G E A P h a r m a S y s t e m s G E A Ly o p h i l G m b H

Risk Based Design in Lyophilizer Projects

GEA Lyophil GmbH

Focus• Brief overview of risk management tools

• Opportunities and benefit

• Evaluation of risks and possibilities of risk reduction

• Risk management as part of project management

• Project focus on “real” process requirements

• Organisation of Lyophilizer projects in accordance with a risk-based approach

• Influence to life cycle phases like planning, design, manufacturing, testing and operation

GEA Lyophil GmbH

Quality Risk Management according ICH Q9• “The evaluation of the risk to quality should be based on

scientific knowledge and ultimately link to the protection of the patient; and

• The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk.”

GEA Lyophil GmbH

Overview of risk management process (ICH Q9)

Risk Identification

Risk Evaluation

Risk Reduction

Risk Acceptance

Risk Events

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Output / Result of the Quality RiskManagement Process

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InitiateQuality Risk Management Process

GEA Lyophil GmbH

Overview of risk management tools- ICH Q9 Definitions

• Risk Assessment• consists of the identification of hazards and the analysis and

evaluation of risks associated with exposure to those hazards.• 1. What might go wrong?• 2. What is the likelihood (probability) it will go wrong? • 3. What are the consequences (severity)?

• Risk identification• is a systematic use of information to

identify hazards referring to the risk question or problem description.• Define limits and interfaces• Define intended use and restrictions• Define responsibilities

GEA Lyophil GmbH

Overview of risk management tools- ICH Q9 Definitions

• Risk analysis • is the estimation of the risk associated with the identified hazards.

• Risk evaluation • compares the identified and analyzed risk against given risk criteria.

Risk evaluations consider the strength of evidence for all three of the fundamental questions.

GEA Lyophil GmbH

Overview of risk management tools- ICH Q9 Definitions

• Risk control• might focus on the following questions:

• Is the risk above an acceptable level? • What can be done to reduce or eliminate risks? • What is the appropriate balance among benefits, risks and resources? • Are new risks introduced as a result of the identified risks being

controlled?

• Risk reduction• focuses on processes for mitigation or

avoidance of quality risk when it exceeds a specified (acceptable) level.

• Risk acceptance • formal decision to accept the residual risk.

GEA Lyophil GmbH

Overview of risk management tools- ICH Q9 Definitions

• Risk review• The output/results of the risk management process should be

reviewed to take into account new knowledge and experience.

• Risk communication• is the sharing of information about risk and risk management

between the decision makers and others.

Factor for successful risk mitigation:Consequent and correct usage of risk management tools

GEA Lyophil GmbH

Methods: Fault Tree Analysis, FTA

FaultFault

Why ?

Because …

Why ?

GEA Lyophil GmbH

Factor for successful risk mitigation:Consequent and correct usage of risk management tools

GEA Lyophil GmbH

Risk-Based Decision Making during Life Cycle

Steps to be focused in presentation

GEA Lyophil GmbH

URS should define clearly and preciselywhat the regulated company…

state anyconstraints

anddocumen-tation req.

and defineregulatory

wants thesystem to

do,

GAMP 5 Tab le 6 .1

GEA Lyophil GmbH

Factors influencing URSCompany

Specific Req.

OrganizationalReq.

(Bad) Experience

Legal Req.

Copy & Paste

Commercial Aspects

Nice to have

Not specific Req.

GEA Lyophil GmbH

This approach will lead to:+ highly customized systems including all requirements+ systems which fits into company restrictions

- very expensive systems- a kind of prototype including all related risks- mix out of 2 different quality systems- Not proven technology

Factor for successful risk mitigation:Focus on essential requirements

GEA Lyophil GmbH

Expertise within GMP Projects

• Who knows the GMP requirements of a product?

• Who has the responsibility regarding GMP conformity?

• Who knows all technical details within the equipment?

• Who knows which different solutions are on the market?

Factor for successful risk mitigation:Responsibilities according to expertise

RegulatedCompany

Supplier

√

√

√

√

GEA Lyophil GmbH

Risk Management as Part of Supplier Selection

Phas

e 1

Customer to define GMP related process requirements

Supplier 1

Technical offer basic design

Supplier 2

Technical offer basic design

End

Phas

e 2 Supplier 1

Risk Assessment technical needs

Supplier 2 Risk Assessment technical needs

End

Phas

e 3 Supplier 1

Risk Assessment validation & documentation

Target Phase 1: Definition of basic process requirements, like temp. and pressure ranges

Target Phase 3: Definition of Project Control, Responsibilities, Test and Documentation, Summary

Target Phase 2: Design requirements: cleaning concept, loading/ unloading concept, redundancy

Audit Supplier 1 Audit Supplier 2 Audit Supplier 3

Supplier 3

Technical offer basic design

GEA Lyophil GmbH

Risk Management during Design Phase• The highest risk is not to get what is required

• Key questions for each phase:• What are the real required features? • Where starts the “nice to have” area?• Who should do the activity?

GEA Lyophil GmbH

Advantage of Risk-Based Design

direct

indirect

Process

critical Non criticalComponents

Evaluation of risks may reduce all activities (design, manufacturing, testing and documentation).

GEA Lyophil GmbH

Advantage of Risk-Based Design

Legal Req.

Extraction of possible risks

SupplierSpec.

GoodPractice

URS

GMP require-ments

GEA Lyophil GmbH

Risk Management during Design Phase• Design and functionality is based on current requirements• GMP and safety related components will be detected• Critical process parameters, steps and events will be

determined• Project team members will get a deeper view into the process • Interdisciplinary teams ease further communication within the

project (e.g. engineering vs production vs QA)

GEA Lyophil GmbH

Risk Management during Design Phase• Priorities for the qualification and validation activities will be

identified• Documented evidence and description of the scope of

qualification and validation activities will be clarified• Traceability is assured from risk detection to end of validation • Testing and documentation can be limited to previously

defined objects. No ‘dead paper’!

Factor for successful risk mitigation:Design focused consequently towards GMP risks

GEA Lyophil GmbH

Controls for leveraging supplier involvement• The regulated companies remain responsible during entire

process

• It is not about trust! It is about controlled relationship!

• Each possible supplier contribution to the project must be seen before the start and also supervised during performance

GEA Lyophil GmbH

Controls for leveraging supplier involvement• Decision making must be visible and structured:Activity Performed by Why Controls

Functional Spec.

Supplier DetailedKnowledge

Standard Doc. verified during pre audit/ final to be approved

Design Review

Supplier/ RegulatedCompany

Both shouldapprove design docs.

Regulated company to crosscheck against Specification

(GMP) Risk assessment

RegulatedCompany

Procces understanding

Supplier should participate and contribute

Test-documents (e.g. IQ/OQ)

Supplier More experience with dedicated equipment

Pre-approved documents/ supervision during testing/ final approval

Factor for successful risk mitigation:Controlled and documented decision making process

GEA Lyophil GmbH

Factors for successful risk mitigationConsequent and correct usage of risk assessment tools

Responsibilities according to expertise

Focus on essential requirements

Design focused consequently towards GMP risks

Controlled and documented decision making process

GEA Lyophil GmbH

Disadvantages of risk based project design • Difficulty to estimate the cost of the project

• Difficulty to estimate the duration of the project

• Time and personnel intensive start phase

• Open discussion may lead to uncomfortable results (e.g. chosen supplier is not the right one)

GEA Lyophil GmbH

Advantages of risk based project design • Clarifications in early project phases (e.g. scope, terms and

‚way of doing‘) will save time, money and reduce confrontations at the end

• Proven technology may be used more often

• Supplier knowledge should be used where ever reasonable

• Amount of documentation and testing should be limited to the real needs. No ‘dead papers’!

• Design is based on requirements not on standard specifications. No ‘dead functionality’!

GEA Lyophil GmbH