The document summarizes recent initiatives by the FDA related to pharmaceutical quality and process validation. It discusses the Critical Path Initiative, ICH Q8, Q9, and Q10 guidelines, revisions to CGMP regulations, FDA's quality system guidance, process validation approaches, and progress implementing process analytical technologies. It also notes some remaining challenges around process monitoring and validation, and data evaluation.

1. 5/9/2008
CDER Office of Compliance and the
Critical Path Initiative
“Since the initial report, we have broadened our
Pharmaceutical Quality for thinking about the Critical Path Initiative to include
veterinary medicines, generic drugs, and even foods.
the 21st Century For all product areas, the basic idea is to reduce
uncertainty about product performance throughout the
product lif cycle through scientific research. W h
d life l h h i ifi research. We have
h
set up a large number of collaborations with partners to
Temple University get this research done, in areas as disparate as drug
May 06, 2008 manufacturing and clinical trial design.” -Janet Woodcock
8/17/07
Joseph Famulare, Deputy Director
Sustainability of product quality throughout the product
FDA CDER Office of Compliance lifecycle is a major role of the Office of Compliance
FDA Initiatives: A Quality Timeline Scope of Recent Guidances
Process
Product Monitoring/
Design Continuous
Process Manufacturing Verification
Design
2004 2005 2006 2007 2008
ICH Q8/Q8(R) - Pharmaceutical Development
PAT Guidance
ICH Q9 – Quality Risk Management
FDA Guidance on Quality Systems (9/06)/
ICH Q10 – Pharmaceutical Quality Systems
CGMP Revisions
Modernizing and harmonizing CGMPs
Phased approach …1-2-3
…1-
Revisions to First Phase – ‘non-controversial’:
‘non-
Withdraw proposed 1996 changes
CGMP R
Regulations
l ti Change no asbestos filter to no particle shedding
material
Potable water can be as defined by, e.g., Japan
and EU
Equipment needing to be sterilized shall be
sterilized
1

2. 5/9/2008
CGMP Revisions (cont.) CGMP Revisions (cont.)
First Phase – ‘non-controversial’ (cont.):
‘non- Second Phase: ‘substantive’ issues
Eliminate second person check on automated Proposed rule being drafted
equipment Includes incorporation of essential quality system
Require sterile container depyrogenation elements
processes to be validated
Require bioburden testing, as necessary, on in-in-
process material
Require that both aseptic fill as well as other
sterilization processes be validated
FDA’s Quality System Guidance
Result of the CGMPs for the 21st Century Initiative –
finalized August 2006
Encourages the use of modern quality management
Pharmaceutical Quality y
systems
System Emphasizes self-management of change
self-
Consistent with overall efforts to reduce manufacturing
supplements – 21 CFR 314.70 revisions
Pharmaceutical Quality Systems
ICH Quality Vision - 2003
ICH Q10
A new vision for ensuring product quality
Three new letters to learn as we approach the Desired (Brussels, July 2003)
2003)
State for pharmaceutical manufacturing in the 21st A harmonized pharmaceutical quality system applicable
Century across the life cycle of the product emphasizing an
integrated approach to quality risk management and
science
PQS New ICH guidelines (high level guidelines, more
visionary, less prescriptive, flexible regulatory
approaches)
Pharmaceutical Development (Q8)
Quality Risk Management (Q9)
How did we get here? Are there challenges ahead? Pharmaceutical Quality Systems (PQS) (Q10)
2

3. 5/9/2008
ICH Quality Vision ICH Q10 PQS
Pre-
Pre-2003: quantitative guidance Pharmaceutical Technology
Manufacturing Discontinuation
Development Transfer
Post-
Post-2003: strategic guidance
Q8/Q9/Q10 For companies with : Management Responsibilities
Quality Risk 1. Good design and
The Regulatory Management
Quality System control strategies
(Q9) 2. Good Risk Process Performance & Product Quality monitoring
Quality Risk Management strategies CAPA
Management 3.
3 Good Quality Systems
PQS elements Change Management
Management review
Quality by Design
(Pharmaceutical Quality
Development)
by Design Reduced regulatory
Quality Knowledge Management
Systems (Q8)
burden: Enablers
• Reduction of Quality risk Management
submissions on
changes/variations
Existing GMP ’s
GMP’ Quality • Inspection of quality
Systems systems
GMP
(Q10)
ICH Q10 Key Points ICH Q10 Content
Common terminology 1. Pharmaceutical Quality System
Definition and maintenance of the Quality
System 2. Management Responsibility
The role of management, including senior
g g
management 3. Continual Improvement of Process
Identification of performance indicators and Performance and Product Quality
management of trends to achieve highly capable
processes 4. Continual Improvement of the Pharmaceutical
Effective change control procedures Quality System
ICH Q10 Content (cont.) ICH Q10 Content (cont.)
1. PHARMACEUTICAL QUALITY SYSTEM 2. MANAGEMENT RESPONSIBILITY
Scope / Objectives Management Commitment / Quality Policy /
Relationship of ICH Q10 to Quality Planning
Regional GMP Requirements ISO Standards and ICH Q7
Resource Management / I
R M Internall
Regulatory Approaches
Communication
Enablers
Knowledge management Management Review
Quality Risk management Oversight of Outsourced Activities
Design & Content Considerations / Quality Manual
3

4. 5/9/2008
ICH Q10 Content (cont.) ICH Q10 Content (cont.)
3. CONTINUAL IMPROVEMENT OF 4. CONTINUAL IMPROVEMENT OF
PROCESS PERFORMANCE AND THE PHARMACEUTICAL QUALITY
PRODUCT QUALITY SYSTEM
Lifecycle Stage Goals PQS Elements Management Review of the PQS
Pharma. Development Monitoring
Monitoring of Internal and External Factors
Tech. Transfer Corrective/Preventive
Manufacturing Actions Impacting the PQS
Product Discontinuation Change Management Outcomes of Management Review and
Management Review Monitoring
Potential Opportunities to Enhance
ICH Q10 Comments
Regulatory Approaches
Docket in E.U., Japan, & U.S. Scenario Potential Opportunity
1. Comply with GMPs Compliance - status quo
Over 300 unique comments
2. Demonstrate effective Opportunity to
Some themes: PQS, including effective • increase use of risk-based approaches
Integration with Other ICH Q Guidelines use of quality risk mgt
f li i k for
f regulatory inspections
l i i
principles (ICH Q9 & Q10)
Lifecycle: Pharmaceutical Development
3. Demonstrate product and Opportunity to:
Definition of “Control Strategy” process understanding, facilitate science-based pharma.
Regulatory Impact including effective use of quality assessment
quality risk mgt enable innovative approaches to
principles (ICH Q8 & Q9) process validation
establish real-time release mechanisms
Potential Opportunities to Enhance
Q10 and Q8 Link
Regulatory Approaches
Scenario Potential Opportunity Processes for pharmaceutical development (Q8 or
4. Demonstrate Opportunity to: equivalent) are key linkages to product realization
effective PQS and increase use of risk-based approaches within the Pharmaceutical Quality System.
product and for regulatory inspections
process facilitate science based pharmaceutical
science-based
understanding, quality assessment Q8 provides for robust development and
including the use optimize science and risk-based post- understanding that serves as the basis for continual
of quality risk approval change processes to maximize improvement.
mgt. principles benefits from innovation and continual
(ICH Q8, Q9, & improvement
Q10) enable innovative approaches to process
validation
establish real-time release mechanisms
4

5. 5/9/2008
Q10 and Q9 Link Quality by Design (QbD)
The Quality System should encourage and
facilitate the use of Quality Risk Management (Q9) A systematic approach to development
approaches throughout the system.
that begins with predefined objectives
The design and application of processes within the and emphasizes product and process
d h i d d
Quality System should be based on appropriate understanding and process control,
risk management principles and methods
based on sound science and quality risk
management (ICH Q8(R), step 2)
Quality by Design (QbD) – A Systematic Approach
(QbD) Implementation Effects of Science and
to Pharmaceutical Development and Manufacturing Quality
Aspects Traditional QbD
Closer collaboration between R & D and Commercial Manufacturing –
Commercialization Initiative
Pharmaceutical Empirical; typically univariate Systematic; multivariate experiments
Restructuring of plants worldwide bringing in closer proximity development ,tech
Development experiments transfer and initial commercial manufacturing
Manufacturing Fixed Adjustable within design Opportunity Costs Tangible business and quality benefits in deviation
Process space; opportunities for reduction, health and safety, quality plan conformance, and reduction in
innovation (PAT) manufacturing losses and recalls.
f i l d ll
Process Control In-
In-process testing for go/no-go;
go/no- PAT tools utilized for
offline analysis System of Integrated Quality Standards in place for Development, Manufacturing,
feedback and feed forward
and Product Surveillance
controls
Product Primary means of control; based Part of the overall quality control Integrated Pharmaceutical Quality System Drives Sustainability and
Specification on batch data at time of strategy; based on desired product Improvement Manufacturing was approximately $200 million under plan for
submission performance (safety and efficacy) one year, and approximately $70 million under plan the next year due to
quality system improvements
Control Strategy Mainly by intermediate and end Risk-
Risk-based; controls shifted
product testing upstream; reducing product Deviations reduced 70%.
variability; real-time release
real-
Lifecycle Reactive to problems & OOS; Continual improvement facilitated
Management post-
post-approval changes needed
CGMP Quality Program
Accomplishments Where Do the Challenges Lie?
CDER,CBER,CVM,ORA
Aseptic Processing Guidance, Part 11 Guidance, Update of the
Validation Compliance Policy Guide, Phase 1 IND CGMP Draft Comments heard:
Guidance and Proposed Rule, Study of CGMP regulations,
Application to PIC/s, Guidance on Out of Specification Test How do I release the batch with real time
Results, Development of the PI Curriculum, Guidance on release? Can I default to “traditional end product
Glycerin Testing, PAT, CGMP Q&A. ICH Strategy, ICH Q10
Coming Soon: testing
testing”
Guidance on the Prevention of Cross Contamination of What is considered Out of Trend Out of Spec
Potent Compounds
Technology Transfer Initiative and Warrants an Investigation
ICH Implementation Working Group
What does process validation look like.
Lifecycle Approach to Process Validation
Guidance
5

6. 5/9/2008
Where Do the Challenges Lie? (cont.) Where Do the Challenges Lie? (cont.)
Testing and Release for Distribution: For each Data, Trends and Investigations: requirement
batch of drug product there shall be appropriate under US CGMP to review annually
laboratory determination.... Modern manufacturing methods and controls
make this possible in real time
Doesn t
Doesn't have to be end product
Not all trends require investigations, however
Real time release is sufficient and does not have to “unexplained discrepancies” do
be backed up with “traditional end product testing” Manufacturers should be better able to understand
nor is it appropriate to substitute at will those with real time monitoring and controls
The “need” to do “traditional testing” is covered by
stability
Process Validation
Process Validation Old Approach ?
Process Validation for Active Two decades old
Pharmaceutical Ingredients is enforceable Design/development foundation weak
under the Statute Emphasizes replication at commercial scale
p p
does not promote a fuller process understanding
Statutory cGMP provision at 501(a)(2)(b) of making deviation/problem analysis dubious
the Federal Food, Drug, and Cosmetic Act biased batches
feasible and valuable
Does not sufficiently enable appropriate
CGMP guidance available - ICH Q7A regulatory oversight
Process Validation Lifecycle Approach to
Process Validation
The ‘process’ of process validation Lifecycle
Overall validation is not “complete” but ongoing
Requires comprehensive process design to identify and
Series of activities taking place over mitigate significant sources of variability
achieve process understanding
the ‘life’ of the product/process
life’
May incorporate risk management
Recognizes that more knowledge will be gained during
commercial distribution
6

7. 5/9/2008
Lifecycle Approach
to Process Validation Commercial Production
Revised Process Validation Guidance (in progress) Validation in production
Process Design:
Lab, pilot, small-scale, and commercial scale studies to
small-
establish process Activities to continually assure that the process
remains in a state of control
Process Qualification:
Facility, utilities, and equipment
Confirm commercial process design
Commercialization:
Monitor, collect information, assess
Maintenance, continuous verification, process
improvement
Monitoring Periodic Evaluation
Timely monitoring of critical Re-
Re-validation – not using this term in the revised
operating and performance Process Validation Guidance
parameters
Monitoring of product
Production h
P d i phase monitoring
i i
characteristics (e.g., stability, product
specifications) evaluate quality indicator data, changes, and adverse trends
Monitoring adequacy of personnel periodically decide if new studies, e.g., conformances
training and material, batches or other verification experiments, need to be done
facility/equipment
Investigate problems for root cause Retrospective
and implement corrective action
FDA’s View of PAT Tools
Process Analytical Technologies
Process Analytical Technology (PAT)
a system for designing, analyzing, and controlling
PAT tools can be categorized as:
manufacturing Process analyzers
through timely measurements of critical quality and
performance attributes of raw and in-process materials and
f ib f d in-
i i l d Process control tools
processes Multivariate tools for design, data acquisition
with the goal of ensuring final product quality
and analysis
PAT Fundamental Tenets
Quality cannot be tested into the product; it should be Continuous improvement and knowledge management
built-in or should be by design
built- tools
PAT Goals
Enhance understanding and control of processes
PAT is more than just an analyzer!
7

8. 5/9/2008
FDA Progress in PAT Implementation FDA Progress in PAT Implementation
Training CMC Review experience
1st PAT Cadre – 15 investigators and reviewers ONDQA CMC pilot program
trained PAT Tools in all CMC pilots
PAT tools used in development
2nd PAT Cadre – 45 investigators and reviewers In-
In-process controls of manufacturing
being trained Process analyzers used for end-product release, including real time
end-
release
Pharmaceutical Inspectorate – training
incorporates fundamentals of PAT CMC applications outside the pilot
Model based feed-forward control
feed-
Reviewer training – multiple sessions on many PAT for product/batch release
aspects of PAT Additional implementation for generic and veterinary drugs
Industry Progress: Examples of Industry Progress: Examples of
PAT Tools in Development Process Analyzers in Manufacturing
In-
In-line laser light scattering analyzer to monitor Monitoring only:
nucleation during crystallization Assay by on-line measurement
on-
FTIR and FBRM (Focus Beam Reflectance Identity by on-line measurement
on-
Measurement) to understand crystal growth and
M t) t d t d t l th d On-
On-line particle size monitoring
nucleation Monitoring and control:
At-
At-line DSC to monitor crystalline form Table compression weight check and adjustment
Endpoint determination of blending
At-
At-line pressure test to force drug substance
degradation Weight check and adjustment of powder filling operation
Adjustment of process parameters based on starting material
At-
At-line particle size distribution monitoring attributes
NIR to understand & design blending process
Implementation of PAT
Implementation of PAT
Regulators/FDA Challenges Industry Challenges
Training reviewers and investigators
Lack of experience in developing and implementing
Developing new approaches for review and inspection
Integration of review and inspection
y
PAT systems
Communicating expectations to industry Training of scientific, operational and regulatory
International harmonization personnel
Industry’s apprehension in adopting new Fear of change
approaches and investing in new technologies Perceived regulatory risks
Industry’s apprehension in sharing information Investment - more resources needed initially
with FDA Management support crucial
8

9. 5/9/2008
What are the Challenges that
Lie Ahead?
Global Market Place
Variable Regulation or Understanding
of Product Quality
Economic Pressures and Incentives
The Need for Industry to Control
Sources and Outsourcing of Activities
9