quality risk management -...

Quality Risk Management

According to ASTM E2500: Standard Guide for Specification, Design and Verification for Pharmaceutical and Biopharmaceutical Manufacturing Systems and EquipmentBrian Evald Andreasen, May 2009

[email protected] telephone: +4530751381

Agendaen

Fra indbydelsen:•På mødet vil Brian Andreasen fra NNE Pharmaplan fortælle om hans erfaringer med at implementere standarden hos Pfizer globalt.

•Han vil give et overblik over indholdet i standarden sammenholdt med traditionel kvalificering,

•og der vil blive givet konkrete eksempler på RiskManagement og Verifikation.

NNE Pharmaplan, my workplace

• Over 80 years of experience in the pharma and biotech industries

• Spanned over 3 continents across Europe, North America and Asia

• Workforce 2008: More than 1500

• Turnover 2007: DKK 1.444M, €194M, $249M

• ISO 9001 certified since 1995; certified worldwide in 2008

• ISO 14001 certified since 2003

Global reach - local knowledge

Where is the best Quality?

Traditional

C&Q

New Risk Based Verification Approach

David Dolgin, Abbott2008 Washington ASTM C&Q

The benefits from E2500 are incredible……

Moves away from ‘paper quality’ and rigid documentation practices -to product quality and patient safety.

Faster project executionFocus on patient safetySignificantly reduces documentationEnhanced process understandingSaves time and resourcesHigher production yield (OEE)Improved quality at less costs - better use of expertiseCompliance with Health Authorities expectationsto risk based approach

Thus, improved quality, major cost reduction (above 40%), faster to market and longer time to take the right decisions for investments.

…and p

roba

bly tr

ue

The Pfizer case

Pfizer is the largest pharmaceutical company in the world

They had with support from NP implemented a risk based verification system globally in the company according to the new ASTM E2500 standard.(Before Pfizer had a traditional C&Q approach according to ISPE C&Q guide Vol 5 similar to NN)

•By adapting the new risk based approach…Pfizer expect to:

• save 40% of all expenses to Commissioning and Qualification • Eliminate between 2 and 6 month of project execution time.

• Get improved quality level

ASTM!!!!What is that….?

• Large voluntary standards development organization

• Not-for-profit organization

• Established in 1898

• Purpose is to develop standards in response to market needs

• Technical standards for materials, products, systems, and services

• HQ in Philadelphia,• Sub-offices in London, Mexico City &

Beijing

ASTM Committee E55

• Established Spring 2003

• Development of standardized nomenclature and definitions of terms recommended practices, guides, test methods, specifications, and performance standards for the manufacture of pharmaceutical products.

Issued Standards (Pharma) :

• E2363-06a Standard Terminology Relating to Process Analytical Technology in the Pharmaceutical Industry

• E2474-06 Standard Practice for Pharmaceutical Process Design Utilizing Process Analytical Technology

• E2500-07 Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment

• E2503-07 Standard Practice for Qualification of Basket and Paddle Dissolution Apparatus

• E2537-08 Standard Guide for Application of Continuous Quality Verification to Pharmaceutical and Biopharmaceutical Manufacturing

• WK5930 Standard Practice for Risk Assessment and Risk Control as it Impacts the Design, Development, and Operation of PAT Processes for Pharmaceutical Manufacture (Gawayne Mahboubian Jones)

• WK5935 Standard Guide to Process Understanding (Jean Marie Geoffroy)

• WK9192 Standard Practice/Guide for the Application of Continuous processing in the Pharmaceutical Industry (Trevor Page)

• WK15151 Standard Guide on Sampling (Joep Timmermans)

• WK9182 Standard Guide for Verification of Process Analytical Technology (PAT) Control Systems (Bruce Davis)

• WK9191 Standard Guide for Multivariate Data Analysis Related to Process Analytical Technology (Chun Cai)

• WK13538 Standard Practice for Identification of Critical Attributes of Raw Materials in Pharmaceutical Industry (Marino Nebuloni) WK11898 Standard Practice for Real-time Release of Pharmaceutical Water for the Total Organic Carbon Attribute (Rich Godec)

• WK15778 Guide for Science-based and Risk-based Cleaning Process Development and Validation (Andrew Walsh)

• WK16888 Guide for Validation of PAT Methods (Jim Rydzak)

Work Items in Progress (E55.01)

Essence of the E2500

The scope and extent of quality risk management forspecification, design, and verification activities and documentation should be based on the risk to product quality and patient safety.

The level of effort, formality and documentation of the quality risk management process should becommensurate with thelevel of risk.

Important TermsCritical Quality Attributes (CQA)

Dissolution

Disintegration

Hardness

Contentuniformity

Apperance

A Critical Quality Attribute is defined as a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range or distribution to ensure the desired product quality (ICH Q8)

Slide 13

Important TermsCritical Process Parameters

Dissolution

Disintegration

Hardness

Contentuniformity

Apperance

Pressure

Flow

pH

Pressure

dP

Speed

Pressure

Velocity

Velocity

pHTime

Pressure

Pressure

Conc

Time

A Critical Process Parameter is defined as a process parameter whose variability has an impact on a CQA and therefore should be monitored or controlled to ensure the process parameters produces the desired quality (ICH Q8)

Slide 14

Important Terms Critical Aspects

Dissolution

Disintegration

Hardness

Contentuniformity

Apperance

Critical Aspects are defined as functions, features, abilities, and performance or characteristics necessary for the manufacturing process and systems to ensure consistent product quality and patient safety (ASTM E-2500-07)Sanitary

design

Vision system for monitoring

GMP

Batch documentation

Calibration

Filter integrityParameter alarms Non turbulent

agitor

Slide 15

Important TermsSubject Matter Experts (SME)

SME is defined by ASTM as:

• Individuals with specific expertise and responsibility in a particular area or field (for example, quality unit, engineering, automation, development, operations, and so forth).

The SME role & responsibilities

From E2500

• Subject matter experts should take the lead role in the verification of manufacturing systems as appropriate within their area of expertise and responsibility.

• Subject matter expert responsibilities include planning and defining verification strategies, defining acceptance criteria, selection of appropriate test methods, execution of verification tests, and reviewing results.

Risk Based ApproachThe old way

Impact Assessment – (systems & Components)

• Evaluating design for impacting the product quality, but no evaluation of the level of potential risk for product and patient.

• No Risk Mitigation• System and component level focused • Component Impact Assessment is conducted after design development.

Direct Impact

Indirect Impact

C NC

Risk Based Approach The new way

Ongoing and iterative Risk Management process

From CQA and CPP are defined to ………handover for operation.

Risk 1 ..…

Slide 19

Quality Risk Management –

Risk Based Approach The new way

• Definition of CQA, CPP & Critical aspects• Risk ranking• Risk mitigation:

Design solutionsControl strategyDesign ReviewSuppliers selectionSME allocationTestDocumentationetc

Risk 1 ..…

Slide 20

Quality Risk Management –

Quality Risk Management Determination of Critical Aspects

Risk 1 ..…Critical Aspects must be identified during the risk

Management process.

Critical Aspects are derived directly from CQA and the general GMP compliance issues.

Critical Aspects are subject to risk assessment and risk mitigation; if possible and Verification testing.

Well knownvendor

ExactCopy

EquipmentSimple

EquipmentCustomized

Complex processand

many interfaces

Customized

Newtechnology

Customized

Well knowntechnology

NewVendor

BadVendor

ManualEquipment

Quality Risk ManagementIdentifying potential Risk

Critical ProcessParameter

Unstable process

Slide 22

Quality Risk ManagementRisk Mitigation – Safe design solutions & Control strategy

PATMonitoring

EquipmentMonitoring

PATMonitoring

ManualMonitoring

Risk 1 ..…

Sanitary issue:Removal of pumps,

by using gravity

Slide 23

Quality Risk ManagementRisk Mitigation - Vendor Assessment

Documentation? Experienced employee?

New Technology?

Custom made

or bulk?

Interfaces

to other disciplines

or vendors ?

Risk 1 ..…

Quality Risk ManagementRisk Mitigation -Design Review (DR)

The DR is an important part of the risk management process, and DR must be focused on the risk aspects:

• Design meets the mitigated unacceptable riskderived from the risk assessment process.

• Planned Verification testing and acceptance criteria are sufficient and commensurate to level of quality risk.

• Design Meets relevant Critical aspects and ensure that Critical Process Parameters can be controlled to the desired level

• The Critical Quality Attributes (CQA) can be ensured by the proposed design

Risk 1 ..

…

√√√

√√

√√√√

Quality Risk ManagementUse of Vendors test results etc

Vendors test documentation may be used as part of the verification documentation, if the vendor is assessed, and there is evidence of:

• An acceptable vendor quality system,

• Vendor technical capability

• Vendor application of GEP such that information obtained from the vendor will be accurate and suitable to meet the purpose of verification.

If inadequacies are found then we have to mitigate potential risks by applying specific, targeted, additional verification checks or other controls rather than repeating vendor activities and replicating vendor documentation.

Quality Risk ManagementTest- planning

MappingCQA & CPP

Critical Aspects &

Risk Assessment

Risk Mitigation

PlanningVerification

Commensurate with the

level of risk Vendor test

SME Approval

Intensive testSME participation & SME approval

Vendor testSME surveillance

Graphic ModelIssued by ASTM

Quality Risk Management Process

CQACPP

Criticalaspects

RiskRanking

RiskMitigation

+New

ranking

Design+

DERissues

Vendorissues

Verification SMEInvolve-

ment

Link to illustration

Risk Mitigation

Quality activities commensurate with the level of risk.

Pfizer ASTM E2500 Transformation

Pfizer CaseASTM E2500 Transformation

• Transformation from C&Q to Verification based on ASTM E2500

• Part of a Lean project to streamline current practicesand enable more productioncapacity for the same investment capital

• Transformation project done by global Engineering & Quality team together withNNE Pharmplan

• 2 project phases:• Gap mapping & Scope

Setting• Document writing, review

and approval• Pilot implementation ongoing

Pfizer C&Q

Pfizer Verification

Pfizer CaseASTM E2500 Transformation - 2

• Combines E2500 with Quality by Design principles and Lean methods

• Integrates• Engineering• Automation• Quality• Maintenance etc.

• Based on Quality by Design Quality Risk Management principles (ICH Q8, Q9, Q10)

• Applies to new and legacymanufacturing systems

• Global Engineering Rollout on all sites is ongoing

Pfizer Verification

ASTM E2500 Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment

Quality by Design in NNE Pharmaplan:Transform C&Q to ASTM VerificationClient

• Pfizer• Global Engineering - for global use on all

manufacturing sites

Service• Transformation of Pfizer C&Q program to

the ASTM E2500 standard for Verification, for use globally

• Combined with a Pfizer Lean Program to streamline current practices and getmore value of investments – both onmoney and time

• 3 months delivery time• 5 consultants in NP Consulting Denmark

and USA plus global roll-out assistance

Deliverables• Full update of existing procedures to

ensure the harvesting of benefits of theVerification approach instead of thetraditional validation approach ofCommissioning and Qualification

What’s in it• Faster and more cost-effective

verification compared to traditional’validation’

DissolutionDisintegration

HardnessContent uniformity

Apperance

Customer Quote:”We selected NNE Pharmaplan for the workbecause these guys really understands the QbD principles in practice. You guys really got it!”

Client Case 2008

C&Q vs Verification Opportunities

C&

Q C

ost

#1 Fewer systems in Quality Unit scope

#5 Reduce Periodic Review Scope

100%#2 Leverage GEP & Subject Matter Experts (Less details)

#3 Leverage Supplier Documentation#4 Avoid repetition of tests etc.

Verifica

tion

Co

st

#6 Reduce number of docs retained etc.#7 Flexibility and Scalability

#8 Other

1st Generation – and the next:Face the Learning Curve

• Every new paradigm has its learning curve• 1st Generation is not always right• Example: From the Horse Cap to the 1st Generation Taxi

1st Generation Taxi 2nd Generation Taxi

[email protected] telephone: +4530751381

Back up slides

A Brief Validation History

First FDA Validation Guideline1987

• “Process validation is

establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a

product meeting its pre-determined specifications and quality characteristics” GUIDELINE ON GENERAL PRINCIPLES OF

PROCESS VALIDATIONMAY, 1987 FDA CDER, CBER, CDRH

ISPE C&Q Baseline Guide 2001

• “The application of this C&Q process helps to ensure that the appropriate resources are applied to those systems and components within a facility that have the potential to affect product quality; and secondly, provides the rationale to reduce the scope of work for the qualification of the plant, while still ensuring compliance for the product(s).”

• Commissioning (i.e. GEP)• Qualification (i.e. QA)

ISPE Baseline Engineering Guide Commissioning & Qualification(Baseline Guide 5) 2001

New FDA Process Validation GuideDRAFT Nov. 2008

• “Effective process validation contributes significantly to assuring drug quality.

• The basic principle of quality assurance is that a drug should be produced that is

fit for its intended use

• This principle incorporates the understanding that the following conditions exist:

• Quality, safety, and efficacy are designed or built into the product.

• Quality cannot be adequately assured merely by in-process and finished-product inspection or testing.

• Each step of a manufacturing process is controlled to assure that the finished product meets all design characteristics and quality attributes including specifications. “

DRAFT

Stage 1 – Process DesignStage 2 – Process QualificationStage 3 – Continued Process Verification

C&Q vs. ASTM E2500

Old C&Q

New VerificationRisk Based ApproachASTM E2500

ProcessValidation

Engineering Change Management

QA Change Control

IQ & OQ

CommissioningEnhanced Design Review

Design Development

PQ

ProcessValidation

Engineering Change Management QA ChangeControl

Performance Testing

CommissioningDesign Review

Design Development

PT

Verification overviewFrom ISPE’s draft of coming new Verification guideline

Planning Verification

From E-2500:

• The acceptance criteria and verification strategy should be documented in appropriate verification plans.

• The verification plan should define what constitutes acceptable documentation of subsequent verification activities.

• The verification plan should be developed and approved by subject matter experts.

• Verification plans for systems containing critical aspects should be approved by the quality unit.

Graphic modelNNE Pharmaplans model

NNE Pharmaplan is involved in thenew Pharma Standard Settings

• NNE Pharmaplan is closely involved in thesetting of the new standards of thepharmaceutical industry

• ASTM Committee E55 on Manufacture of Pharmaceutical Products

• ISPE• PDA• We have participated in setting the new

standards of the pharmaceutical industryin ISA, GAMP, ISPE, PDA and ASTM for 20 years

• We call it ”More than Engineering…”

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