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FDA Compliance and Regulatory SymposiumUnderstanding the FDA’s Latest cGMP
Guidances: Opportunities and Pitfalls
Claudio Pincus, President, The Quantic GroupR. Owen Richards, President, Quantic Regulatory Services
Daniel Pincus, Consultant, The Quantic Group
9AM Thursday August 25Harvard University
Copyright 2005, The Quantic Group, All Rights Reserved
5N Regent Street Suite 502 Livingston, NJ 07039 (973) 992 0505The Quantic Group sm
©2005, All Rights Reserved -2-Quantic
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 Quantic’s capabilities or experiences. These Methodologies remain the exclusive property of The Quantic Group, Ltd.
ContactClaudio Pincus, PresidentThe Quantic Group, Ltd. 5N Regent Street Suite 502Livingston, NJ [email protected] 992 0505
©2005, All Rights Reserved -3-Quantic
There are emerging efforts to improve the industry
“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
Introduction
1. J
. Ram
sbot
ham
, Sol
vay,
Gol
d S
heet
, Jun
e 20
042.
G. M
iglia
ccio
, Pfiz
er G
loba
l Ope
ratio
ns V
P, G
old
She
et J
une
2004
3. A
dapt
ed fr
om D
. Ells
wor
th, G
old
She
et, A
pril
2005
FDA oversight and pre-approval of manufacturing change will be replaced by the company making the change, subject to routine inspection3
“The present state is focused on documentation, following SOPs validating the process, meeting specifications, and not changing the process”2
“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
©2005, All Rights Reserved -4-Quantic
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
Industry has actively participated in the development and hopes that consistency will provide for a more competitive pharmaceutical manufacturing environment
Introduction
©2005, All Rights Reserved -5-Quantic
“The desired state … is for there to be a process control strategy that prevents or mitigates the risk of producing a poor quality
product”1
Introduction
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
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
1.D
. Hor
owitz
, FD
A, 8
/24/
04
2.J.
Fam
ular
e, C
DE
R, 2
004
Pre
sent
atio
n to
CH
PA
©2005, All Rights Reserved -6-Quantic
Current Situation
Faces resource cuts Industry’s technical challenges are increasingly complex Difficult to enforce manufacturing standards globally, with more
sites Perceived as a barrier to innovation, not an enabler
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
Lower trust in both FDA and Industry Seeks lower cost medications without compromising quality
cGMPs for the 21st Century
FDA
Industry
Public
©2005, All Rights Reserved -7-Quantic
The Objectives of the 21st Century Approach
The primary objectives of that initiative were to encourage innovation and new manufacturing technologies, to focus the agency’s resources on the areas of manufacturing considered to pose the most risk, and to improve the consistency and predictability of the agency’s 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
cGMPs for the 21st Century
1. F
rom
CG
MP
s to
Crit
ical
Pat
h, L
. Bus
h, P
harm
Tec
h, J
uly
2004
©2005, All Rights Reserved -8-Quantic
FDA desires for industry to have more knowledge and more control
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
cGMPs for the 21st Century
1.
Ph
arm
ace
utic
al C
GM
Ps
for
the
21st
Cen
tury
-Ris
k-B
ase
d A
pp
roa
ch F
ina
l Re
po
rt,
Se
pt 2
00
4
2.
D.
Ells
wo
rth,
FD
A,
Gol
d S
hee
t, M
ay
200
5
©2005, All Rights Reserved -9-Quantic
FDA’s “cGMPs for 21st Century” Initiative
In response to today’s challenges facing pharmaceutical manufacturing and quality,FDA launched its “Pharmaceutical cGMPs for the 21st Century” to:*
Focus FDA’s 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 FDA’s drug quality
regulatory programs by integrating enhanced quality systems approaches into the agency’s business processes and regulatory policies
1.
Ph
arm
ace
utic
al C
GM
Ps
for
the
21st
Cen
tury
-Ris
k-B
ase
d A
pp
roa
ch F
ina
l Re
po
rt,
Se
pt 2
00
4
2.
Fro
m c
GM
Ps
to t
he
Cri
tica
l Pa
th: F
DA
Fo
cuse
s o
n In
no
vatio
n,
Qu
alit
y a
nd
Co
ntin
uou
s Im
pro
vem
en
t – I
nsi
de a
nd
Ou
t, L
au
ra B
ush
. P
harm
ace
utic
al T
ech
no
log
y, J
uly
20
04
cGMPs for the 21st Century
©2005, All Rights Reserved -10-Quantic
Risk-Based Model for GMP Inspection and Product Quality Review
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 manufacturer’s understanding of its product and process Robustness of quality system Public health impact Manufacturer’s 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 manufacturer’s understanding of process control and
quality
cGMPs for the 21st Century
1. P
harm
aceu
tical
CG
MP
s fo
r th
e 21
st C
entu
ry, R
isk-
Bas
ed A
ppro
ach,
Fin
al R
epor
t, S
ept.
2004
©2005, All Rights Reserved -11-Quantic
Quality System Approaches
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
cGMPs for the 21st Century
1. P
harm
aceu
tical
CG
MP
s fo
r th
e 21
st C
entu
ry, R
isk-
Bas
ed A
ppro
ach,
Fin
al R
epor
t, S
ept.
2004
©2005, All Rights Reserved -12-Quantic
Science-Based Policies
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 post-approval
manufacturing changes
1. P
harm
aceu
tical
CG
MP
s fo
r th
e 21
st C
entu
ry, R
isk-
Bas
ed A
ppro
ach,
Fin
al R
epor
t, S
ept.
2004
©2005, All Rights Reserved -13-Quantic
Integration of Pre-Approval and cGMP Inspection Programs
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
cGMPs for the 21st Century
1. P
harm
aceu
tical
CG
MP
s fo
r th
e 21
st C
entu
ry, R
isk-
Bas
ed A
ppro
ach,
Fin
al R
epor
t, S
ept.
2004
©2005, All Rights Reserved -14-Quantic
International Collaboration for Compliance
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
cGMPs for the 21st Century
1. P
harm
aceu
tical
CG
MP
s fo
r th
e 21
st C
entu
ry, R
isk-
Bas
ed A
ppro
ach,
Fin
al R
epor
t, S
ept.
2004
©2005, All Rights Reserved -15-Quantic
Rule and Guidance Interpretations
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 ruleValidation 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 disseminationWarning 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
cGMPs for the 21st Century
1. P
harm
aceu
tical
CG
MP
s fo
r th
e 21
st C
entu
ry, R
isk-
Bas
ed A
ppro
ach,
Fin
al R
epor
t, S
ept.
2004
2. F
DA
Con
fere
nce
Rep
ort,
Dru
g Q
ualit
y S
yste
m: C
GM
Ps
for
a N
ew E
ra –
200
43.
J. F
use,
Jou
rnal
of V
alid
atio
n T
echn
olog
y, N
ov 2
004
©2005, All Rights Reserved -16-Quantic
FDA’s Next Steps
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 FDA’s 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 FDA’s 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
1. P
harm
aceu
tical
CG
MP
s fo
r th
e 21
st C
entu
ry, R
isk-
Bas
ed A
ppro
ach,
Fin
al R
epor
t, S
ept.
2004
©2005, All Rights Reserved -17-Quantic
Let’s 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
Systems thinking is a framework for seeing interrelationships rather than things, for seeing patterns of change rather than static snapshots3
The Quality System
1. D
. Hor
owitz
, FD
A, 8
/24/
042.
The
Qua
ntic
Gro
up3.
P. S
enge
, The
Fift
h D
isci
plin
e, 1
994
©2005, All Rights Reserved -18-Quantic
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:
Process Reliability and Product Consistency Batch Release, Stability, APR, Validation
Manufacturing & Lab Decision Process Change Control, Deviations, Notification to Management
Facility Reliability and Product Purity Facility Design, Facility Qualification, Contamination Control
The Quality System
1 A
s de
fined
by
The
Qua
ntic
Gro
up
©2005, All Rights Reserved -19-Quantic
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
The Quality System
©2005, All Rights Reserved -20-Quantic
Deming’s Plan-Do-Check-Act was a keystone in design of cGMP in the 1960’s
Do in Control
Check/Detect/Audit
Correct
Plan/Prevent
The Quality System
©2005, All Rights Reserved -21-Quantic
FDA Definition of Quality System Elements
The FDA definitionFor 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
The Quality System
©2005, All Rights Reserved -22-Quantic
Management Controls Quality System
Do In Control
Check/Detect/Audit
Correct
Plan/Prevent
. . . Everyone predictably responds
Organizational effectiveness for compliance is where . . .
The Quality System
©2005, All Rights Reserved -23-Quantic
Right now I think the agency has a view that it is actually involved too extensively in the management of change to pharmaceutical
processes1
The current regulatory review process before launch sets specifications, followed by the pre-approval inspectionMost 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
Design Space
1 A
dapt
ed fr
om D
. Ells
wor
th In
terv
iew
, Gol
d S
heet
s, A
pril
2005
©2005, All Rights Reserved -24-Quantic
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 react1
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
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
Design Space
1 A
dapt
ed fr
om D
. Ells
wor
th In
terv
iew
, Gol
d S
heet
s, A
pril
2005
©2005, All Rights Reserved -25-Quantic
FDA oversight and pre-approval of manufacturing change will be replaced by the company making the change, subject to routine inspection1
The benefit to industry is the later flexibility in the development process. It allows for continuous improvement and the management of change
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
Design Space
1 A
dapt
ed fr
om D
. Ells
wor
th In
terv
iew
, Gol
d S
heet
s, A
pril
2005
©2005, All Rights Reserved -26-Quantic
The New Quality System Incorporates Science, Change Process, Risk & Management Control
Do in Control
Check/Detect/Audit/Measure
Correct
Plan/PreventDesign SpaceDesign Space
PAT
RiskReal time test and trending
Processes and products
Revisit procedures, validation and organizations
Redesign
In-process parametersIn-house change process
Design Space
©2005, All Rights Reserved -27-Quantic
Risks are seen differently by agency and industry, with different actions needed at different stages
FDA•Risk decisions used to prioritize inspection resources
•Uses risk-based framework to prioritize sites for cGMP inspection
•Determines risk at the Plan 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 confidence
Site Risk Potential
Product Process Facility
Risk
Risk = Frequency x Severity -> SRP = %P x %P x %F
FDA
©2005, All Rights Reserved -28-Quantic
Risks are seen differently by agency and industry, with different actions needed at different stages
Industry
•Risk decisions are driven by company objectives
•Evaluates business, technical and compliance risks in the process of developing and manufacturing drugs
•Determines the risk-tolerance through decisions made at the Planning stage. Evaluates and reacts to risks that are identified in the Detect stage, including FDA inputs
Plan
Operate
Detect
Correct
Risk
Technology/Design Risk
Regulatory Risk
Business
Risk
Implementation
Risk
INDUSTRY
©2005, All Rights Reserved -29-Quantic
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)
FDA Enforcement
©2005, All Rights Reserved -30-Quantic
Culture & Compliance FDA Enforcement’s View
To avoid Consent Decrees, injunctions and related enforcement actions:1
Create and foster a corporate spirit (“Culture”) of compliance Establish internal systems and controls to define, measure,
monitor and assure compliance Obtain qualified, experienced, independent evaluations of your
company’s compliance Take prompt and comprehensive action to correct the violative
situation Monitor the corrective action to assure the fix works in both the
short term and long term Communicate promptly and constructively with FDA
Any attempt to excuse a violation on FDA’s 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
FDA Enforcement
1 E
. Blu
mbe
rg, D
eput
y A
ssoc
iate
, Offi
ce o
f Chi
ef C
ouns
el, O
ffice
of t
he
Com
mis
ione
r, F
DA
2 G
Dav
id H
orow
itz, F
DA
8/2
4/04
Prevent
Detect
Detect
Correct
Correct
Correct
©2005, All Rights Reserved -31-Quantic
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.
Consent Decrees
©2005, All Rights Reserved -32-Quantic
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
Management Controls
©2005, All Rights Reserved -33-Quantic
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 Roles, responsibilities and resources
of Quality Units to detect and correct deficiencies
President
Q
Q
MFG R&D
Dev ClinProdEng
QA
/QC
Management Controls
©2005, All Rights Reserved -34-Quantic
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
Q
Q
MFG R&D
Dev ClinProdEng
The Quality Unit
©2005, All Rights Reserved -35-Quantic
Implications of Management Controls on the Quality Unit
“Adequate” is open to interpretation
Challenges past behavior and decisions
Process is Intrusive
The Quality Unit
©2005, All Rights Reserved -36-Quantic
There are emerging efforts to improve the industry
Introduction
1 G
. Mig
liacc
io, P
fizer
Glo
bal O
pera
tions
VP
, Gol
d S
heet
Jun
e 20
04
US Pharmaceutical industry now has an opportunity and a duty to effect changes,So thatThe public health is ensured, andMore value is returned to shareholders
Is industry up to the challenge?
“The present state is focused on documentation, following SOPs validating the process, meeting specifications, and not changing the process”1
“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