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

Development (Quality specifications)

Manufacturing (Process capability)Regulatory approval and compliance

Minimum Regulatory “Sigma” Level for Drugs?

Under cGMP when failures/recalls exceeds 10% - no longer “validated.”

The minimum regulatory "Sigma” ~ 1.65? CP SIGMA DEFECTS COST CLASS

0.67 2 5% 25-35% Not CapableCompetitive

1.0 3 0.13% 20-25% Average1.33 4 60 ppm 12-18% Healthy1.66 5 1 ppm 4-8% Superior2.0 6 2 ppb 1-3% World Class

FDA Science Board 11/16/01: PricewaterhouseCooper Presentation(Modified by AH)

Pharmaceuticals

Semiconductor

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)

THIS IS A ONLY A CONCEPT AND PROPOSAL DRAFT

Draft – Not for Implementation.

Guidance for Industry

Applications related to use ofProcess Analytical Technologies inDrug Substance and Drug Product

Manufacturing

Lead Guidance development team: FDA, CDER, OPS; with input fromFDA PAT Steering Committee, formed on January 7, 2002.

This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted within 60days of publication in the Federal Register to the notice announcing the availability of thedraft guidance. Submit comments to Dockets Management Branch (HFD-305), Food andDrug Administration, 12420 Parklawn Drive, Room 1-23, Rockville, MD 20857. Allcomments should be identified with the docket number listed in the notice of availabilitythat publishes in the Federal Register.

For questions regarding this draft document, contact: Rajendra Uppoor, 301-594-5358.

U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Date

Table of Contents

I. INTRODUCTION

II. SCOPE OF THE GUIDANCE

III. TYPE OF SUBMISSIONS

IV. MECHANISM TO INTRODUCE PATs IN MANUFACTURING

V. WHAT DATA TO COLLECT

VI. SUBMISSION OF APPLICATIONS

VII. REVIEW OF PAT SECTION OF AN APPLICATION

VIII. REAL-TIME QA (PARAMETRIC RELEASE) BASED ON USE OF PATs

IX. TESTS ON DRUG SUSTANCE AND DRUG PRODUCT

X. IMPLEMENTATION AND FUTURE TRANSITIONS

GLOSSARY OF TERMS

REFERENCES

Options for Introducing PAT

A. Currently marketed “robust” products. PAT to improve efficiency (minimalimprovement in quality assurance)

B. Currently marketed products that needimprovement. Step wise PAT approach - first improve quality and then improvethe efficiency

C. New products. PAT utilized throughoutdevelopment and scale-up. Lab basedtests to ensure shelf-life and/or forestablishing “public standards.”

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?