fda compliance and regulatory symposium understanding the fda’s latest cgmp ... · 2005-10-06 ·...

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 -1-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

1. J

. Ram

sbot

ham

, Sol

vay,

Gol

d Sh

eet,

June

200

42.

G. M

iglia

ccio

, Pfiz

er G

loba

l Ope

ratio

ns V

P, G

old

Shee

t Jun

e 20

043.

Ada

pted

from

D. E

llsw

orth

, Gol

d Sh

eet,

April

200

5

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, followingSOPs 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 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 framework

Regulatory 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 product

1.D

. Hor

owitz

, FD

A, 8

/24/

042.

J. F

amul

are,

CD

ER, 2

004

Pres

enta

tion

to C

HPA


Current Situation

Faces resource cutsIndustry’s 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 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 andsafety1

The FDA wants to take a new role as an enabler of the innovationand change itself and industry to meet this new additional role


1. F

rom

CG

MPs

to C

ritic

al P

ath,

L. B

ush,

Pha

rmTe

ch, J

uly

2004


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


1. P

harm

aceu

tical

CG

MP

s fo

r the

21st

Cen

tury

-Ris

k-B

ased

App

roac

h Fi

nal R

epor

t, S

ept 2

004

2. D

. Ells

wor

th, F

DA

, Gol

d S

heet

, May

200

5


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 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 arebased on state-of-the-art scienceEnhance 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

1. P

harm

aceu

tical

CG

MP

s fo

r the

21st

Cen

tury

-Ris

k-B

ased

App

roac

h Fi

nal R

epor

t, S

ept 2

004

2. F

rom

cG

MP

s to

the

Crit

ical

Pat

h: F

DA

Foc

uses

on

Inno

vatio

n, Q

ualit

y an

d C

ontin

uous

Im

prov

emen

t –In

side

and

Out

, Lau

ra B

ush.

Pha

rmac

eutic

al T

echn

olog

y, J

uly

2004



Risk-Based Model for GMP Inspection and Product Quality Review

To more efficiently and effectively use FDA resources to protectpublic 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 processRobustness of quality systemPublic health impactManufacturer’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 efficacyEvaluate a manufacturer’s understanding of process controland quality


1. P

harm

aceu

tical

CG

MP

s fo

r the

21s

tC

entu

ry, R

isk-

Base

d Ap

proa

ch, F

inal

Rep

ort,

Sept

. 200

4


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 characteristicsProcesses to achieve quality by designRisk management and assessmentCAPAChange controlQuality Unit

Quality Systems ModelManagement responsibilitiesResourcesManufacturing operationsEvaluation activities


1. P

harm

aceu

tical

CG

MP

s fo

r the

21s

tC

entu

ry, R

isk-

Base

d Ap

proa

ch, F

inal

Rep

ort,

Sept

. 200

4


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 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 assurance

Comparability 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 changes

1. P

harm

aceu

tical

CG

MP

s fo

r the

21s

tC

entu

ry, R

isk-

Base

d Ap

proa

ch, F

inal

Rep

ort,

Sept

. 200

4


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 operationsParticipate in other investigations that require their technicalexpertise

Revised PAI inspection programEliminates mandatory categories for conducting inspections


1. P

harm

aceu

tical

CG

MP

s fo

r the

21s

tC

entu

ry, R

isk-

Base

d Ap

proa

ch, F

inal

Rep

ort,

Sept

. 200

4


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 developmentQ9: Risk Management principles and toolsQ10: Quality systems enhancements emphasizing change controls


1. P

harm

aceu

tical

CG

MP

s fo

r the

21s

tC

entu

ry, R

isk-

Base

d Ap

proa

ch, F

inal

Rep

ort,

Sept

. 200

4


Rule and Guidance Interpretations

FDA 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 rule

ValidationDeletes the reference to “three validation batches” at commercial scaleRecognizes emerging technologies (PAT).

Aseptic processingIncorporates a more risk-based approachModernization and automation

Dispute ResolutionMechanism to surface scientific and technical disagreements related to GMPs for resolution and dissemination

Warning 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 Counsel


1. P

harm

aceu

tical

CG

MP

s fo

r the

21s

tC

entu

ry, R

isk-

Base

d Ap

proa

ch, F

inal

Rep

ort,

Sept

. 200

42.

FD

A C

onfe

renc

e R

epor

t, D

rug

Qua

lity

Syst

em: C

GM

Ps fo

r a N

ew E

ra –

2004

3. J

. Fus

e, J

ourn

al o

f Val

idat

ion

Tech

nolo

gy, N

ov 2

004


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 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 approval

Revise 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 FDA’s 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 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

1. P

harm

aceu

tical

CG

MP

s fo

r the

21s

tC

entu

ry, R

isk-

Base

d Ap

proa

ch, F

inal

Rep

ort,

Sept

. 200

4


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

1. D

. Hor

owitz

, FD

A, 8

/24/

042.

The

Qua

ntic

Gro

up3.

P. S

enge

, The

Fift

h D

isci

plin

e, 1

994


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 ConsistencyBatch Release, Stability, APR, Validation

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

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

The Quality System

1 As

def

ined

by

The

Qua

ntic

Gro

up


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, andreports, 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 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 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 idealValidation may not be adequate to assure the process capabilityContinuous improvement is not optimal, lack of adopting innovation

Design Space

1 Ad

apte

d fro

m D

. Ells

wor

th In

terv

iew

, Gol

d Sh

eets

, Apr

il 20

05


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

1 Ad

apte

d fro

m D

. Ells

wor

th In

terv

iew

, Gol

d Sh

eets

, Apr

il 20

05


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

1 Ad

apte

d fro

m D

. Ells

wor

th In

terv

iew

, Gol

d Sh

eets

, Apr

il 20

05


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

Do in Control

Check/Detect/Audit/Measure

Correct

Plan/PreventDesign SpaceDesign Space

PAT

Risk Real 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 complianceEstablish internal systems and controls to define, measure, monitor and assure complianceObtain qualified, experienced, independent evaluations of your company’s 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 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 wouldcause an unsafe or ineffective product to be marketed2

FDA Enforcement

1 E.

Blu

mbe

rg, D

eput

y As

soci

ate,

Offi

ce o

f Chi

ef C

ouns

el, O

ffice

of th

e C

omm

isio

ner,

FDA

2 G

Dav

id H

orow

itz, F

DA

8/24

/04

Prevent

Detect

Detect

Correct

Correct

Correct


Consent Decrees are Court enforced “contracts” . . .

. . . created to ensure the prompt correctionof 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 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:

PreventOrganizational structure and responsibilities of ALL involved in manufacture

PREVENTQualification of personnel and appropriate numbers

DETECT and CORRECTRoles, 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

1 G

. Mig

liacc

io, P

fizer

Glo

bal O

pera

tions

VP,

Gol

d Sh

eet J

une

2004

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, followingSOPs 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 fda’s latest cgmp ... · 2005-10-06 ·...

Documents