Transcript No Slide Title

Quality Systems and Risk Management
Approaches for Networked Drug
Development
David A. Moyer
VP, Regulatory Compliance Programs
Fulcrum Pharma Developments, Inc.
PDA SciTech Summit
Orlando, Florida
March 10, 2004
Tailored Networked Team
Project Team
Advisory
Boards
Sponsor
Regulatory/QA
CMC
Contract
Manufacturing
Organizations
Project
Manager
Project
Leader
Clinical
Preclinical
Project
Manager
Preclinical
Contract Labs
How do Regulators View Network
Prepared Submissions?
> Submission sponsor bears ultimate
responsibility - no difference!
> Expectation is to have an integrated
approach to quality even though many
quality systems are involved –
– Preclinical Supplier must meet GLP
– CRO(s) must meet GCP
– Drug Substance and Drug Product CMOs must
meet GMP
– Electronic data must meet appropriate 21 CFR
Part 11 security and retrieval requirements
Quality System Foundation
> It is essential to have a quality system in place at
the core of a drug development program that
complements, but does not interfere with the
suppliers’ programs.
Components of the Core
Program
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Project Quality Plans
Vendor qualification and approval system
Document control and record retention policy
Regulatory inspections policy
Staff training program
Program management procedures
Standardized audit plans for major development
activities
> Procedures for electronic records management,
including secure data sharing with clients
Quality Pyramid
Qual
System
Project
Quality Plan
Project Plan
Standard Operating Procedures
Standard Operating
Procedures
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Quality Policy
Document Control (Internal & External)
Employee Training
Project Plan and Protocol Development
Supplier Evaluation and Approval
IT Security
Data QA
Generation of Regulatory Documentation
Quality Policy
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Generation and execution of Project Quality Plan (PQP)
Performance of supplier audits and assessments in
accordance with PQP
Conduction of internal audits on an annual basis
Statement of quality and ethical standards
Statement and standards for suppliers
Review and approval of deliverables
Policy for data access to regulatory authorities and
third party consultants
Commitment to ensure internal and external (supplier)
compliance with applicable regulations
Document Control
Essential Elements
> A set of procedures to guide internal
generation of critical documentation to
satisfy regulatory guidelines
> A system for integrating internally and
externally generated documents to ensure
consistency while still protecting supplier
proprietary information
> Also covered by Supplier and Quality
Agreements in most cases
Planning for Quality
> Begins with development of project plan
– Gain complete understanding of project
objectives from:
• Sponsor project information
• Information in Master Service and Quality Agreements
• Supplier capabilities and performance history
> Risk Assessment Using M.I.R.S
– i.e. Capturing the Issues
Issues: Capturing and Providing
Context
Message, Issue, Response, Support
> Prepared based on team input and documented in
tables
> MIRS supports planning and communication based on
identifying objectives and issues at the beginning and
then regularly reviewing and updating
> MIRS tables are a useful and simple way of structuring
and recording project information
> MIRS tables are a communication tool and support
preparation of documents
M.I.R.S. to Define, Capture and
Communicate Information
Message
Issue
What do
we want or
need to
say and
what can
we say?
What
stands in
the way of
the
message?
Response/
Rationale
Support
How do we Where are
overcome the data?
the issue?
/ What
reasoning
supports
our
message?
The MIRS Knowledge
Process
Message
Issues
Response/
Rationale
Support
Claims
Issues
New Studies
Designs/data
Features and
benefits
Challenges
Refutation
Risks
Scientific
precedent
Completed/
ongoing
studies
Advantages
Comparisons
Interpretations
Conclusions
Publications
Re-analysis
Conflicting
Results
Guidelines
Expert opinion
Precedents
Questions
M.I.R.S. Example
Message
Issues
Response/
Rationale
Support
Final purification
a) Why was
a) Polymorph A a) Lab data
step is controlled,
polymorph A
is the most
(thermoresulting in
the selected
stable form.
dynamic and
consistent
form?
stability data)
b) Current
production of
b) Would
recrystallizb) LIMS data
polymorph A, which
polymorph B
ation
(Polymorph B,
is stable and
alter the
process
which is
doesn’t change in
outcome of
ensures
specified, has
drug substance or
bioconsistent
not been seen
drug product.
availability?
formation of
since the
Optimized
polymorph A.
current
purification
method of
procedure leads to
synthesis was
the highest quality.
established).
Project Quality Plan
> Project Quality Plan is a fully integrated
subset of the Project Plan. It defines:
– Quality expectations for each drug development
project
– Processes and activities to be completed to
ensure quality expectations are achieved at the
internal project management level and by
suppliers
– Rationale for specifying internal review criteria
and external supplier assessment methodology
Building Supplier Relationships
Supplier
Evaluation
Supplier
Qualification
Master
Service
Agreement
Supplier
Audit
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Culture and goals
Strategic fit
Overall expertise
Services provided
• Specific expertise and previous experience
• General capabilities e.g. facilities
equipment, staff and workload
• Organization structure, staff turnover and
affiliation
• Financial stability
• Project management, communication and
reporting
• Audit of Quality systems
• Tailored project audits
Planning Onsite Audits
SUPPLIER
TASKS ALLOCATED
AREA
TARGET
AUDIT
DATES
EXPECTED
DURATION
CMO 1
> QC testing of API and
Drug Product
> Drug Product Release
> Packaging, Labeling &
Distribution
> Supply of CTM Tablets
GMP
December
2003
2 days
onsite
CRO1
>Study Monitor / Drug
Safety Follow-up
GCP
February
2004
1 day
onsite
Issue and Resolution Log
SUPPLIER
CMO1
CRO1
DATE OF AUDIT
SIGNIFICANT
ISSUES
RESOLUTION
DETAILS
December 10-11, 1) Frequent
1) Review
2003
problems with
methods
dissolution
transfer
testing
package/run
comparative
2) Packaging
tests
area material
control
2) Send auditor
concern
to monitor
packaging
February 12,
2004
No significant
issues identified
Not Applicable
Risk Management and
the New FDA
“The CGMP regulations for drugs have not
been updated in 25 years . . . Continuous
quality improvement in manufacturing
hasn’t been the subject of as much
attention in the pharmaceutical industry . . .
FDA’s broad-based program is working on
developing new guidance based on the
latest science of risk management and
quality assurance.”
Quotes by Mark B. McClellan, M.D., Ph.D.
FDA’s Strategic Action Plan – August 2003
Process Analytical
Technology
The goal of PAT is to understand and control
the manufacturing process, i.e., quality
cannot be tested into products; it should be
built-in or should be by design.
Fantastic solution to promote innovation
given appropriate resources, but what risk
management/quality improvement options
are available to “little pharma” and
companies with existing products?
Risk Management for the
“Little Guy”
Hazard Analysis at Critical Control
Points (HACCP)
An Old Tool with a New Purpose
Back to the Future –
Ahead to the Past
> HACCP is a tried and tested methodology for
monitoring and managing processes
> Used by the FDA to protect US food supply since the
1970s
– Since December 1995, FDA requirement for seafood
producers to use HACCP principles - estimated to
prevent 20 - 60,000 seafood poisonings/year
> HACCP is:
– Simple by design
– Proactive in practice
– Easily incorporated into pharmaceutical compliance
programs
Steps for Building the
HACCP Plan
I.
II.
III.
IV.
Define potential hazards (hazard analysis)
Identify measurable critical control points
Determine critical limits for control points
Establish control point monitoring
procedures
V. Develop corrective action strategies for
critical control point deviations
VI. Design effective documentation system
VII. Verify effectiveness of plan - periodically
Preliminary Steps for Development of
Hazard Analysis Plan
> Establish a HACCP Team, including
Manufacturing, Quality, Engineering,
Validation, Development and the Laboratory
> Develop Master Scope Document describing
the process or processes to be covered
> Create Process Flow Diagram(s)
> Group similar/equivalent processes together
for consistency
STEP I - Conduct a Hazard
Analysis
> If you have a formal Corrective Action/Preventive
Action (CAPA) Program - just harvest the data
> What are the hazards?
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Equipment Failures
Critical Utility Failures
Process Failures
Computer Automation Failures
Documentation System Failures
Operator/Analyst Errors
Training System Shortfalls
Testing and Measurement Shortfalls
STEP II - Identify the Critical
Control Points (CCPs)
> A GMP-compliant company has a head start on Step II.
Most CCPs for equipment, process, utilities, and
computer automation are (should be!) documented in
validation files
> Challenge is to study CAPA data to learn about the
most variable component – PEOPLE
> What do you look for? Repetitive errors:
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Batch records
Process steps
Pieces of equipment
Test procedures
> Determine root cause of errors – this identifies CCPs
Step III - Establish Critical Limits for Each
Critical Control Point
> Like Step II, most CCP limits for equipment, process, utilities, and
computer automation are established and documented in validation
files
> Creativity needed to cover the rest of your operation - examples of
miscellaneous control limits based on deviations from normal
trends:
Control Parameter
Source of Control Limit
Check Point
Calibration Deviations
Calibration Database
Calibration Log
Yield Fluctuations
Annual Batch Record Review
Batch Review
Raw Material Variations
Vendor Quality Program
QC Insp & Release
Mechanical Failures
Preventive Maintenance Pgm
Maintenance Log
Training Failure
CAPA Program
Batch Review
Step IV - Establish Monitoring
Procedures (1)
"If you can't describe what you are doing as a
process, you don't know what you're doing"
– W. Edwards Deming
> Step IV ties all the GMP control systems together
and creates a very powerful proactive tool
> Monitoring procedures are standard activities done
routinely - by an employee or by mechanical
means (including computer controls) - that
measure the process at a given CCP and create a
record for future use
Step IV - Establish Monitoring
Procedures (2)
> Elements of the process:
– Requires input from cross-functional team
– Intervals of measurement determined by
considering potential corrective action responses
– Team must determine impact of a "critical HACCP
finding", i.e., does process need to stop?
– Format for reporting findings to a centralized
point must be established
Worksheet for Determining Monitoring
Procedures
HACCP PLAN DEVELOPMENT FORM: MONITORING
PROCEDURES AND FREQUENCY
Process or System Category:
Process Step/CCP
Critical Limits
Monitoring Procedures
(Who, What, When,
How)
Step V - Establish Corrective
Actions (1)
> CAPA program and HACCP come together at Step V by
which time the team has determined the:
– Critical Control Points (CCPs)
– Critical Limits for each Control Point
– Means of Measuring Performance at the CCPs
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Step V requires team to answer:
1. Has the cause of a deviation been identified and eliminated?
2. Will the CCP be under control after corrective action has been
taken?
3. Have measures to prevent recurrence of the deviation been
established?
4. Do corrective action procedures ensure that no product which is
injurious to health or otherwise adulterated because of the
deviation enters commerce?
Step V - Establish Corrective
Actions (2)
> Tools for getting the job done:
– Meaningful statistical feedback from CAPA
Program
– Root cause analysis techniques
– Responsible employees trained in the principles
of cGMP
STEP VI - Establish Record Keeping
Procedures
> Comprehensive list of all CCPs monitored
plus electronic and/or paper raw data
collection files
> Quarterly summary of findings by type of
hazard
> List of batches potentially affected by CCP
deviations
> Reports formal root cause analysis
evaluations
STEP VII - Establish Verification
Procedures
> HACCP process built on foundation and principles of
total quality system
– Objective is continuous process improvement
– Only achievable by becoming master of every step in your
process – no one else can/should know it better
> The verification process confirms that HACCP plan is
working and involves:
1. Validation of initial phase in which plan is tested and reviewed to
determine that CCPs are effective and relevant to a wellcontrolled process
2. Ongoing verification to ensure that monitoring activities provide
necessary data without negatively impacting the process
3. Annual reassessment (and modification, if necessary) of HACCP
plan to ensure continued relevance of CCPs
Summary
> FDA quality expectations for drug development are
the same for “big” and “small” pharma irrespective
of outsourcing used.
> The organization responsible for management of a
drug development project must have a core quality
program that serves as a foundation for applying
quality principles across the project.
> Supplier selection and management are key
components of drug development project quality.
> M.I.R.S. and HACCP are two simple risk
management tools that can be applied to any size
project.