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FDA Compliance and Regulatory SymposiumUnderstanding the FDAs Latest cGMP Guidances: Opportunities and PitfallsClaudio Pincus, President, The Quantic GroupR. Owen Richards, President, Quantic Regulatory ServicesDaniel Pincus, Consultant, The Quantic Group

9AM Thursday August 25Harvard University

Copyright 2005, The Quantic Group, All Rights Reserved5N Regent Street Suite 502 Livingston, NJ 07039 (973) 992 0505

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Copyright 2005,All Rights Reserved The Quantic Group, Ltd., Livingston, NJThis document contains and refers to methodologies that are a Trade Secret of The Quantic Group, Ltd. and are presented with the purpose of describing Quantics 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


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 1Introduction1. J. Ramsbotham, Solvay, Gold Sheet, June 20042. G. Migliaccio, Pfizer Global Operations VP, Gold Sheet June 20043. Adapted from D. Ellsworth, Gold Sheet, April 2005FDA oversight and pre-approval of manufacturing change will be replaced by the company making the change, subject to routine inspection3The present state is focused on documentation, following SOPs validating the process, meeting specifications, and not changing the process2The 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


FDA is Defining Expectations for IndustryFDA 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


The desired state is for there to be a process control strategy that prevents or mitigates the risk of producing a poor quality product1IntroductionThe desired state of manufacturing2Product quality and performance achieved and assured by design of effective and efficient manufacturing processesContinuous improvement approaches, with innovative use of new technology as desired

The desired state of regulation2[Transparent regulations] and up-to-date guidanceManaged within a quality systemUses a risk management frameworkRegulatory policies and procedures tailored to recognize the level of scientific knowledge supporting product applications and cGMP coverage of productsRisk based regulatory scrutiny that weighs factors such as the capability of process control strategies to prevent or mitigate risk of producing a poor quality productD. Horowitz, FDA, 8/24/04J. Famulare, CDER, 2004 Presentation to CHPA


Current SituationFaces resource cutsIndustrys technical challenges are increasingly complexDifficult to enforce manufacturing standards globally, with more sitesPerceived 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 industryBecause of regulatory constraints, Industry has been slow to adopt innovative technologies to improve products and operationsPressure to reduce costsGlobal manufacturing subject to not harmonized regulatory requirementsOutsourcing has become a viable alternative with regulatory implications

Lower trust in both FDA and IndustrySeeks lower cost medications without compromising qualitycGMPs for the 21st CenturyFDA

Industry

Public


The Objectives of the 21st Century Approach

The primary objectives of that initiative were to encourage innovation and new manufacturing technologies, to focus the agencys resources on the areas of manufacturing considered to pose the most risk, and to improve the consistency and predictability of the agencys 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 Century1. From CGMPs to Critical Path, L. Bush, Pharm Tech, July 2004


FDA desires for industry to have more knowledge and more controlFDA 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 areRisk-based orientationIntegrated quality systems orientationScience-based policies and standardsInternational cooperationStrong public health protectioncGMPs for the 21st Century1. Pharmaceutical CGMPs for the 21st Century-Risk-Based Approach Final Report, Sept 20042. D. Ellsworth, FDA, Gold Sheet, May 2005


FDAs cGMPs for 21st Century InitiativeIn response to todays challenges facing pharmaceutical manufacturing and quality, FDA launched its Pharmaceutical cGMPs for the 21st Century to:*Focus FDAs resources on areas of greatest manufacturing riskEncourage innovation and early adoption of advanced manufacturing technologiesFacilitate industry application of modern quality management techniques, including implementation of quality systems approachesEncourage the use of risk-based approaches to focus on critical areasEnsure regulatory review, compliance and inspection policies are based on state-of-the-art scienceEnhance the consistency and coordination of FDAs drug quality regulatory programs by integrating enhanced quality systems approaches into the agencys business processes and regulatory policies1. Pharmaceutical CGMPs for the 21st Century-Risk-Based Approach Final Report, Sept 20042. From cGMPs to the Critical Path: FDA Focuses on Innovation, Quality and Continuous Improvement Inside and Out, Laura Bush. Pharmaceutical Technology, July 2004cGMPs for the 21st Century


Risk-Based Model for GMP Inspection and Product Quality ReviewTo 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 manufacturers understanding of its product and processRobustness of quality systemPublic health impactManufacturers 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 efficacyEvaluate a manufacturers understanding of process control and qualitycGMPs for the 21st Century1. Pharmaceutical CGMPs for the 21st Century, Risk-Based Approach, Final Report, Sept. 2004


Quality System ApproachesFDA wants its regulatory practices to encourage implementation of modern quality systems and risk management systems to satisfy cGMPs.ByModern quality systems that correlate closely with regulatory requirementsAchieving product quality characteristicsProcesses to achieve quality by design Risk management and assessmentCAPAChange controlQuality UnitQuality Systems ModelManagement responsibilitiesResourcesManufacturing operationsEvaluation activitiescGMPs for the 21st Century1. Pharmaceutical CGMPs for the 21st Century, Risk-Based Approach, Final Report, Sept. 2004


Science-Based PoliciescGMPs for the 21st CenturyFDA 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.PATPAT brings a systems perspective to the design and control of manufacturing processesRegulatory framework to encourage voluntary development and implementation of innovative approaches in pharmaceutical development, manufacturing and quality assuranceNew 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 performanceFacilitates introduction of new technologies to improve efficiency and effectiveness of manufacturing process design and control and quality assuranceComparability ProtocolsAllows manufacturing changes without the submission of a prior approval supplementEstablish to facilitate continuous improvement and innovationSystemic, risk-based approach to review and approval process for post-approval manufacturing changes1. Pharmaceutical CGMPs for the 21st Century, Risk-Based Approach, Final Report, Sept. 2004


Integration of Pre-Approval and cGMP Inspection ProgramsPharmaceutical 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 operationsParticipate in other investigations that require their technical expertise

Revised PAI inspection programEliminates mandatory categories for conducting inspectionscGMPs for the 21st Century1. Pharmaceutical CGMPs for the 21st Century, Risk-Based Approach, Final Report, Sept. 2004


International Collaboration for ComplianceHarmonization 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 developmentQ9: Risk Management principles and toolsQ10: Quality systems enhancements emphasizing change controlscGMPs for the 21st Century1. Pharmaceutical CGMPs for the 21st Century, Risk-Based Approach, Final Report, Sept. 2004


Rule and Guidance InterpretationsFDA has implemented the guiding principles through various rule and guidance interpretations.

Part 11Addresses uncertainties of regulatory specifications, particularly by narrowly defining electronic records subject to the ruleValidationDeletes the reference to three validation batches at commercial scaleRecognizes emerging technologies (PAT).Aseptic processingIncorporates a more risk-based approachModernization and automationDispute ResolutionMechanism to surface scientific and technical disagreements related to GMPs for resolution and disseminationWarning Letter Review by Office of General CounselAll proposals to issue warning letters to manufacturers are reviewed by the centers and the Office of the Chief CounselcGMPs for the 21st Century1. Pharmaceutical CGMPs for the 21st Century, Risk-Based Approach, Final Report, Sept. 20042. FDA Conference Report, Drug Quality System: CGMPs for a New Era 20043. J. Fuse, Journal of Validation Technology, Nov 2004


FDAs Next StepscGMPs for the 21st CenturyThe next phase of the cGMPs for the 21st Century initiative include:1Develop additional guidance on quality systems to enhance and modernize the regulation of pharmaceutical manufacturing and product qualityContinue development of the risk-based pharmaceutical quality assessment system that will replace the current CMC review to remove hurdles to continuous improvement following drug approvalRevise the 1987 guideline on Process Validation to include 21st century concepts, including risk management and a lifecycle approachContinue to explore and formalize risk-based tools to enhance FDAs regulatory oversightRefine cGMPs and meet our harmonization (internal and international) goalsContinue timely communication of our current thinking on various quality issues to the public to facilitate compliance with FDA requirementsFurther enhance FDAs 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 approach1. Pharmaceutical CGMPs for the 21st Century, Risk-Based Approach, Final Report, Sept. 2004


Lets define systemsGMPs are best viewed from a systems perspective The whole exceeds the sum of the parts1A system is a design of integrated components that can measure the performance of the whole and can predictably and consistently detect and correct deficiencies2Systems thinking is a framework for seeing interrelationships rather than things, for seeing patterns of change rather than static snapshots3The Quality System1. D. Horowitz, FDA, 8/24/042. The Quantic Group3. P. Senge, The Fifth Discipline, 1994


Product Quality Systems Definition1A 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 ConsistencyBatch Release, Stability, APR, ValidationManufacturing & Lab Decision Process Change Control, Deviations, Notification to ManagementFacility Reliability and Product PurityFacility Design, Facility Qualification, Contamination ControlThe Quality System1 As defined by The Quantic Group


FDA Quality System DefinitionThis 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 KThe Quality System


Demings Plan-Do-Check-Act was a keystone in design of cGMP in the 1960sDo in ControlCheck/Detect/AuditCorrectPlan/PreventThe Quality System


FDA Definition of Quality System ElementsThe FDA definitionFor each of the following items, the firm should have written and approved procedures . . . Verified through observation wherever possible . . . Product reviews at least annuallyComplaint reviews, quality and medicalDiscrepancy and failure investigations related to manufacturing and testing includes corrective action where appropriateChange controlProduct Improvement ProjectsReprocess/ReworkReturns/SalvagesRejectsStability FailuresQuarantine productsValidationTraining/qualification of employees in quality control unit functionsThe Quality System


Management Controls Quality SystemDo In ControlCheck/Detect/ AuditCorrectPlan/Prevent. . . Everyone predictably respondsOrganizational effectiveness for compliance is where . . . The Quality System


Right now I think the agency has a view that it is actually involved too extensively in the management of change to pharmaceutical processes1The 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:1Product and process development may not be idealValidation may not be adequate to assure the process capabilityContinuous improvement is not optimal, lack of adopting innovationDesign Space1 Adapted from D. Ellsworth Interview, Gold Sheets, April 2005


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 react1Part 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 dataDesign Space1 Adapted from D. Ellsworth Interview, Gold Sheets, April 2005


FDA oversight and pre-approval of manufacturing change will be replaced by the company making the change, subject to routine inspection1The 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 courseDesign Space1 Adapted from D. Ellsworth Interview, Gold Sheets, April 2005


The New Quality System Incorporates Science, Change Process, Risk & Management ControlDo in ControlCheck/Detect/Audit/MeasureCorrectPlan/PreventDesign SpaceDesign SpacePATRiskReal time test and trendingProcesses and productsRevisit procedures, validation and organizationsRedesignIn-process parametersIn-house change processDesign Space


Risks are seen differently by agency and industry, with different actions needed at different stages RiskRisk = Frequency x Severity -> SRP = %P x %P x %FFDA

FDARisk decisions used to prioritize inspection resourcesUses risk-based framework to prioritize sites for cGMP inspectionDetermines risk at the Plan stage, primarily through the Approval process for new drugs and the pre-approval of changesBased on product history, process characteristics, and facility historyUses the site risk potential to evaluate which sites to audit in the Detect stagePrimarily focused on product risk to patients, but also risks of non-supply and risk to consumer confidence


Risks are seen differently by agency and industry, with different actions needed at different stages RiskTechnology/Design RiskRegulatory RiskBusiness RiskImplementationRiskINDUSTRY

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


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


Culture & Compliance FDA Enforcements ViewTo avoid Consent Decrees, injunctions and related enforcement actions:1Create and foster a corporate spirit (Culture) of complianceEstablish internal systems and controls to define, measure, monitor and assure complianceObtain qualified, experienced, independent evaluations of your companys complianceTake prompt and comprehensive action to correct the violative situationMonitor the corrective action to assure the fix works in both the short term and long termCommunicate promptly and constructively with FDA

Any attempt to excuse a violation on FDAs 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 marketed2FDA Enforcement1 E. Blumberg, Deputy Associate, Office of Chief Counsel, Office of the Commisioner, FDA2 G David Horowitz, FDA 8/24/04PreventDetectDetectCorrectCorrectCorrect


Consent Decrees are Court enforced contracts . . .. . . created to ensure the prompt correction of certain deficiencies while safeguarding the public.

Related to:ProductsFacilitiesSystemsOrganizational Structures

to achieve compliance with Laws & Regulations.Consent Decrees


Management Controls and Quality Unit Warning Letter IssuesThe 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 requirementsManagement Controls


Consent Decree Requirement for Evaluation of Management ControlsEvaluate the ADEQUACY of:

PreventOrganizational structure and responsibilities of ALL involved in manufacturePREVENTQualification of personnel and appropriate numbersDETECT and CORRECTRoles, responsibilities and resources of Quality Units to detect and correct deficiencies

PresidentQQMFGR&DDevClinProdEngQA/QCManagement Controls


Consent Decree Requirement for the Evaluation of Quality UnitsConsultant 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 PresidentQQMFGR&DDevClinProdEngThe Quality Unit


Implications of Management Controls on the Quality UnitAdequate is open to interpretation

Challenges past behavior and decisions

Process is Intrusive

The Quality Unit


There are emerging efforts to improve the industry Introduction1 G. Migliaccio, Pfizer Global Operations VP, Gold Sheet June 2004US 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 process1The 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

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