FDA Compliance and Regulatory Symposium Understanding the FDAs Latest cGMP Guidances: Opportunities and Pitfalls Claudio Pincus, President, The Quantic.

FDA Compliance and Regulatory SymposiumUnderstanding the FDA’s Latest cGMP

Guidances: Opportunities and Pitfalls

Claudio Pincus, President, The Quantic GroupR. Owen Richards, President, Quantic Regulatory Services

Daniel Pincus, Consultant, The Quantic Group

9AM Thursday August 25Harvard University

Copyright 2005, The Quantic Group, All Rights Reserved

5N Regent Street Suite 502 Livingston, NJ 07039 (973) 992 0505The Quantic Group sm

©2005, All Rights Reserved -2-Quantic

Copyright 2005,All Rights Reserved

The Quantic Group, Ltd., Livingston, NJ

This document contains and refers to methodologies that are a Trade Secret of The Quantic Group, Ltd. and are presented with the purpose of describing Quantic’s 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” 1

Introduction

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FDA oversight and pre-approval of manufacturing change will be replaced by the company making the change, subject to routine inspection3

“The present state is focused on documentation, following SOPs validating the process, meeting specifications, and not changing the process”2

“The 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 Industry

FDA 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

product”1

Introduction

The desired state of manufacturing2

Product quality and performance achieved and assured by design of effective and efficient manufacturing processes

Continuous improvement approaches, with innovative use of new technology as desired

The desired state of regulation2

[Transparent regulations] and up-to-date guidance Managed within a quality system Uses a risk management framework

Regulatory policies and procedures tailored to recognize the level of scientific knowledge supporting product applications and cGMP coverage of products

Risk based regulatory scrutiny that weighs factors such as the capability of process control strategies to prevent or mitigate risk of producing a poor quality product

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Current Situation

Faces resource cuts Industry’s technical challenges are increasingly complex Difficult to enforce manufacturing standards globally, with more

sites Perceived 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 industry

Because of regulatory constraints, Industry has been slow to adopt innovative technologies to improve products and operations

Pressure to reduce costs Global manufacturing subject to not harmonized regulatory

requirements Outsourcing has become a viable alternative with regulatory

implications

Lower trust in both FDA and Industry Seeks lower cost medications without compromising quality

cGMPs for the 21st Century

FDA

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 agency’s resources on the areas of manufacturing considered to pose the most risk, and to improve the consistency and predictability of the agency’s 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


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FDA desires for industry to have more knowledge and more control

FDA 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 are

Risk-based orientation

Integrated quality systems orientation

Science-based policies and standards

International cooperation

Strong public health protection


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FDA’s “cGMPs for 21st Century” Initiative

In response to today’s challenges facing pharmaceutical manufacturing and quality,FDA launched its “Pharmaceutical cGMPs for the 21st Century” to:*

Focus FDA’s resources on areas of greatest manufacturing risk Encourage innovation and early adoption of advanced manufacturing

technologies Facilitate industry application of modern quality management

techniques, including implementation of quality systems approaches Encourage the use of risk-based approaches to focus on critical areas Ensure regulatory review, compliance and inspection policies are based

on state-of-the-art science Enhance the consistency and coordination of FDA’s drug quality

regulatory programs by integrating enhanced quality systems approaches into the agency’s business processes and regulatory policies

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Risk-Based Model for GMP Inspection and Product Quality Review

To 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 manufacturer’s understanding of its product and process Robustness of quality system Public health impact Manufacturer’s 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 efficacy Evaluate a manufacturer’s understanding of process control and

quality


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Quality System Approaches

FDA wants its regulatory practices to encourage implementation of modern quality systems and risk management systems to satisfy cGMPs.By

Modern quality systems that correlate closely with regulatory requirements

Achieving product quality characteristics Processes to achieve quality by design Risk management and assessment CAPA Change control Quality Unit

Quality Systems Model Management responsibilities Resources Manufacturing operations Evaluation activities


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Science-Based Policies


FDA 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.PAT

PAT brings a systems perspective to the design and control of manufacturing processes

Regulatory framework to encourage voluntary development and implementation of innovative approaches in pharmaceutical development, manufacturing and quality assurance

New 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 performance

Facilitates introduction of new technologies to improve efficiency and effectiveness of manufacturing process design and control and quality assurance

Comparability Protocols Allows manufacturing changes without the submission of a prior approval

supplement Establish to facilitate continuous improvement and innovation Systemic, risk-based approach to review and approval process for post-approval

manufacturing changes

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Integration of Pre-Approval and cGMP Inspection Programs

Pharmaceutical 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 operations Participate in other investigations that require their technical expertise

Revised PAI inspection program Eliminates mandatory categories for conducting inspections


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International Collaboration for Compliance

Harmonization 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 development Q9: Risk Management principles and tools Q10: Quality systems enhancements emphasizing change controls


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Rule and Guidance Interpretations

FDA has implemented the guiding principles through various rule and guidance interpretations.

Part 11 Addresses uncertainties of regulatory specifications, particularly by

narrowly defining electronic records subject to the ruleValidation Deletes the reference to “three validation batches” at commercial scale Recognizes emerging technologies (PAT).

Aseptic processing Incorporates a more risk-based approach Modernization and automation

Dispute Resolution Mechanism to surface scientific and technical disagreements related to

GMPs for resolution and disseminationWarning Letter Review by Office of General Counsel All proposals to issue warning letters to manufacturers are reviewed by

the centers and the Office of the Chief Counsel


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FDA’s Next Steps


The next phase of the “cGMPs for the 21st Century” initiative include:1

Develop additional guidance on quality systems to enhance and modernize the regulation of pharmaceutical manufacturing and product quality

Continue development of the risk-based pharmaceutical quality assessment system that will replace the current CMC review to remove hurdles to continuous improvement following drug approval

Revise the 1987 guideline on Process Validation to include 21st century concepts, including risk management and a lifecycle approach

Continue to explore and formalize risk-based tools to enhance FDA’s regulatory oversight

Refine cGMPs and meet our harmonization (internal and international) goals

Continue timely communication of our current thinking on various quality issues to the public to facilitate compliance with FDA requirements

Further enhance FDA’s 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 approach

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Let’s define systems

GMPs are best viewed from a systems perspective – The whole exceeds the sum of the parts1

A system is a design of integrated components that can measure the performance of the whole and can predictably and consistently detect and correct deficiencies2

Systems thinking is a framework for seeing interrelationships rather than things, for seeing patterns of change rather than static snapshots3

The Quality System

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Product Quality Systems – Definition1

A 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 Consistency Batch Release, Stability, APR, Validation

Manufacturing & Lab Decision Process Change Control, Deviations, Notification to Management

Facility Reliability and Product Purity Facility Design, Facility Qualification, Contamination Control

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FDA Quality System Definition

This 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 K

The Quality System


Deming’s Plan-Do-Check-Act was a keystone in design of cGMP in the 1960’s

Do in Control

Check/Detect/Audit

Correct

Plan/Prevent

The Quality System


FDA Definition of Quality System Elements

The FDA definitionFor each of the following items, the firm should have written and approved procedures . . . Verified through observation wherever possible . . . Product reviews at least annually

Complaint reviews, quality and medical Discrepancy and failure investigations related to manufacturing and testing –

includes corrective action where appropriate Change control Product Improvement Projects Reprocess/Rework Returns/Salvages Rejects Stability Failures Quarantine products Validation Training/qualification of employees in quality control unit functions

The Quality System


Management Controls Quality System

Do In Control

Check/Detect/Audit

Correct

Plan/Prevent

. . . Everyone predictably responds

Organizational 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

processes1

The 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:1

Product and process development may not be ideal Validation may not be adequate to assure the process

capability Continuous improvement is not optimal, lack of adopting

innovation

Design Space

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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 react1

Part 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 data

Design Space

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FDA oversight and pre-approval of manufacturing change will be replaced by the company making the change, subject to routine inspection1

The 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 course

Design Space

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The New Quality System Incorporates Science, Change Process, Risk & Management Control

Do in Control

Check/Detect/Audit/Measure

Correct

Plan/PreventDesign SpaceDesign Space

PAT

RiskReal time test and trending

Processes and products

Revisit procedures, validation and organizations

Redesign

In-process parametersIn-house change process

Design Space


Risks are seen differently by agency and industry, with different actions needed at different stages

FDA•Risk decisions used to prioritize inspection resources

•Uses risk-based framework to prioritize sites for cGMP inspection

•Determines risk at the Plan stage, primarily through the Approval process for new drugs and the pre-approval of changes

•Based on product history, process characteristics, and facility history

•Uses the site risk potential to evaluate which sites to audit in the Detect stage

•Primarily focused on product risk to patients, but also risks of non-supply and risk to consumer confidence

Site Risk Potential

Product Process Facility

Risk

Risk = Frequency x Severity -> SRP = %P x %P x %F

FDA


Risks are seen differently by agency and industry, with different actions needed at different stages

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

Plan

Operate

Detect

Correct

Risk

Technology/Design Risk

Regulatory Risk

Business

Risk

Implementation

Risk

INDUSTRY


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 Enforcement’s View

To avoid Consent Decrees, injunctions and related enforcement actions:1

Create and foster a corporate spirit (“Culture”) of compliance Establish internal systems and controls to define, measure,

monitor and assure compliance Obtain qualified, experienced, independent evaluations of your

company’s compliance Take prompt and comprehensive action to correct the violative

situation Monitor the corrective action to assure the fix works in both the

short term and long term Communicate promptly and constructively with FDA

Any attempt to excuse a violation on FDA’s 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 marketed2

FDA Enforcement

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Consent Decrees are Court enforced “contracts” . . .

. . . created to ensure the prompt correction of certain deficiencies while safeguarding the public.

Related to: Products Facilities Systems Organizational Structures

to achieve compliance with Laws & Regulations.

Consent Decrees


Management Controls and Quality Unit Warning Letter Issues

The 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 requirements

Management Controls


Consent Decree Requirement for Evaluation of Management Controls

Evaluate the ADEQUACY of:

Prevent Organizational structure and responsibilities

of ALL involved in manufacture PREVENT

Qualification of personnel and appropriate numbers

DETECT and CORRECT Roles, responsibilities and resources

of Quality Units to detect and correct deficiencies

President

Q

Q

MFG R&D

Dev ClinProdEng

QA

/QC

Management Controls


Consent Decree Requirement for the Evaluation of Quality Units

Consultant 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

President

Q

Q

MFG R&D

Dev ClinProdEng

The Quality Unit


Implications of Management Controls on the Quality Unit

“Adequate” is open to interpretation

Challenges past behavior and decisions

Process is Intrusive

The Quality Unit


There are emerging efforts to improve the industry

Introduction

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. Mig

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VP

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Jun

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US 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 process”1

“The 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

FDA Compliance and Regulatory Symposium Understanding the FDAs Latest cGMP Guidances: Opportunities and Pitfalls Claudio Pincus, President, The Quantic.

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