OPS Update: Process Analytical

Technology Initiative

Ajaz S. Hussain, Ph.D.

Deputy Director
Office of Pharmaceutical Science
CDER, FDA
 Outline
• Current state of process analytical technology in
pharmaceutical manufacturing
• An FDA perspective on the current state of
pharmaceutical manufacturing
• The promise of modern process analytical
technologies: “Win-Win” opportunities for public
health and industry
• Update on the FDA initiative on PAT
 Current State
• Although for many years the pharmaceutical
community has recognized the need for improvements
in pharmaceutical manufacturing, little progress has
been made.
• Scientific and technological advances in the area of
process analytical chemistry, engineering, and
multivariate data analysis offer new opportunities for
improving the overall efficiencies of drug development,
manufacturing, and associated regulatory processes.
 Current State: Process R&D

• During Drug Development Phase

– Process R&D efforts initiated only when there is
a reasonable certainty that a drug would be
approved
• In some cases use of “drug powder in a bottle” for
early clinical trials
– Stay with established technologies and systems
• Avoid technical and regulatory risks
• Adapt the original research process for scale-up

G. P. Pisano. The Development Factory: Unlocking the Potential of

Process Innovation.1997, Harvard Business School Press, Boston, MA.
 Current State: Process R&D

• After approval
– To increase capacity, it is often considered less
risky to maintain the current system and invest
in additional plants and equipment
– G. P. Pisano. The Development Factory: Unlocking the Potential of
Process Innovation.1997, Harvard Business School Press, Boston, MA.

• When is the “right” time for process

improvements and innovation?
When is the “right” time for process
improvement?
• For a few products - never?
– A 1997 FDA Warning Letter: XXX time release
pellets are prepared by hand coating XXX powder.
... This manual process results in formation of
agglomerates and in an accumulation of
ingredients on the sides of the coating pan.
Operators sporadically scrape this undistributed
material …. manually break up agglomerates
….and crushing them during processing
 Current State: Dosage Forms
 For human drugs the oral route of
administration is the preferred and
predominant route
 Evolutionary trend: Dosage forms -to- Drug
Delivery Systems -to- Intelligent Drug Delivery
Systems
 Current State: Material Science

• Many functional (e.g., physical) attributes of

pharmaceutical materials not well
characterized
– Official monographs (USP-NF) focus only on
chemical identity and purity/impurity
• It may not be feasible/practical to define
“functionality” in official monographs
 Current State: Optimization
 A (high) degree of uncertainty on the impact
independent variable(s) have on product quality
and performance
 One-factor-at-a-time experimentation often only
provides information applicable to the conditions
tested.
 Uncertainty with respect to “critical” process variables
 Limited data available at the time of establishing
regulatory specifications
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.
 Current Quality Control Paradigm
• Testing to document quality
– Predominantly “wet chemistry” tests

• Quality can not be tested into products, it

needs to be “built-in”
 PROCESS D WITH QC TESTS:
Cycle Times including BULK ACTIVE

20 DAYS 15 DAYS
BLEND 2:
PRE-BLEND
FILM
GRANULATION
STEP COATING

CHEMICAL
WEIGHING BLEND 1: FINAL COMPRESS BOTTLE
PROCESSING BLEND PACKAGING

10 DAYS 15 DAYS
QC1 QC2 QC3

21-90 DAYS 60 DAYS

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

 Measurement Shows Potential for Improvement
100%

Cost reduction

Time Compression

0%
35 days
3days Best Practice: VA Ratio 50%
 ON-LINE TECHNOLOGY IMPACTS
DOMINANT CYCLE TIMES
STEPS IN THE PROCESS/PLANT IN QC/QA
Process/Unit operation
Interruption of the process
Securing of sample from process
Holding of sample in plant
Documentation and verification of sampling
Transferring of samples to QC lab
Batching of samples in QC
Preparation of test samples
Actual test - separation
Actual test - measurement
Test data collection and processing
Documentation and verification of testing
Transferring of results for review
Decision regarding impact on process
Process/Process Step Primarily Manual Operation
Inventory Hold Actual test

On-line LIF, NIR, Data Analysis, etc.

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
LOOKING BEYOND THE “AVERAGE”
Lots with Exceptions

Lots without Exceptions

OVERALL CYCLE TIMES

0 100 200 300 400 500 600 700 800

LOT NUMBER

NEED FOR FUNDAMENTAL TECHNOLOGY

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

 Impact of Exceptions
(Detailed Analysis of 2 Products)
PERFORMANCE MEASURE VALUE
• Average Cycle time 95 days
• Std dev(Cycle time) > 100 days
• Exceptions increase cycle time by > 50 %
• Exceptions increase variability by > 100%
• Capacity Utilization of “System” LOW

NEED FOR FUNDAMENTAL TECHNOLOGY

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

 Benefits - Increased Effectiveness of
Compliance Infrastructure

2

Direct Cost Recovery

Cost

5

Compliance Gain

0% Level of Compliance 100%

Norman Winskill. Pfizer

Shift the Manufacturing Paradigm

 Total Quality Management System (TQMS)
AstraZeneca Solid Dosage Facility
Plankstadt, Germany

In-Process Control & Monitoring

• Key Process Operations
– Identification / specification of all incoming raw materials in
the dispensaries (& the warehouse)
– Fluid Bed Drier end point control
– Continuous in-line monitoring of blending & end point
control
– In-line monitoring of Tablet Quality parameters against
registered specifications
– 21CFR11 compliant data management system
• Real-time continuous quality assurance
• The platform for parametric release
Ali Afnan
2
TQMS Benefits- I
• Enhanced product quality assurance
• Significant manufacturing cost reduction
• Reduction of product inventory
• The elimination of end-of-line off-line testing
– providing opportunity for a new way of working
– significant increase in supply chain velocity
• Reduces business risk
• I ncreases competitive advantage
• Allows “remote” regulatory inspection

Ali Afnan
3
 Quality by Design? Product Development
Knowledge (Public Databases or in Submissions)
Level of Sophistication Details Resolved
1st
Principles
HIGH HIGH
MECHANISTIC
MODELS

EMPIRICAL
MODELS MEDIUM
MEDIUM
HEURISTIC RULES

LOW (HISTORICAL) DATA DERIVED FROM LOW

TRIAL-N-ERROR EXPERIMENTATION
 “Win-Win” Opportunities

• Optimal application of modern process

analytical technologies can
– Improve quality and manufacturing efficiency
– Reduce the likelihood of scrap/recalls
– Improve the scientific and engineering basis of
many current FDA-Industry debates
 Ensuring High Efficiency of the US
Pharmaceutical Manufacturing
• Provide high quality drugs to the US public in a
timely manner
• Successfully take 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
 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
 FDA Initiative to Facilitate
Introduction of PAT
• Eliminate regulatory uncertainty
– Official position - FDA will accept new
technology that is 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….
 FDA Initiative to Facilitate
Introduction of PAT
– Define a clear science based regulatory process
• Current system “adequate for intended use”
• Introduction of PAT not a requirement
• Define conditions under which PAT may replace
current “regulatory release testing”
• Process for addressing existing “invisible” problems in
marketed products
• Review and inspection practices
• International harmonization
 FDA Initiative to Facilitate
Introduction of PAT
• Seek input and collaboration
– Advisory Committee for Pharmaceutical Science
- Subcommittee on PAT
– Industry (including individual companies)
– Academic Pharmaceutical Engineering and
Process Analytical Chemistry programs
– PQRI
 FDA Initiative to Facilitate
Introduction of PAT: Two Tracks
• General Guidance on PAT • Invite companies to propose
– Information source: ACPS submissions
Subcommittee on PAT and – Hope to receive proposals for
working groups submissions (~3 )
• Meeting #1 2/02 – Review-Inspection plans and
• Meeting #2 (6/02) teams for these submissions
– Draft Guidance • Plan for concurrent
– Workshop development -review-
inspection
– Training (OPS/OC/ORA)
– Final Guidance
• Implementation
– CDER-ORA Team
A Perspective on PAT: One piece of the
puzzle
• “Vision 2020 - I can see clearly
now”
– Quality & performance by design +
Continuous “real time” monitoring of
quality
– Specifications based on mechanistic
understanding of how formulation and
process factors impact product
performance
– High efficiency and capacity utilization
– “Real time” review and inspection from
Rockville, White Oak, NJDO,...
 Ensuring
Optimal Scientific
Applications Foundation
“PAT”
Maximizing
Public Health
Objectives
Product Manufacturing
Quality Efficiency