative For the 21**st** Century* - August 2002 - August 2004
- Comparison of Quality Systems Approaches (*Evaluation of Quality Systems) *
- ISO standards, EU, PIC/S, U.S., Non–pharmaceutical Quality Standards (QSR’s, HAACP)
- Guidance describes a comprehensive quality system model and how CGMP regulations correlate to QS elements
- If implementing a comprehensive quality system, this guidance can help achieve compliance with CGMPs
- Due out by September ‘06

## Intent of the FDA Quality Systems Guidance 

- Implement a modern, comprehensive and robust quality system,
- consistent with CGMPs that,
- defines a state of control to:
- Facilitate the consistent production of high quality, safe and efficacious product
- Facilitate change control - continuous improvement
- Facilitate quality by design - building in quality to process and product
- Facilitate adoption of risk management
- Facilitate harmonization with other quality systems** **

## Why A Harmonized Approach to A Comprehensive, Modern  and Robust Quality System? (Why ICH Q10?)

- Improve quality of pharmaceutical products
- Improve CGMP compliance
- Facilitate continuous improvement
- Necessary for implementation & effective utilization of:
- Quality By Design (Q8 Pharmaceutical Development)
- Risk Management (Q9 Pharmaceutical Risk Management)
- Effective knowledge transfer
- CAPA
- Change control
- Review and Inspection
- Demonstrating state of control
- Ability to manage movement within the design space

## ICH Q10

- Continuous Learning and Improvement
- Much learning takes place through process experience
- Our 21st Century Regulatory System will facilitate this improvement
- Flexibility
- Management and Performance based regulation

## Opportunities

- Moving Manufacturing into the 21st Century
- Identifying Safety Effects of Excipients
- Manufacturing Novel Dosage Forms
- Developing Standards for Instrumentation

- S.Galson, Temple U.
- Spring ‘06

## Standards

- Fully supported by CDER Office of Compliance
- Must be compatible with agency...missions, authorities, priorities and budget resources
- Priority is for specific technical standards
- Should not overlap with existing regulations or policy, or create new policy

## Standards

- Need a process within FDA for support and development
- Expect many to be developed by industry consensus standard groups
- Will be useful supplement to our guidance which set general principles

## Goal

- 	High degree of confidence that drugs possess their represented identity, strength, quality, and purity

**Process Validation**

## The Future of Process Validation?

**Revised Validation Compliance Policy Guide in March 2004:**
- Recognize replication at full-scale as part of development-to-commercial ‘lifecycle’
**“****Conformance batch” phase**
- No expectation of completion prior to approval (but prior to distribution)
- Recognize use of advanced engineering principles and control technologies in ensuring batch quality
- Delete reference to **3** validation (conformance) batches
- Clarify importance of post-market information gathering
- Reference Q7A guidance for APIs
- * *Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval (7132c08/Sec 490.100)*

## Process Validation

**Process Validation is an Enforceable Requirement for **Finished Drug Products:
**21 CFR 211.100(a)**
**“****written procedures... designed to assure...”  **
**21 CFR 211.110(a)**
**“... ****procedures shall be established to monitor the output and validate the performance...”**
- 21 CFR 211.113: validation of sterilization processes
- 21 CFR 211.160: scientifically sound specs + sampling
- FD&C Act Section 506A(b) “Manufacturing Changes” post marketing **requires validation of the effects of a change on the identity, strength, quality, purity and potency**

## “Traditional” Validation Approach

- 1987 -** ***Guideline on General Principles of Process Validation*
- Primary emphasis on replication at full-scale (**3**)
- Lots viewed as “evidence” of process reproducibility
- Significant milestone – just prior to commercial launch

## “Traditional” Validation Approach

- Weaknesses:
- Encourages ‘fixed’ component and processing conditions
- Change is bad
- Discourages fuller process understanding
- Root cause analysis more difficult
- 3 may not be enough; may be too many

## The Future of Process Validation?

**The Future of Process Validation?**

**Process Validation Lifecycle**

## The Future of Process Validation?

***Design:***
- Design / Development phase
- Qualification phase
***Confirm*****:**
- Conformance batch phase
***Monitor and Assess:***
- Maintenance / Optimization phase

## The Future of Process Validation?

- Process Validation Guidance of 1987 is under revision
- Design / Development
- Deliberate
- Amount appropriate for process/product risks
- Leads to process knowledge
- Control input variability and/or
- Process adjusts for input variability

## The Future of Process Validation?

- Qualification of facility/equipment:
- Design
- Build/install
- Verify functionality
- Conformance batch manufacturing
- Final ‘test’ of commercial scale process before distribution
- Normal conditions
- Statistical sampling plan; data analysis
- Meets pre-established expectations

## The Future of Process Validation?

- Maintenance / Optimization
- Timely & sound monitoring of process performance
- Manage changes
- Optimize processing and measuring systems to detect and reduce variability
- CQV (initially & throughout product / process lifecycle)

## Revised API Inspection Compliance Program Guidance Manual CP 7356.002F 

## Compliance Program 7356.002F

- Implementation Date - February 13, 2006
- Defines a systems-based approach for API inspections mirroring the approach in CPG 7356.002
- Systems are described in Appendix A
- Has been customized for API processes
- Explains relevance of ICH Q7A and correlates the systems with Q7A sections

## What's Coming

- Part 11
- PreApproval Inspection Compliance Program
- Pharmaceutical Inspectorate Steering Committee, Implementation Quality System