# Presentation: 657041

## FDA’s Advisory Committee for Pharmaceutical ScienceThe Subcommittee on Process Analytical Technologies (PAT): Overview and Objectives

- Ajaz S. Hussain, Ph.D.
- Deputy Director
- Office of Pharmaceutical Science, CDER, FDA
- February 25, 2002, Gaithersburg, MD.

## Outline

- Overview of the FDA’s PAT Initiative
- What?
- Why?
- When?
- How?
- Goals and Objectives of the PAT-Subcommittee and Working Groups
- What does FDA need/expect from you?

## What are PAT?

- Systems for continuous analysis and control of manufacturing processes based on real-time measurements, or rapid measurements during processing, of quality and performance attributes of raw and in-process materials and processes to assure acceptable end product quality at the completion of  the process.
- Process analytical chemistry tools + information management tools + feedback process control strategies + product & process design and optimization strategies

## PAT for Pharmaceuticals: Why?

- Optimal applications of PAT can improve the capability and the efficiency of pharmaceutical processes while maintaining or improving product quality
- improve process understanding and help to ensure quality was “built in” or “by design”
- reduce the risk of scrap and recalls
- reduce production cycle times and enhance capacity utilization
- in the long run, reduce product development time

## PAT for Pharmaceuticals: Why?

- Current level of product quality is generally _adequate for the intended use_
- The _process_ by which we achieve this level of quality is inefficient
- The current manufacturing paradigm is ***skewed towards testing to document product quality and rejecting (or recalling) products of unacceptable quality***

## PAT for Pharmaceuticals: Why?

- Ensuring high efficiency of the US pharmaceutical manufacturing sector
- Provide high quality drugs to the US public in a timely manner by taking advantage of the many new drug development opportunities offered by advances in biology and chemistry
- Ensure optimal utilization of public and private resources to meet the growing health care needs of the US public
- Minimize risks due to sub-optimal pharmaceutical _*process*_ quality

## PAT for Pharmaceuticals: Why?

- Low manufacturing efficiency, waste (time and resources) and a high “cost of compliance”
- Need for very high level of regulatory scrutiny (review and inspections)
- High proportion of FDA resources needed to ensure adequate product quality
- Recurring problems that do not seem to get resolved
- Continued debates between FDA-industry, few permanent resolutions

## Risks Due to Sub-optimal Pharmaceutical Process Quality

## Minimum Regulatory “Sigma” Level for Drugs?

- Under cGMP when failures/recalls
- exceeds 10% - no longer “validated.”
- The minimum regulatory "Sigma” ~ 1.65?

## Pharmaceutical OOS & Batch “Failures” Rates

- Scrap and rework - we plan for 5-10% *(accepted as necessary)**	**PWHC 11/16/01*
- “It is authors’ experience that ... validation exercise precedes a trouble-free time period in the manufacturing area only to be followed by many hours (possibly days or weeks) of troubleshooting and experimental work after a batch or two of product fails to meet specifications.  This becomes a never-ending task.” *Harwood and Molnar. Using DOE techniques to avoid process problems. Pharm. Dev. Tech. 1998.*

## Risks Due to Sub-optimal Pharmaceutical Process Quality

- Risk of releasing a “poor” quality product
- Recalls are not effective quality control tools
- Drug shortages
- Delay in approval of important drug products
- High potential for disruption in the availability of  important drugs
- Production of low volume “essential” drugs may be adversely effected

## Risks Due to Sub-optimal Pharmaceutical Process Quality

- Regulatory commitments on an inefficient manufacturing process
- Continued optimization activities in the post approval phase (or live with the “validated” but inefficient process)
- Recurring manufacturing difficulties leading to very low efficiency and capacity utilization
- Higher manufacturing and regulatory compliance costs “locked-in”

## Risks Due to Sub-optimal Pharmaceutical Process Quality

- Increased risk of non-approval or delayed regulatory approval
- Increased potential for quality problems confounding the clinical safety and efficacy databases
- Past quality (compliance) problems can delay new drug approvals
- Industry and FDA resources being spent on recurring problems

## When?

- When was this initiative started?
- 3rd quarter 1999 (building on the AOAC International Special Symposium: “ Pharmaceutical Process Control and Quality Assessment by Non-Traditional Means,” October 1993, St. Louis, Missouri)
- FIP’s Millennium Congress, New Technology Forum of the Royal Pharmaceutical Society, PhRMA Technical Conclave, ...
**19 July 2001, ACPS Meeting**
**16 November 2001, FDA Science Board Meeting**
**28 November 2001, ACPS Meeting**
**Recommendation to form a PAT Subcommittee **

## When?

- When can companies submit PAT based applications or submissions to FDA?
- Any time a company is ready to do so
- they should contact the OPS/CDER/FDA to discuss their proposed PAT applications or submissions
- There are many hurdles that seem to hold back PAT applications
- It is widely perceived that FDA will not accept PAT based applications, this is not true

## Need for FDA to Facilitate Introduction of PAT

- Industry is hesitant to introduce PAT in US
- Regulatory uncertainty/risk leads to “Don’t Tell” or “Don’t Use” practice
- New Technology = New Questions
- Method suitability, chemometrics and validation
- Old products + New technology = New Regulatory Concerns
- Problems not visible under the current system
- Mindset: Why change?
- PAT application will add to current regulatory requirements

## How does FDA plan to facilitate introduction of PAT?

- Eliminate regulatory uncertainty
- #1. FDA will accept PAT applications that are based on “good” science
- Develop standards for PAT
- Method suitability and validation
- Multivariate statistical/computer pattern recognition
- Critical process control points and specifications
- Changes, OOS....
- #2. Current system “adequate for intended use”
- #3. Introduction of PAT not a requirement

## How does FDA plan to facilitate introduction of PAT?

- Eliminate regulatory uncertainty
- #4. Define conditions under which PAT may replace current “end product release testing”
- #5. Process for addressing existing “invisible” problems in marketed products
- #6. Review and inspection practices
- #7. International harmonization

## How does FDA plan to facilitate introduction of PAT?: Two Tracks

- General Guidance on PAT
**Information source: ACPS Subcommittee on PAT and working groups**
**Meeting #1 2/25-26/02**
**Meeting #2 (6/02?)**
- Draft Guidance
- Implementation
- CDER-ORA Team

- Invite companies to propose submissions
- Expect to receive proposals for submissions (~3 by 4q 02)
- Review-Inspection plans and teams for these submissions
- Plan for concurrent development -review-inspection

## General (principles) Guidance on PAT

- Proposed Goals and Objectives
- General principles and terminology
- Bring the community on the “same page”
- Address issues related to “regulatory uncertainties”
-  Clarify the regulatory process
- Review and inspection
- Other tangible benefits
- Serve as a tool for building within-company consensus
- Promote research and development activities in the pharmaceutical PAT area

## Guidance Development Process

- PAT Steering Committee
- CDER (OPS/OC) and ORA
- Douglas Ellsworth, Mike Olson/Diane Obrien, Joe Famulare, Frank Holcomb, Moheb Nasr, Yuan Yuan Chiu, Ajaz Hussain (Chair)
- Guidance writer: Raj Uppoor
- Project management: Chris Cole
- Communication tools - Web based and electronic tools (PAT@CDER.FDA.GOV)

## Proposed/Draft

- NOT An NIR Guidance!

## Proposed/Draft

## Options for Introducing PAT

## PAT Subcommittee

- A major source of information for the FDA’s General Guidance on PAT
**At the end of this meeting: **
**Topics to be covered in the guidance (outline)**
**Layout general principles for setting specifications, validation, chemometrics**
**Consensus on benefits, definitions, terminology**
- Meeting #2?
- More details on “optimal” applications, identification and control of critical formulation and process variables, specifications, validation, chemometrics, addressing OOS, .......
- Illustrative examples (for inclusion in the guidance)

## PAT Subcommittee

- Organization
- Industry presentations to focus the discussion
- Questions (see background packet) to stimulate and focus discussion
- Four working groups
- Benefits, technology, definitions/terminology
- Process + Analytical Validation
- Chemometrics
- Product/Process Development
- Only _**two **_meetings planned

## Chemometrics (Kowalski and Wold)

- Multivariate data collection and analysis
- DOE, PCA, PLS, non-linear PLS, neural networks,......
- Calibration, process modeling, pattern recognition and classification, signal correction and compression
- Statistical process control,....
- Need information of the type of tools and general principles (and examples) for “verification” and “validation” of such analyses

## Challenges

- Different perspectives, expertise, and affiliations - can we come on the “same page” by the end of this meeting?
- Are two meetings sufficient to gather the information necessary to develop the general guidance?
- Is the “general guidance” approach the most effective approach?