FDA Compliance and Regulatory Symposium

Understanding the FDAs Latest cGMP Guidances:

Opportunities and Pitfalls
Claudio Pincus, President, The Quantic Group
R. Owen Richards, President, Quantic Regulatory Services
Daniel Pincus, Consultant, The Quantic Group

9AM Thursday August 25

Harvard University
Copyright 2005, The Quantic Group, All Rights Reserved

The Quantic Group sm

5N Regent Street Suite 502 Livingston, NJ 07039 (973) 992 0505

Copyright 2005,
All Rights Reserved
The Quantic Group, Ltd., Livingston, NJ
This document contains and refers to methodologies that are a
Trade Secret of The Quantic Group, Ltd. and are presented with the
purpose of describing Quantics capabilities or experiences. These
Methodologies remain the exclusive property of The Quantic Group,
Ltd.
Contact
Claudio Pincus, President
The Quantic Group, Ltd.
5N Regent Street
Suite 502
Livingston, NJ 07039
www.quanticgroup.com
info@quanticgroup.com
973 992 0505

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2005, All Rights Reserved

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Introduction

There are emerging efforts to improve the industry

The present state is focused on documentation, following

SOPs validating the process, meeting specifications, and
not changing the process2
The desired state, by contrast, would focus on
data analysis, understanding critical to quality
attributes, measuring process capability,
performing continuous quality verification, and
undertaking Continuous improvement 2
FDA oversight and pre-approval of
manufacturing change will be replaced
by the company making the change,
subject to routine inspection3

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2005, All Rights Reserved

1. J. Ramsbotham, Solvay, Gold Sheet, June 2004

2. G. Migliaccio, Pfizer Global Operations VP, Gold Sheet June 2004
3. Adapted from D. Ellsworth, Gold Sheet, April 2005

The ICH vision is to move beyond the limitations of the

current GMPs to create an integrated quality system that
encourages rather than stymies improvement 1

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Introduction
FDA is Defining Expectations for Industry

FDA has initiated a new approach toward cGMPs that creates

opportunities and pitfalls for industry
The new approach has been defined as cGMPs for the 21st

Century and includes multiple components intended to provide

consistency and efficiency

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Industry has actively participated in the development and

hopes that consistency will provide for a more competitive
pharmaceutical manufacturing environment

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Introduction
The desired state is for there to be a process control
strategy that prevents or mitigates the risk of producing a
poor quality product1

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2005, All Rights Reserved

2.

1.

The desired state of regulation2

[Transparent regulations] and up-to-date guidance
Managed within a quality system
Uses a risk management framework
Regulatory policies and procedures tailored to recognize the
level of scientific knowledge supporting product
applications and cGMP coverage of products
Risk based regulatory scrutiny that weighs factors such as
the capability of process control strategies to prevent or
mitigate risk of producing a poor quality product

D. Horowitz, FDA, 8/24/04

J. Famulare, CDER, 2004 Presentation to CHPA

The desired state of manufacturing2

Product quality and performance achieved and assured by
design of effective and efficient manufacturing processes
Continuous improvement approaches, with innovative use of
new technology as desired

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cGMPs for the 21st Century

Current Situation
FDA

Faces resource cuts

Industrys technical challenges are increasingly complex
Difficult to enforce manufacturing standards globally, with

more sites
Perceived as a barrier to innovation, not an enabler

Industry Since 1990 more than a dozen cGMP-related Consent

Decrees have incurred over $20bn in costs to industry
Because of regulatory constraints, Industry has been slow to
adopt innovative technologies to improve products and
operations
Pressure to reduce costs
Global manufacturing subject to not harmonized regulatory
requirements
Outsourcing has become a viable alternative with regulatory
implications
Public

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Lower trust in both FDA and Industry

Seeks lower cost medications without compromising quality

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cGMPs for the 21st Century

The primary objectives of that initiative were to encourage

innovation and new manufacturing technologies, to focus the
agencys resources on the areas of manufacturing considered to
pose the most risk, and to improve the consistency and
predictability of the agencys work in ensuring drug quality and
safety1
The FDA wants to take a new role as an enabler of the innovation
and change itself and industry to meet this new additional role

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1. From CGMPs to Critical Path, L. Bush, Pharm Tech, July 2004

The Objectives of the 21st Century Approach

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cGMPs for the 21st Century

FDA is restructuring its oversight of pharmaceutical quality

regulation by developing a product quality regulatory
system which provides a framework for implementing quality
by design, continuous improvement, and risk management.
The guiding principles are
Risk-based orientation
Integrated quality systems orientation
Science-based policies and standards
International cooperation
Strong public health protection

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2005, All Rights Reserved

1. Pharmaceutical CGMPs for the 21st Century-Risk-Based Approach Final Report, Sept 2004
2. D. Ellsworth, FDA, Gold Sheet, May 2005

FDA desires for industry to have more knowledge and more

control

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cGMPs for the 21st Century

In response to todays challenges facing pharmaceutical manufacturing

and quality,
FDA launched its Pharmaceutical cGMPs for the 21 st Century to:*
Focus FDAs resources on areas of greatest manufacturing risk
Encourage innovation and early adoption of advanced manufacturing

technologies

Facilitate industry application of modern quality management

techniques, including implementation of quality systems approaches

Encourage the use of risk-based approaches to focus on critical

areas

Ensure regulatory review, compliance and inspection policies are

based on state-of-the-art science

Enhance the consistency and coordination of FDAs drug quality

regulatory programs by integrating enhanced quality systems

approaches into the agencys business processes and regulatory
policies

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1. Pharmaceutical CGMPs for the 21st Century-Risk-Based Approach Final Report, Sept 2004
2. From cGMPs to the Critical Path: FDA Focuses on Innovation, Quality and Continuous
Improvement Inside and Out, Laura Bush. Pharmaceutical Technology, July 2004

FDAs cGMPs for 21st Century Initiative

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cGMPs for the 21st Century

To more efficiently and effectively use FDA resources to protect

public health, FDA now uses a risk-based model to prioritize
manufacturing sites for GMP inspection and product quality review.
The risk model considers the intensity and frequency of FDA
inspections, including:
The manufacturers understanding of its product and process
Robustness of quality system
Public health impact
Manufacturers compliance status and history

FDA applies the risk model to the product quality review process
to:
Focus on critical pharmaceutical quality attributes and their

relevance to safety and efficacy

Evaluate a manufacturers understanding of process control

and quality

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2005, All Rights Reserved

1. Pharmaceutical CGMPs for the 21st Century, Risk-Based Approach, Final Report,
Sept. 2004

Risk-Based Model for GMP Inspection

and Product Quality Review

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cGMPs for the 21st Century

FDA wants its regulatory practices to encourage implementation of

modern quality systems and risk management systems to satisfy
cGMPs.
By
Modern quality systems that correlate closely with regulatory
requirements
Achieving product quality characteristics
Processes to achieve quality by design
Risk management and assessment
CAPA
Change control
Quality Unit
Quality Systems Model
Management responsibilities
Resources
Manufacturing operations
Evaluation activities

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1. Pharmaceutical CGMPs for the 21st Century, Risk-Based Approach, Final Report,
Sept. 2004

Quality System Approaches

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cGMPs for the 21st Century

FDA encourages the application of enhanced science and engineering knowledge in

regulatory decision-making, establishment of specifications, and evaluation of
manufacturing processes to improve the efficiency and effectiveness of both
manufacturing and regulatory decision-making.
PAT
PAT brings a systems perspective to the design and control of
manufacturing processes
Regulatory framework to encourage voluntary development and
implementation of innovative approaches in pharmaceutical development,
manufacturing and quality assurance
New technologies are available that provide information on physical,
chemical, and microbiological characteristics of materials to improve process
understanding and to measure, control, and/or predict quality performance
Facilitates introduction of new technologies to improve efficiency and
effectiveness of manufacturing process design and control and quality
assurance
Comparability Protocols
Allows manufacturing changes without the submission of a prior approval
supplement
Establish to facilitate continuous improvement and innovation
Systemic, risk-based approach to review and approval process for postapproval manufacturing changes

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2005, All Rights Reserved

1. Pharmaceutical CGMPs for the 21st Century, Risk-Based Approach, Final Report,
Sept. 2004

Science-Based Policies

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cGMPs for the 21st Century

Pharmaceutical inspectorate seeks to improve the integration of

the pre-approval and cGMP inspection programs by using highly
trained individuals within Office of Regulatory Affairs (ORA) to:
Conduct inspections of pharmaceutical operations
Participate in other investigations that require their technical

expertise

Revised PAI inspection program

Eliminates mandatory categories for conducting inspections

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1. Pharmaceutical CGMPs for the 21st Century, Risk-Based Approach, Final Report,
Sept. 2004

Integration of Pre-Approval and cGMP Inspection Programs

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cGMPs for the 21st Century

Harmonization of international quality standards in the face of a

global economy to achieve public health goals and leverage
resources.
International Conference on Harmonization (ICH) quality standards:
Q8: Quality by Design and pharmaceutical development
Q9: Risk Management principles and tools
Q10: Quality systems enhancements emphasizing change
controls

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2005, All Rights Reserved

1. Pharmaceutical CGMPs for the 21st Century, Risk-Based Approach, Final Report,
Sept. 2004

International Collaboration for Compliance

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cGMPs for the 21st Century

FDA has implemented the guiding principles through various rule and
guidance interpretations.
Part 11
Addresses uncertainties of regulatory specifications, particularly
by narrowly defining electronic records subject to the rule
Validation
Deletes the reference to three validation batches at commercial
scale
Recognizes emerging technologies (PAT).
Aseptic processing
Incorporates a more risk-based approach
Modernization and automation
Dispute Resolution
Mechanism to surface scientific and technical disagreements
related to GMPs for resolution and dissemination
Warning Letter Review by Office of General Counsel
All proposals to issue warning letters to manufacturers are
reviewed by the centers and the Office of the Chief Counsel

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2005, All Rights Reserved

1. Pharmaceutical CGMPs for the 21st Century, Risk-Based Approach, Final Report,
Sept. 2004
2. FDA Conference Report, Drug Quality System: CGMPs for a New Era 2004
3. J. Fuse, Journal of Validation Technology, Nov 2004

Rule and Guidance Interpretations

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cGMPs for the 21st Century

The next phase of the cGMPs for the 21st Century initiative include: 1
Develop additional guidance on quality systems to enhance and modernize

the regulation of pharmaceutical manufacturing and product quality

Continue development of the risk-based pharmaceutical quality assessment

system that will replace the current CMC review to remove hurdles to
continuous improvement following drug approval

Revise the 1987 guideline on Process Validation to include 21st century

concepts, including risk management and a lifecycle approach

Continue to explore and formalize risk-based tools to enhance FDAs

regulatory oversight

Refine cGMPs and meet our harmonization (internal and international) goals
Continue timely communication of our current thinking on various quality

issues to the public to facilitate compliance with FDA requirements

Further enhance FDAs own quality systems (including more mechanisms to

facilitate communication within the FDA)

Continue and expand on opportunities to integrate science-based policy

standards into our product quality regulatory approach

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2005, All Rights Reserved

1. Pharmaceutical CGMPs for the 21st Century, Risk-Based Approach, Final Report,
Sept. 2004

FDAs Next Steps

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The Quality System

Lets define systems

GMPs are best viewed from a systems perspective The whole

exceeds the sum of the parts1

A system is a design of integrated components that can

measure the performance of the whole and can predictably and

consistently detect and correct deficiencies2

rather than things, for seeing patterns of change rather than

static snapshots3

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2005, All Rights Reserved

1. D. Horowitz, FDA, 8/24/04

2. The Quantic Group
3. P. Senge, The Fifth Discipline, 1994

Systems thinking is a framework for seeing interrelationships

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The Quality System

Product Quality Systems Definition1

A series of interrelated processes or activities

representing an integrated approach
to the philosophy and practices
contributing to drug substance and drug product
safety, identity, strength, purity and quality
The Product Quality Systems definition groups
the processes and activities into three main categories:

Batch Release, Stability, APR, Validation

Manufacturing & Lab Decision Process

Change Control, Deviations, Notification to Management

Facility Reliability and Product Purity

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Facility Design, Facility Qualification, Contamination Control

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1 As defined by The Quantic Group

Process Reliability and Product Consistency

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The Quality System

FDA Quality System Definition
This system assures overall compliance with cGMPs
and internal procedures and specifications
The system includes the quality control unit
and all of its review and approval duties
(e.g. change control, reprocessing, batch release,
annual product review, validation protocols, and
reports, etc.).
It includes all product defect evaluations
and evaluation of returned and salvaged drug products
See the CGMP regulation, 21 CFR 211 Subparts B, E, F, G, I, J, and K

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The Quality System

Demings Plan-Do-Check-Act was a keystone in design of cGMP in
the 1960s

Plan/Prevent

Correct

Do in Control

Check/Detect/
Audit

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The Quality System

FDA Definition of Quality System Elements
The FDA definition
For each of the following items, the firm should have written and approved
procedures . . . Verified through observation wherever possible . . .
Product reviews at least annually
Complaint reviews, quality and medical
Discrepancy and failure investigations related to manufacturing and
testing includes corrective action where appropriate
Change control
Product Improvement Projects
Reprocess/Rework
Returns/Salvages
Rejects
Stability Failures
Quarantine products
Validation
Training/qualification of employees in quality control unit functions

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The Quality System

Management Controls
Quality System

Organizational effectiveness for compliance is where . . .

Plan/Prevent

Correct

Do In Control

Check/Detect/
Audit

. . . Everyone predictably responds

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The current regulatory review process before launch sets

specifications, followed by the pre-approval inspection
Most changes are managed through an FDA prior-approval
process1
Issues with current regulatory approach:1
Product and process development may not be ideal
Validation may not be adequate to assure the process
capability
Continuous improvement is not optimal, lack of
adopting innovation

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2005, All Rights Reserved

1 Adapted from D. Ellsworth Interview, Gold Sheets, April 2005

Design Space
Right now I think the agency has a view that it is actually
involved too extensively in the management of change to
pharmaceutical processes1

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Design Space
It is really a multi-dimensional space that defines how different
variables interact with each other and shows all the different things
that can happen and how the process and product will react 1

The data can be developed and shared with FDA

Design Space requires a multivariate analysis of related

critical to quality parameters

Design space allows FDA to base their agreement on

specifications on data

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2005, All Rights Reserved

1 Adapted from D. Ellsworth Interview, Gold Sheets, April 2005

Part of the solution is the new focus on Design Space, a

concept for filing additional development data at approval to
justify broader manufacturing parameters based on the
science of the product1

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Design Space
FDA oversight and pre-approval of manufacturing change will be
replaced by the company making the change, subject to routine
inspection1

The benefits come in the post approval process, when

changes within the design space parameters are allowed
and will simply be reviewed on the next cGMP inspection as
a matter of course

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2005, All Rights Reserved

1 Adapted from D. Ellsworth Interview, Gold Sheets, April 2005

The benefit to industry is the later flexibility in the

development process. It allows for continuous
improvement and the management of change

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Design Space
The New Quality System
Incorporates Science, Change Process, Risk & Management Control

Redesign

Plan/Prevent

Design Space

In-house change process

Design Space
In-process parameters

Correct

Do in Control

Revisit procedures,
validation and
organizations

PAT

Check/Detect/
Audit/Measure

Risk

Real time test and trending

Processes and products

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Risk
Risks are seen differently by agency and industry, with
different actions needed at different stages
FDA

FDA
Risk decisions used to prioritize
Site Risk Potential
inspection resources
Uses risk-based framework to
prioritize sites for cGMP
Product
Process
Facility
inspection
Risk = Frequency x Severity
Determines risk at the Plan
-> SRP = %P x %P x %F
stage, primarily through the
Approval process for new drugs
and the pre-approval of changes
Based on product history,
process characteristics, and
facility history
Uses the site risk potential to
evaluate which sites to audit in
the Detect stage
Primarily focused on product
risk to patients, but also risks of
non-supply and risk to consumer
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confidence

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Risk
Risks are seen differently by agency and industry, with
different actions needed at different stages

Industry

INDUSTRY
Technology/Design Risk
ess
Busin
R i sk

Plan

Correct

Im
p
R i s l em
e
k

Operate
Detect
Regulatory Risk

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nta
tio
n

Risk decisions are driven by

company objectives
Evaluates business,
technical and compliance
risks in the process of
developing and
manufacturing drugs
Determines the risktolerance through decisions
made at the Planning stage.
Evaluates and reacts to risks
that are identified in the
Detect stage, including FDA
inputs

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FDA Enforcement
US v. Park (1975)
US v. Dotterweich (1943)

Industry has the responsibility to put in place systems for

assurance and prevention
The assurance provisions of the Act are deemed
demanding, but industry has chosen this work, and retains
the responsibility to protect the public (Park)
There is no one else who is in a position to act
preventively to avoid problems with public health
(Dotterweich)

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FDA Enforcement

To avoid Consent Decrees, injunctions and related enforcement

actions:1
Prevent Create and foster a corporate spirit (Culture) of
compliance
Detect Establish internal systems and controls to define, measure,
monitor and assure compliance
Detect Obtain qualified, experienced, independent evaluations of
your companys compliance
Correct Take prompt and comprehensive action to correct the
violative situation
Correct Monitor the corrective action to assure the fix works in
both the short term and long term
Correct Communicate promptly and constructively with FDA
Any attempt to excuse a violation on FDAs failure to discover the
problem during previous inspections will not be heard
sympathetically. It is your responsibility to assure the continuous
compliance of your processes and products1
FDA does not bear the burden to prove that a GMP violation would
cause an unsafe or ineffective product to be marketed2

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1 E. Blumberg, Deputy Associate, Office of Chief Counsel, Office of the

Commisioner, FDA
2 G David Horowitz, FDA 8/24/04

Culture & Compliance

FDA Enforcements View

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Consent Decrees
Consent Decrees are Court enforced contracts . . .

. . . created to ensure the prompt correction

of certain deficiencies
while safeguarding the public.
Related to:
Products
Facilities
Systems
Organizational Structures

to achieve compliance with Laws & Regulations.

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Management Controls
Management Controls and
Quality Unit Warning Letter Issues

The QUALITY ASSURANCE UNIT failed to follow written procedures,

which require OVERSIGHT and REVIEW responsibilities

Company failed to have a QUALITY CONTROL UNIT adequate to

perform its functions and responsibilities

Company failed to establish procedures for MANAGEMENT with

executive responsibility to review the suitability and effectiveness

of the quality system to ensure that the system satisfies the
requirements

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Management Controls
Consent Decree Requirement for
Evaluation of Management Controls

Evaluate the ADEQUACY of:

Prevent

Organizational structure and responsibilities

of ALL involved in manufacture
PREVENT
Qualification of personnel and appropriate
numbers
DETECT and CORRECT
President
Roles, responsibilities and resources
of Quality Units to detect and correct
MFG
Q R&D
deficiencies

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Prod

QA/QC

Eng

Dev

Clin

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The Quality Unit

Consent Decree Requirement for the
Evaluation of Quality Units
Consultant to evaluate whether the Quality Unit Program is:
Comprehensive
Adequate to ensure compliance (In Place) and followed (In Use)
Inclusive of policies, compliance monitoring, internal audits,

training, investigations, records management

President

Eng

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MFG

R&D

Prod

Dev

Clin

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The Quality Unit

Implications of Management Controls on the Quality Unit

Adequate is open to interpretation

Challenges past behavior and decisions
Process is Intrusive

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Introduction

There are emerging efforts to improve the industry

The desired state, by contrast, would focus on

data analysis, understanding critical to quality
attributes, measuring process capability,
performing continuous quality verification, and
undertaking Continuous improvement 1
US Pharmaceutical industry now has an opportunity and a
duty to effect changes,
So that
The public health is ensured, and
More value is returned to shareholders
Is industry up to the challenge?

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2005, All Rights Reserved

1 G. Migliaccio, Pfizer Global Operations VP, Gold Sheet June 2004

The present state is focused on documentation, following

SOPs validating the process, meeting specifications, and
not changing the process1

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