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 - PowerPoint PPT Presentation

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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

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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


1
Quality Systems and Risk Management Approaches
for Networked Drug DevelopmentDavid A.
MoyerVP, Regulatory Compliance ProgramsFulcrum
Pharma Developments, Inc.PDA SciTech
SummitOrlando, FloridaMarch 10, 2004
2
Tailored Networked Team
Project Team
Sponsor
3
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

4
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.

5
Components of the CoreProgram
  • 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

6
Quality Pyramid
Qual System
Project Quality Plan
Project Plan
Standard Operating Procedures
7
Standard OperatingProcedures
  • 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

8
Quality Policy
  • 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

9
Document ControlEssential 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

10
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

11
Issues Capturing and ProvidingContext
  • 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

12
M.I.R.S. to Define, Capture and Communicate
Information
Message Issue Response/ Rationale Support
What do we want or need to say and what can we say? What stands in the way of the message? How do we overcome the issue? / What reasoning supports our message? Where are the data?
13
The MIRS Knowledge Process
Message Issues Response/ Rationale Support
Claims Features and benefits Advantages Interpretations Conclusions Issues Challenges Risks Comparisons Conflicting Results Questions New Studies Refutation Scientific precedent Re-analysis Expert opinion Designs/data Completed/ ongoing studies Publications Guidelines Precedents
14
M.I.R.S. Example
Message Issues Response/ Rationale Support
Final purification step is controlled, resulting in consistent production of polymorph A, which is stable and doesnt change in drug substance or drug product. Optimized purification procedure leads to the highest quality. Why was polymorph A the selected form? Would polymorph B alter the outcome of bio-availability? Polymorph A is the most stable form. Current recrystalliz-ation process ensures consistent formation of polymorph A. Lab data (thermo-dynamic and stability data) LIMS data (Polymorph B, which is specified, has not been seen since the current method of synthesis was established).
15
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

16
Building Supplier Relationships
SupplierEvaluation
Supplier Qualification
Supplier Audit
17
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
18
Issue and Resolution Log
SUPPLIER DATE OF AUDIT SIGNIFICANT ISSUES RESOLUTION DETAILS
CMO1 December 10-11, 2003 Frequent problems with dissolution testing Packaging area material control concern Review methods transfer package/run comparative tests Send auditor to monitor packaging
CRO1 February 12, 2004 No significant issues identified Not Applicable
19
Risk Management andthe New FDA
  • The CGMP regulations for drugs have not been
    updated in 25 years . . . Continuous quality
    improvement in manufacturing hasnt been the
    subject of as much attention in the
    pharmaceutical industry . . . FDAs 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.
  • FDAs Strategic Action Plan August 2003

20
Process AnalyticalTechnology
  • 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?

21
Risk Management for theLittle Guy
Hazard Analysis at Critical Control Points
(HACCP)
An Old Tool with a New Purpose
22
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

23
Steps for Building the HACCP Plan
  1. Define potential hazards (hazard analysis)
  2. Identify measurable critical control points
  3. Determine critical limits for control points
  4. Establish control point monitoring procedures
  5. Develop corrective action strategies for critical
    control point deviations
  6. Design effective documentation system
  7. Verify effectiveness of plan - periodically

24
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

25
STEP I - Conduct a HazardAnalysis
  • If you have a formal Corrective Action/Preventive
    Action (CAPA) Program - just harvest the data
  • What are the hazards? 
  • Equipment Failures
  • Critical Utility Failures
  • Process Failures
  • Computer Automation Failures
  • Documentation System Failures
  • Operator/Analyst Errors
  • Training System Shortfalls
  • Testing and Measurement Shortfalls

26
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
  • Batch records
  • Process steps
  • Pieces of equipment
  • Test procedures
  • Determine root cause of errors this identifies
    CCPs

27
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
28
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

29
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

30
Worksheet for Determining Monitoring Procedures
HACCP PLAN DEVELOPMENT FORM MONITORING PROCEDURES AND FREQUENCY Process or System Category HACCP PLAN DEVELOPMENT FORM MONITORING PROCEDURES AND FREQUENCY Process or System Category HACCP PLAN DEVELOPMENT FORM MONITORING PROCEDURES AND FREQUENCY Process or System Category
Process Step/CCP Critical Limits Monitoring Procedures (Who, What, When, How)



31
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
  •  Step V requires team to answer
  • Has the cause of a deviation been identified and
    eliminated?
  • Will the CCP be under control after corrective
    action has been taken?
  • Have measures to prevent recurrence of the
    deviation been established?
  • Do corrective action procedures ensure that no
    product which is injurious to health or otherwise
    adulterated because of the deviation enters
    commerce?

32
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

33
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

34
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
  • Validation of initial phase in which plan is
    tested and reviewed to determine that CCPs are
    effective and relevant to a well-controlled
    process
  • Ongoing verification to ensure that monitoring
    activities provide necessary data without
    negatively impacting the process
  • Annual reassessment (and modification, if
    necessary) of HACCP plan to ensure continued
    relevance of CCPs

35
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.
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