Pda Sci Tech

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Quality Systems and Risk Management

Approaches for Networked DrugDevelopment

David A. Moyer

VP, Regulatory Compliance ProgramsFulcrum Pharma Developments, Inc.

PDA SciTech Summit

Orlando, FloridaMarch 10, 2004


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Tailored Networked Team

Project TeamAdvisoryBoards

Project

Manager

Preclinical

Contract Labs

Project

ManagerContract

Manufacturing

Organizations

Regulatory/QA

Clinical

Preclinical

Project

LeaderCMC

Clinical

Contract Research

Organization

Project

Manager

Sponsor


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How do Regulators View NetworkPrepared Submissions?

> Submission sponsor bears ultimateresponsibility - no difference!

> Expectation is to have an integratedapproach to quality even though manyquality systems are involved Preclinical Supplier must meet GLP

CRO(s) must meet GCP

Drug Substance and Drug Product CMOs mustmeet GMP

Electronic data must meet appropriate 21 CFR Part11 security and retrieval requirements


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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.


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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


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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


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Quality Policy

> Generation and execution of Project Quality Plan (PQP)

> Performance of supplier audits and assessments inaccordance 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 thirdparty consultants

> Commitment to ensure internal and external (supplier)compliance with applicable regulations

D C l


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Document ControlEssential Elements

>A set of procedures to guide internalgeneration of critical documentation to

satisfy regulatory guidelines

> A system for integrating internally and

externally generated documents to ensureconsistency while still protecting supplier

proprietary information

> Also covered by Supplier and Quality

Agreements in most cases


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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


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Issues: Capturing and ProvidingContext

Message, Issue, Response, Support

> Prepared based on team input and documented intables

> MIRS supports planning and communication based on

identifying objectives and issues at the beginning andthen regularly reviewing and updating

> MIRS tables are a useful and simple way of structuringand recording project information

> MIRS tables are a communication tool and supportpreparation of documents


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M.I.R.S. to Define, Capture andCommunicate Information

Message Issue Response/

Rationale

Support

What do wewant or need

to say andwhat can wesay?

What standsin the way of

themessage?

How do weovercome the

issue? / Whatreasoningsupports ourmessage?

Where arethe data?

Th MIRS K l d


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The MIRS KnowledgeProcess

Message Issues Response/

Rationale

Support

Claims

Features andbenefits

Advantages

Interpretations

Conclusions

Issues

Challenges

RisksComparisons

ConflictingResults

Questions

New Studies

Refutation

Scientificprecedent

Re-analysis

Expert opinion

Designs/data

Completed/ongoing studies

Publications

Guidelines

Precedents


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M.I.R.S. Example

Message Issues Response/

Rationale

Support

Final purification step iscontrolled, resulting inconsistent productionof polymorph A, whichis stable and doesnt

change in drugsubstance or drugproduct. Optimizedpurification procedureleads to the highestquality.

a) Why waspolymorph Athe selectedform?

b) Would

polymorph Balter theoutcome of bio-availability?

a) Polymorph A isthe most stableform.

b) Currentrecrystalliz-

ation processensuresconsistentformation ofpolymorph A.

a) Lab data(thermo-dynamicand stabilitydata)

b) LIMS data

(Polymorph B,which isspecified, hasnot been seensince the currentmethod of

synthesis wasestablished).


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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 toensure quality expectations are achieved at the

internal project management level and by

suppliers

Rationale for specifying internal review criteria

and external supplier assessment methodology


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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


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Planning Onsite Audits

SUPPLIER TASKS ALLOCATED AREA TARGET

AUDIT DATES

EXPECTED

DURATION

CMO 1 > QC testing of API and DrugProduct

> Drug Product Release

> Packaging, Labeling &Distribution

> Supply of CTM Tablets

GMP December 2003

2 days onsite

CRO1 >Study Monitor / Drug SafetyFollow-up

GCP February 20041 day onsite


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Issue and Resolution Log

SUPPLIER DATE OF AUDIT SIGNIFICANTISSUES

RESOLUTIONDETAILS

CMO1 December 10-11,2003

1) Frequentproblems withdissolutiontesting

2) Packaging areamaterial controlconcern

1) Review methodstransferpackage/runcomparativetests

2) Send auditor tomonitorpackaging

CRO1 February 12, 2004 No significantissues identified

Not Applicable

Ri k M t d


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Risk Management andthe New FDA

The CGMP regulations for drugs have notbeen updated in 25 years . . . Continuousquality improvement in manufacturinghasnt been the subject of as muchattention in the pharmaceutical industry . . .

FDAs broad-based program is working ondeveloping new guidance based on thelatest science of risk management andquality assurance.

Quotes by Mark B. McClellan, M.D., Ph.D.

FDAs Strategic Action Plan August 2003

P A l ti l


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Process AnalyticalTechnology

The goal of PAT is to understand and controlthe manufacturing process, i.e., qualitycannot be tested into products; it should bebuilt-in or should be by design.

Fantastic solution to promote innovationgiven appropriate resources, but what riskmanagement/quality improvement optionsare available to little pharma andcompanies with existing products?

Ri k M t f th


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Risk Management for theLittle Guy

Hazard Analysis at Critical ControlPoints (HACCP)

An Old Tool with a New Purpose

Back to the Future


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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 the1970s Since December 1995, FDA requirement for seafood

producers to use HACCP principles - estimated to prevent20 - 60,000 seafood poisonings/year

> HACCP is:

Simple by design

Proactive in practice Easily incorporated into pharmaceutical compliance

programs

Steps for Building the


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Steps for Building theHACCP 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 systemVII. Verify effectiveness of plan - periodically

Preliminary Steps for Development of


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Preliminary Steps for Development ofHazard Analysis Plan

> Establish a HACCP Team, includingManufacturing, 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 togetherfor consistency

STEP I Conduct a Hazard


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STEP I - Conduct a HazardAnalysis

> If you have a formal Corrective Action/PreventiveAction (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

STEP II Identify the Critical


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STEP II - Identify the CriticalControl Points (CCPs)

> A GMP-compliant company has a head start on Step II.

Most CCPs for equipment, process, utilities, andcomputer automation are (should be!) documented invalidation 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

Step III Establish Critical Limits for Each


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Step III - Establish Critical Limits for EachCritical 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


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Step IV - Establish MonitoringProcedures (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 togetherand creates a very powerful proactive tool

> Monitoring procedures are standard activities doneroutinely - by an employee or by mechanical means

(including computer controls) - that measure theprocess at a given CCP and create a record forfuture use

Step IV - Establish Monitoring


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> 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 MonitoringProcedures (2)

Worksheet for Determining Monitoring


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Worksheet for Determining MonitoringProcedures

HACCP PLAN DEVELOPMENT FORM: MONITORINGPROCEDURES AND FREQUENCY

Process or System Category:

Process Step/CCP Critical Limits Monitoring Procedures

(Who, What, When, How)

Step V - Establish Corrective


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Step V - Establish CorrectiveActions (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 beentaken?

3. Have measures to prevent recurrence of the deviation been

established?4. Do corrective action procedures ensure that no product whichis injurious to health or otherwise adulterated because of thedeviation enters commerce?

Step V - Establish Corrective


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Step V - Establish CorrectiveActions (2)

> Tools for getting the job done:

Meaningful statistical feedback from CAPA

Program

Root cause analysis techniques

Responsible employees trained in the principles ofcGMP

STEP VI - Establish Record Keeping


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STEP VI - Establish Record KeepingProcedures

>Comprehensive list of all CCPs monitoredplus electronic and/or paper raw datacollection files

> Quarterly summary of findings by type of

hazard

> List of batches potentially affected by CCPdeviations

> Reports formal root cause analysisevaluations

STEP VII - Establish Verification


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STEP VII - Establish VerificationProcedures

> 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 yourprocess no one else can/should know it better

> The verification process confirms that HACCP plan isworking 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 providenecessary data without negatively impacting the process

3. Annual reassessment (and modification, if necessary) of HACCPplan to ensure continued relevance of CCPs

S


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Summary

> FDA quality expectations for drug development are

the same for big and small pharma irrespectiveof outsourcing used.

> The organization responsible for management of a

drug development project must have a core quality

program that serves as a foundation for applyingquality 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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