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Quality Systems and Risk Management Approaches for Networked Drug Development David A. Moyer VP, Regulatory Compliance Programs Fulcrum Pharma Developments,

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Presentation on theme: "Quality Systems and Risk Management Approaches for Networked Drug Development David A. Moyer VP, Regulatory Compliance Programs Fulcrum Pharma Developments,"— Presentation transcript:

1 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

2 Tailored Networked Team Project Team Advisory Boards Project Manager Preclinical Contract Labs Project Manager Contract Manufacturing Organizations Regulatory/QA Clinical Preclinical Project Leader CMC Clinical Contract Research Organization Project Manager 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 Core Program >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 Standard Operating Procedures Project Plan Project Quality Plan Qual System

7 Standard Operating Procedures >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 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

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 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

12 M.I.R.S. to Define, Capture and Communicate Information MessageIssueResponse/ 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 MessageIssuesResponse/ 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 MessageIssuesResponse/ 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. a)Why was polymorph A the selected form? b)Would polymorph B alter the outcome of bio- availability? a)Polymorph A is the most stable form. b)Current recrystalliz- ation process ensures consistent formation of polymorph A. a)Lab data (thermo- dynamic and stability data) b)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 Supplier Evaluation Supplier Qualification Supplier Audit Master Service Agreement 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 Culture and goals Strategic fit Overall expertise Services provided

17 Planning Onsite Audits SUPPLIERTASKS ALLOCATEDAREATARGET AUDIT DATES EXPECTED DURATION CMO 1>QC testing of API and Drug Product >Drug Product Release >Packaging, Labeling & Distribution >Supply of CTM Tablets GMPDecember days onsite CRO1>Study Monitor / Drug Safety Follow-up GCPFebruary day onsite

18 Issue and Resolution Log SUPPLIERDATE OF AUDITSIGNIFICANT ISSUES RESOLUTION DETAILS CMO1December 10-11, )Frequent problems with dissolution testing 2)Packaging area material control concern 1)Review methods transfer package/run comparative tests 2)Send auditor to monitor packaging CRO1February 12, 2004 No significant issues identified Not Applicable

19 Risk Management and the 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 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?

21 Risk Management for the Little 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 ,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 I.Define potential hazards (hazard analysis) II.Identify measurable critical control points III.Determine critical limits for control points IV.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

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 Hazard Analysis >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 ParameterSource of Control LimitCheck Point Calibration DeviationsCalibration DatabaseCalibration Log Yield FluctuationsAnnual Batch Record ReviewBatch Review Raw Material VariationsVendor Quality ProgramQC Insp & Release Mechanical FailuresPreventive Maintenance PgmMaintenance Log Training FailureCAPA ProgramBatch 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 >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 Step IV - Establish Monitoring Procedures (2)

30 Worksheet for Determining Monitoring Procedures HACCP PLAN DEVELOPMENT FORM: MONITORING PROCEDURES AND FREQUENCY Process or System Category: Process Step/CCPCritical LimitsMonitoring 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: 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?

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: 1.Validation of initial phase in which plan is tested and reviewed to determine that CCPs are effective and relevant to a well- controlled 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

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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