# Presentation: 276402

## D. Christopher Watts, Ph.D.
Office of Pharmaceutical Science, CDER, FDA

Science Seminar Series for the Office of Commissioner 
April 9, 2004

- D. Christopher Watts, Ph.D.
- Office of Pharmaceutical Science, CDER, FDA
- Science Seminar Series for the Office of Commissioner
- April 9, 2004

**Process Analytical Technology****(PAT):****What’s in a name?**

## The Questions

- What is PAT?
- Why is PAT necessary?
- How will PAT help?
- Industry
- Agency
- Public Health
- How does PAT relate to other FDA Initiatives?
- Where are we going with PAT?

## What is PAT?

- A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance
- Scientific principles and tools supporting innovation
- PAT Tools
- Process Understanding
- Risk-Based Approach
- Integrated Approach
- Regulatory Strategy accommodating *innovation*
- PAT Team approach to Review *and* Inspection
- Joint training and certification of staff

## What is PAT?

- A system for:
- designing, analyzing, and controlling manufacturing
- timely measurements (i.e., during processing)
- critical quality and performance attributes
- raw and in-process materials
- processes
*“**Analytical“ *includes:
- chemical, physical, microbiological, mathematical, and risk analysis
- conducted in an integrated manner

## PAT = Process Understanding

- A process is well understood when:
- all critical sources of variability are identified and explained
- variability is managed by the process
- product quality attributes can be accurately and reliably predicted
- Accurate and Reliable predictions reflect process understanding
- Process Understanding inversely proportional to risk

## The Genesis of PAT: A Proactive Initiative

- Began at ACPS Discussions in July, 2001
- FDA Science Board Meetings (11/01, 4/02)
- Current state of Pharmaceutical Manufacturing
- Industrial Practice
- FDA Regulation
- Science Board support for FDA’s proposal to facilitate innovation

*http://www.fda.gov/cder/OPS/PAT.htm#scienceboard*

## Current Paradigm:
Utilisation levels - 15% or less
Scrap and rework - plan for 5-10% 
Time to effectiveness - takes years
Hesitant to Innovate
Incentive?
Manufacturing Costs: $90 Billion

**Current Paradigm:**
- Utilisation levels - 15% or less
- Scrap and rework - plan for 5-10%
- Time to effectiveness - takes years
- Hesitant to Innovate
- Incentive?
- Manufacturing Costs: $90 Billion

- Why PAT? Industry Perspective

***Ray Scherzer, FDA Science Board,  Apr 2, 2002***

## Why PAT? FDA Perspective

-  An increasing burden on FDA resources:
- ~ 4,000 manufacturing supplements annually
- Unable to meet statutory biennial GMP inspection requirement
- Lower scrutiny of non-domestic industry
- Cost implications for the industry from:
-  Low manufacturing and QA efficiency

*Dr. Janet Woodcock,FDA Science Board*

## Why PAT? Public Health Perspective

- US Drug products are of high quality, BUT:
- Increasing trend toward manufacturing-related problems
- Recalls - 176 in 1998 rising to 354 in 2002
- Loss of availability of essential drugs
- Disruption of manufacturing operations
- Negative impact on new drug approvals
- Efficient pharmaceutical development and manufacturing are vital components of the “Critical Path” leading to an effective U.S. health care system

*Dr. Janet Woodcock,FDA Science Board*

##  (CAMP, R. Scherzer. FDA Sci. Board. 4/9/02)

*Quality by Design: A Challenge to the Pharma Industry*
-  (CAMP, R. Scherzer. FDA Sci. Board. 4/9/02)

## How can PAT help?Example: Current Tablet Production

***Raw Material Dispensing***

***Blending***

***Compression***

- Identification Tests (Chemical Only)

- Test Product Quality for Release     (Active Only)

- No Tests (Time Based)

- End-Product Focused  Testing to Document Quality

- Process at Risk

## Current Tablet Production: Testing to Document Quality

- What is the Product Test?
- Typically 30 Tablets/batch (1,000,000)
- What process Information does this provide?
- None. Testing is Product focused.
- Will we see “failures”?
- Expect number of “failing” tablets/batch, even though 30 tablets/batch “pass”
- 4% of batches may fail, even though not different from a “passing” batch
- Does this facilitate process understanding and control?
- No

## One “Innovative” Approach

**Ideal Tablet**

-  “New Technology” in Manufacturing Process
-  Analyze every tablet

## “Innovative” Approach:Still Testing to Document Quality

- What is the Product Test?
- Test every tablet (all 1,000,000)
- What process Information does this provide?
- None.  Testing is still Product focused.
- Better estimate of Variability in Final Product
- Why the variability?
- ?
- Change acceptance criteria?
- Allow some outside 75%-125%
- Facilitate process understanding and control?
- No

## PAT Approach: Quality by Design

- Focus on Process Understanding
- What parameters are critical to Product Quality?
- Experimental Design
- How do we analyze these parameters?
- Appropriate Instrumentation
- How do we control these parameters throughout the process?

## Experimental Design: Establishing the “Critical Parameter(s)”

- 	*Critical to Product Quality

- Parameter 1
- Disintegrant Level*
- Parameter 3
- Parameter 4
- Active Particle Size*
- Interaction 1
- Interaction 2
- Interaction 3
- Interaction 4
- Interaction 5

## PAT Approach: Particle Size

- _Understand Raw Material_
-  Analyzer in Dispensing
-  What is the material?
-  What is Particle Size?
-  Predictive Models for Blend

## PAT: Analyze and Control

-  Analyzer on Blender
-  Particle Size?
-  Disintegrant mixed?
-  Stop blend with desired particle size and mix                          (not time based)

- _Understand and Control Blend_

## Example: Current Tablet Production

***Raw Material Dispensing***

***Blending***

***Compression***

- Identification Tests (Chemical Only)

- Test Product Quality for Release     (Active Only)

- No Tests (Time Based)

- End-Product Focused  Testing to Document Quality

- Process at Risk

## PAT Tablet Production

***Compression***

- Functional Tests (Chemical and Physical)

- Validate Process Control

- Control Blending              (Particle Size &       Disintegrant Distribution)

- Process Focused

- Mitigate the Process Risk

***Predictive Models***

## PAT: Risk-Managed Approach to Regulatory Scrutiny

- Expect an inverse relationship between the level of process understanding and the risk of producing a poor quality product
- Well understood process  less restrictive regulatory approaches to manage change
- Focus on process understanding can facilitate risk-managed regulatory decisions and innovation

## FDA CGMP Initiative
Risk-based regulation
“Non-impeding” regulation
Consistent regulation

Success based on Broad Cooperation
Industry
Academia
FDA
http://www.fda.gov/bbs/topics/NEWS/2002/NEW00829.html

- FDA CGMP Initiative
- Risk-based regulation
- “Non-impeding” regulation
- Consistent regulation
- Success based on Broad Cooperation
- Industry
- Academia
- FDA
- http://www.fda.gov/bbs/topics/NEWS/2002/NEW00829.html

- PAT and CGMP Initiative

## PAT and The “Critical Path”

- http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.pdf

## PAT and The “Critical Path”

- http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.pdf

## PAT, CGMP, and The Critical Path

**Process Analytical Technology**

**Encourage Innovation**

**New Technologies**

**CGMP’s for the 21st Century**

**The Critical Path**

**Risk-Management**

**Broad Cooperation:**
**Industry, Academia, FDA**

## Next Steps for PAT

- Next Steps for PAT

- First PAT Approval
- Finalize PAT Guidance
- Continued Training of FDA Staff
- Expand the Scope of PAT
- Office of Biotechnology Products
- ASTM Technical Committee
- Research (Intra- and Extramural)
- Office of Testing and Research
- Pfizer CRADA
- NSF IAG
- Support Policy Development and Training

## Next Steps

- FDA Science Forum
- Quality by Design (QbD) Breakout Session
- Chair: Dr. Janet Woodcock

## Acknowledgements

- Office of the Commissioner
- Committee for the Advancement of FDA Science (CAFDAS)
- Dr. Arifa Khan
- Linda Huntington
- Joanne Locke
- Mrs. Helen Winkle
- Dr. Ajaz Hussain
- Dr. Ali Afnan
- Dr. Rob Lyon
- Dr. Pat Faustino

## Contact

- Email:
- PAT@cder.fda.gov
- wattsc@cder.fda.gov
- PAT on the Web:
- http://www.fda.gov/cder/OPS/PAT.htm
- Phone:
- (301)-443-5197