12/05/09 PPB09

Chor Sing Tan1, Tim Hughes2, Joe Bertolini1

1R&D, CSL Bioplasma, Australia2R&D, CSL Limited, Australia

Improving Reliability and Efficiency of a Biopharmaceutical Manufacturing

Facility: Risk-based Analysis

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Biopharmaceutical

• Biopharmaceutical products for therapeutic and vaccination are derived from:

• Manufacturing processes are complex because:

Cell culture: recombinant and vaccine productsPlasma: antibodies, clotting factors

Products are sensitive toward surrounding conditionsProducts need to be highly purified and safeIn-depth understanding on the process and products is required

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Challenges

• Safety and efficacy of the products are paramount because patients come first

Market is competitive Manufacturers want to reduce costMinimise wastageMaximise equipment utilisation

• Can process economics, efficiency and reliability be achieved without compromising product quality?

Need best process & engineering practises

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Problems

• Aging and ever-changing requirement of production facilities

• Achieving quality requires increasing effort and cost to meet regulatory compliance

• Increasing production cost – energy, material, resources, wastage

• Production downtime and equipment under-utilisation

• Maintenance requirement

• Poor use of statistical control and capture of process data, results in the inability to understand causes of manufacturing problems

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From concept to market

Validation, QbD, DOE

Process understanding and economic

QbD, DOE

LEAN engineering

Patient

R&D, product and process design

Material

Process

Facilities

Product

Manufacturing

Regulatory, clinical trials (ICH GCP), risk management

GMP code

GMP code

Regulatory and quality management

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Desired state of manufacturing environment

• A maximally efficient, agile, flexible pharmaceutical manufacturing environment that reliably produces high-quality drug products without extensive regulatory oversight

• Use a risk based analysis to ensure efficiency and reliability of process equipment and utilities

To provide direction for continuous improvement initiativesTo demonstrate that manufacturing quality is as essential as the quality of the product and development process

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• Hybrid method of: HAZOP (process)FMEA (equipment, component)FTA (deviation)

• It includes analysing risks related to:

Documentation Production data Project management HSE GMP

Design and installationSoftware and process controlValidation activitiesRoutine QC testingProcess transferPreventative Maintenance (PM)

Risk based analysis

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Risk based analysis – a case study

• Site: Pilot scale clinical manufacturing facility

• Objectives:

To identify initiatives to improve efficiency and reliability of the facility To prepare the facility for future activities and capacity expansion

Process equipment – bioreactor, chromatography systemUtilities – WFI, HVAC, effluent plantOperation design, space, manufacturing practises and project management

• Areas assessed:

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ProceduresRisk 1

Item Risk 2

Risk 3Risk 4

Risk 6

Risk 5

Risk 1

Risk 1

Current control

Reliability, efficiency and robustness

Quality and compliance

Workplace HSEProduct quality

Risk elimination and minimisation

Reliable, robust and high quality utility/system

Recommendations

Risk 1

Risk 1

ItemRisk

assessment

InformationP&ID, SOP, validation files,

GMP guidelines, maintenance record, site inspection and communication

with internal and external departments

Detection

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Risk analysis parameters

o Reliability (Re) – ability of the unit operation or system to operate consistently and produce utilities/services of specified quality standards

o Efficiency (E) – ability of the unit operation or system to operate with minimum human intervention, minimal resources and to achieve itsoperation purposes on time and reduce downtime

o Robustness (Ro) – ability of the unit operation or system to support current and future product development activities, especially multi-product manufacturing

o GMP compliance (G) –process areas to operate with GMP-compliant utilities and services at above its specified quality standards

o Product quality (P) – ability of the unit operation or system to impose minimal negative impact on intermediate and final clinical products

o Workplace safety (H) – safe working environment for the operators and adhere to health and safety regulations and guidelines

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Water for injection plant – maintenanceItem Issue/failure mode Risk Control/s

Intensity of UV lamp is not monitored or alarmed

UV unit

No consistent frequency of UV lamp replacement

Undetectable UV lamp failure

High microbial/bioburden load in WFI supply

Visually check if UV is on (weekly basis)

Microbial testing

Impact (Immediate and final) Recommendation

Reliability – High risk (out of specification of microbial load during processing)

Efficiency – High risk (reprocess of product, breakdown of equipment – downtime of processing campaign)

GMP compliance – High risk (deviations)

Product quality – Medium risk (compromise product quality)

Set up alarm on UV lamp failure, i.e. loss of intensity, to Supervisory Control and Data Acquisition (SCADA)

Ensure preventative maintenance is carried out to replace UV lamp, coincides with its shelf-life recommended by manufacturer

Secondary sanitisation option

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Water for injection plant – documentationItem Issue/failure mode Risk Control/s

Misleading labelling of heat exchanger, temperature sensor and pipes

P&ID and labels

Installed components, i.e. valves and temperature sensor, deviates from official P&ID – no change management in place

Confusion during repair and emergency response

Regulatory non-compliance – compromise results of status of IQ, OQ and PQ

Not available

Impact (Immediate and final) Recommendation

Reliability – High risk (doubt: equipment is not performing to its design intention)

Efficiency – High risk (prolong downtime and delay emergency repair response)

GMP compliance – High risk (regulatory non-compliance)

Product quality – Medium risk (compromise product quality)

Initiate change management to address deviations

Establish equipment reference list to coincide with official P&ID, utilise database software for change control

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Bioreactor – process design

Item Issue/failure mode Risk Control/s

Sparger Main microsparger installed has only one gauge size

Microsparger with one gauge size only may not satisfy cell culture operation parameter (1/4” for 60L and 3/8” for 500L).

Yield of cell growth is compromised –gas bubble size is insufficient for optimum oxygen transfer

Ring sparger at the top of the reactor is the alternative option

Impact (Immediate and final) Recommendation

Reliability – High risk (process parameter not met)

Robustness – Medium risk (modification is needed for other cell culture operation)

Product quality – High risk (compromise product yield)

Sparger ring size should be thought out during equipment design and prior to installation and equipment delivery for a particular process.

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Heating Ventilation Air Condition (HVAC) –software monitoring & control

Item Issue/failure mode Risk Control/s

Alarm system to SCADA

Excessive alarms - all alarms (critical or non-critical) – room temperature, pressure and door status are reported and require acknowledgement

Every alarm to the control system is an operation deviation and out of specification of the facility.

Not all alarms are investigated – mostly non-critical

Alarm acknowledged in SCADA

Passed IQ/OQ/PQ

Impact (Immediate and final) Recommendation

Reliability – High risk (doubt on environmental control –system is unreliable)

Efficiency – High risk (downtime, excessive attentions are required)

GMP compliance – High risk (regulatory non-compliance)

Reassess alarm reporting system

Alarm for critical and prolong deviation

Alert on non critical and should be self-regulated by the control system

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Heating Ventilation Air Condition (HVAC) –validation and engineering

Item Issue/failure mode Risk Control/s

Process area classification

Higher class for non-critical process area, i.e. Class C in corridor, waste disposal

Potential risk of not meeting strict classification during at increased production activity

Regulator to hold company to responsibility when deviation occurred and compromise compliance of facilities

PQ at in rest classification

OQ/PQ

Impact (Immediate and final) Recommendation

Efficiency – High risk (strict classification = strict control, more monitoring and cleaning campaign required)

Robustness – High risk (future plant expansion is compromised – increased activity)

GMP compliance – High risk (regulatory non-compliance on non value added scenario)

Room classification should be classified according to activities and production intention

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From risk analysis to improvement

Design and installationProcess control Software monitoringMaintenance supportValidationEquipment and asset deliveryHealth and safety systemManufacturing practices

Understand and define the risks through a transparent process and address them

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Outcome and implications

Maintenance

Validation

Requirement for facilities delivery and process transfer

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Maintenance

• Good manufacturing process does not result in efficient production activities and high quality products, if facilities cannot deliver reliable services

to identify critical components during production activities

to identify and establish the effective Preventative Maintenance programs

• Risk based analysis helps:

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Validation (1)

• Classic validation approach

Consists of structured IQ’s, OQ’s and PQ’s with associated acceptance criteria

Assumes that processes are controlled and predictable

Validation and manufacturing processes still fail – effort, cost and time are required to resolve the issues

• Validation activities only confirm a well-defined and well developed process

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Validation (2)

• Risk Based approachApproach validation by identifying process related risks and reducing risks to acceptable limits and satisfy its specified requirements

Shift focus away from IQ/OQ and subscribe to Good Engineering Practices of the supplier

Focus on PQ to measure process performance and subsequent product quality

Test and measure a range of parameters that matter, ensuring user requirements are met

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Validation (3)

• Validation – Risk Based approach

Performance Qualification (PQ)

DOE QbD

PAT

Risk based analysis

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Requirement for facilities delivery and process transfer

o Facilities

o Process

Ensure transparency in process transfer between R&D, engineering and manufacturing – no surprises

Clarify ownership – ensure smooth transfer of manufacturing facilities from contractor to company and to productionProduction should seek to own and fully understand the facilities deliveredInteraction between new and existing equipment is the key to an efficient and reliable operation

o Give emphasis on effective change management system to enhance traceability of the changes, related to critical elements

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Conclusions (1)

o Risk based analysis approach in validation, engineering design, process transfer and maintenance – pivotal to a reliable and efficient manufacturing facilities

o Facilities delivery should ensure various level of risks are eliminated throughout the design, commissioning, installation and PQ processes

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Conclusions (2)

o Documents are important to record events occurred and to improvethe transparency of process transfer and facilities delivery forsubsequent manufacturing activities

o All documents should reflect the risk based analysis by adoptingassessment parameters (Re, E, Ro, G, P, H)

o Give more emphasis on process data capturing exercise – it provides means to define, analyse and improve the process

o Employ continuous scrutiny on efficiency and reliability of equipment through a systematic risk based approach

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Acknowledgement

o Paul Gardiner

o Clinical Manufacturing Facilities (CMF), CSL Limited

o Medical and Research, R&D, CSL Bioplasma

o R&D, CSL Limited