Considering the additional risks of operating bio tech processes in a ball room facility 2

Facility Efficiency - Regulatory, GMP Challenges

Robin Payne

(On behalf of the BPOG Room Classification / Closed

Systems work stream)

‘Considering the Additional Risks of Operating BioTech Processes in a ‘Ball Room’ Facility’

BioPhorum Operations Group

Thursday the 14th November 2013, 16:30-17:15

Objectives

• Show how collaboration can

move an industry forwards;

• Challenge the industry to take managed risks with new technology to increase the flexibility of manufacturing facilities and hence increase access to drugs for patients.

Nov 2013 ISPE Strasbourg 2

Content

• BioPhorum Operations Group (BPOG) • Controlled Non-Classified Spaces

• Flexibility

• Multi-Product Application

• Risk Assessment with Scenarios

• The Way Forwards

Nov 2013 3 ISPE Strasbourg

BPOG – The BioPhorum Operations Group

An Exclusive Collaboration Group ‘Helping move the biopharmaceutical industry forwards.’ Constitution: 22 medium to large enterprises with global reach. The Goal: To accelerate the rate at which the biopharmaceutical industry attains

a lean state by building an exclusive community of member companies, focusing on emerging industry challenges and importing and customising appropriate external best practice to deliver outstanding results.

See www.biophorum.com for additional details


http://www.biophorum.com/

Collaboration Approach / Benefits


1. Contacts and networks

2. Comparison of competence

3. Sharing experience & knowledge

4. Cooperative development of best practice &

implementation approaches

5. Customer-centric standards / consistent position

with regulators / influence supply base

The Collaboration Process

• Identify a Theme;

• Decompose into Topics;

• Develop Shared Understanding

– Background

– Common Language

– Meaningful Deliverables

• Deliver;

• Review and Capture Learning


Bittner, E. & Leimeister, J. M. (2013): Why Shared Understanding Matters - Engineering a Collaboration Process for Shared Understanding to Improve Collaboration Effectiveness in Heterogeneous Teams. In: 46th Hawaii International Conference on System Sciences (HICSS) , Maui, Hawaii.

CNC Space for Bulk Drug Substance Operations: The Theme

Technology, with risk based approaches, can eliminate the need for clean rooms in

biopharmaceutical drug substance manufacture.


Enablers for Flexible Facilities and Manufacturing

• Process design and understanding – Understand the process

– Simplify the process

– Make it continuous

• Flexible organizations – Mindset and skills

– Communication and KM

• Advanced controls and testing – Automation

– Data acquisition/analysis

– Reduced testing

• Facility design – Modularization

– Single use components

– Controlled Non-Classified Spaces

– Multi-product manufacturing


CNC definition and expectations

Element Standard / Policy

A cGMP manufacturing area designed to produce a consistent and controlled environment, but not necessarily monitored to a given environmental classification

Chalk, S., et.al.; “Challenging the Cleanroom Paradigm for Biopharmaceutical Manufacturing of bulk Drug Substances,” BioPharm. Intl., August, 2011

Closed or functionally closed processes Probst, S, CLOSED-SYSTEM PROCESSING: AN ENABLING TECHNOLOGY FOR FLEXIBLE FACILITIES, IBC Flexible Facilities, 2013

Architectural Finish Cleanable and durable surfaces Minimize particle generation

Gowning Hairnet / beard covers Dedicated shoes or shoe covers, Appropriate PPE

Particulates and Bioburden Not routinely monitored

Air Changes, Temperature, Humidity (HVAC)

Appropriate for safety, comfort and heat dissipation

Air Filtration HEPA filters NOT required but filtration recommended

sterilized

sterilized

sterilized

Sterile tubing fuser or

aseptic connector


Controlled Non-Classified (CNC) DS Manufacturing

Benefits

• Lower Operating Costs

– Gowning/transitions

– Environmental Monitoring

– Energy

• Lower Construction Costs

– HVAC equipment and ducting

– Personnel and material airlocks

• Faster construction and qualification

– Delay capital investment

Considerations

• High degree of assurance that process equipment is closed

• Defining risk based and effective design and operating principles

• Facility organization to manage the interface between manufacturing and external environments

• Managing planned and unplanned system breaches

• Assurance of environmental control


Functionally Closed Processing

• System Closure established and maintained during processing

• Limited environmental exposure (or none) between processing; pre-use sanitization

• Consideration for system impact on environment during “open” status


Closed Processing: Stainless Steel Systems

• More complex design

• Vessel and transfer line can be steamed and sanitized without opening

• Integrity testing possible

• Precedent for CNC manufacturing

• Facility segregation may not be necessary

May not be flexible!


Closed Processing: Single-Use Systems

Γ-sterilized

Γ-sterilized

Γ-sterilized

Sterile tubing fuser or aseptic connector

• Design complexity borne by the vendor, not the end user.

• Possibility of leaks (integrity test may not be possible)

• Bag seams

• Tubing engagements

• Peristaltic pump tubing wear or misalignment

Γ-sterilized


Functionally Closed Systems: Burden of Proof

NEED PROOF! Functionally-Closed Connection

in CNC ≥

Open Connection in Grade C

What could be in a CNC environment?

• Bacteria, mold, virus

• Cell culture material (from spill)

• In-Process API from another process

Sanitization measures need to be validated


Application of CNC to Concurrent Multi-Product Design Concept


• Concurrent multi-product process: A facility where different products of the same or different class are manufactured at the same time in parallel.

– More challenging than a ‘campaign’ scenario where production has been sequenced to allow temporal segregation with effective cleaning and changeover.

• Application of Quality and Scientific Risk Management approaches

– Special considerations for product class, product compatibility and requirement for product containment

• Assumptions

– Shared media/buffer prep, bioreactor, harvest and purification process operations

– Extensive use of single use components

– Product specific validated cleaning for product contact equipment/parts

– Enhanced controls for some operations (inoc. prep, column packing, final DS filtration)

– Compatible products requiring no special handling

Controlled Non-Classified (CNC) plus Multi-Product Manufacturing

Benefits

• Lower Operating Costs

– Gowning/transitions

– Environmental Monitoring

– Energy

– Capacity Utilization

• Lower Construction Costs

– HVAC equipment and ducting

– Personnel and material airlocks

• Faster construction and qualification

– Delay capital investment

Considerations • Defining risk based and effective

design and operating principles • The additional complexity of

procedural controls and flow-path management without physical or temporal segregation

• Facility organization to manage the interface between manufacturing and external environments

• Managing planned and unplanned system breaches – Risk cross contamination

• Contamination detection and lot disposition

• Assurance of environmental control


Closed Systems, Flexible Manufacturing and CNC Ballrooms

Typical Single

Use Bags /

Containers Flow Transition Spaces,

separate or combined, as appropriate to facility Flow Transition Spaces,

separate or combined, as appropriate to facility

Matls. Matls. Matls. Matls.

Common Media Prep.

Common Buffer Prep

Chromatography Line 1 Cell Culture Line 1

Final Purification Line 1

Matls.

Materials

Personnel

Equipment

Waste

Typical Bio-Reactor

SS or Single Use

Chromatography Line 2


Matls. Matls. Matls.

Matls. Matls.

Matls. Matls.

Cell Culture Line 2

Materials

Personnel

Equipment

Waste

New Challenges to the Cleanroom Paradigm for Multi-Product Facilities - Additional challenges to the new cleanroom paradigm from concurrent multiproduct manufacturing of bulk drug substances in a controlled non-classified (CNC) ballroom environment. May 1, 2013, By: Simon Chalk, Scott Probst, Ken Green, Russell Moser, Frank Urbanski, Matthew Zicaro, Paul Smock, Larry Pranzo, Liz Dooley, Phil McDuff BioPharm International pp. 38-47

http://www.biopharminternational.com/biopharm/Feature+Rotating+Article/New-Challenges-to-the-Cleanroom-Paradigm-for-Multi/ArticleStandard/Article/detail/813380

















Risk Based Operating Principles Principles Multi-product CNC ball room

Risks Mitigation

Process

Definition

Process not capable to

meet quality specs.

Equipment or process

step not closed or

reliable.

Ability to inactivation/removal of endogenous agents.

Robust controls for endogenous and adventitious agents.

Application of QRM principles for control philosophies.

Selection of closed and reliable process technologies.

Application of localized classified environment.

Product Risk

Profiles

Product cross-

contamination.

Operator exposure.

Procedures to manage breaches and temporary openings.

Appropriate cleaning and changeover for designated products.

Rapid analytical detection for potential contaminants.

Robust tracking, monitoring & disposition of product batches/lots.

Product & material environmental health & safety assessment.

Operational

philosophies

Inadequate controls.

Operational systems

overly complex.

Delay to

facility/product

approval.

Facility not fully

optimized for

throughput.

Detailed ops and procedural controls for CNC ballroom.

Minimize manual handling via automation.

Staffing resources to perform all aspects of DS processing.

Solicit external regulatory feedback on design and operation.

Alignment of internal Quality and Regulatory activities.

Review scheduling, cleaning, changeover and maintenance

programs.



Risks Mitigation

Process

Definition

Process not capable

to meet quality

specs.

Equipment or

process step not

closed or reliable.

Ability to inactivation/removal of

endogenous agents.

Robust controls for endogenous and

adventitious agents.

Application of QRM principles for

control philosophies.

Selection of closed and reliable process

technologies.

Application of localized classified

environment.



Risks Mitigation

Product

Risk

Profiles

Product cross-

contamination.

Operator exposure.

Procedures to manage breaches and

temporary openings.

Appropriate cleaning and changeover

for designated products.

Rapid analytical detection for potential

contaminants.

Robust tracking, monitoring &

disposition of product batches/lots.

Product & material environmental

health & safety assessment.



Risks Mitigation

Operational

philosophies

Inadequate controls.

Operational systems

overly complex.

Delay to

facility/product

approval.

Facility not fully

optimized for

throughput.

Detailed ops and procedural controls for

CNC ballroom.

Minimize manual handling via

automation.

Staffing resources to perform all aspects

of DS processing.

Solicit external regulatory feedback on

design and operation.

Alignment of internal Quality and

Regulatory activities.

Review scheduling, cleaning, changeover

and maintenance programs.


Structured Approaches to Risk Assessment

• Standard Risk Assessment;

• Failure Mode Effects Analysis;

• Hazard and Critical Control Point Analysis.


Interacting Elements for Contamination Control


Defining terms; Closed,

Functionally Closed and Open

Verifying a System is Closed

Temporarily Open; Returning to Closed State

Unplanned Breaches;

Effective response

Viral Cross Contamination;

Risk Management

Responses to Potential Areas of Regulatory Scrutiny are being developed


Verification Risks

• Pre-Assembly: – Supplier audit; – Unit integrity testing; – Radiation and other forms of sterilisation; – Certificate of Analysis;

• Assembly: – Product design; – Cleaning and sterilisation at connections; – System integrity testing – filters; – Validated procedures;

• In Production: – Raw materials – culture media – additional treatments; – Measures and sampling – temperature, O2/CO2; – More possible? Pressure changes, rheometry, turbidity, UV, pH – rapid sample

analysis


Typical

Single Use Bags /

Containers

Flow Transition Spaces,


Flow Transition Spaces, separate or combined,

as appropriate to facility


Matls.

Common Media Prep.

Common Buffer Prep


Cell Culture Line 1

Final Purification

Line 1

Matls.

Materials

Personnel

Equipment

Waste

Typical

Bio-Reactor

SS or Single Use


Final Purification

Line 2

Matls. Matls.

Matls.

Matls. Matls.

Matls. Matls.

Cell Culture Line 2

Materials

Personnel

Equipment

Waste

Breach Risks - Upstream

• Significant loss from single use reactor bag: – Causes:

• Flaws in manufacture; • Flaws introduced in assembling the system; • Flaws introduced in running the system;

– Detection: • Visual; • Conductivity; • Pressure drop?

– Mitigation: • Validated spill procedure; • Include sample taking; • Investigation;

– Outcome for Directly Affected Product – Outcome for Adjacent Product


Typical

Single Use Bags /

Containers




separate or combined,



Matls.

Common

Media Prep. Common Buffer Prep


Cell Culture Line 1

Final Purification

Line 1

Matls.

Materials

Personnel

Equipment

Waste

Typical

Bio-Reactor SS or Single Use



Matls. Matls.

Matls.

Matls. Matls.

Matls. Matls.

Cell Culture Line 2

Materials

Personnel

Equipment

Waste



• Flaws in manufacture; Inspection – all or sample • Flaws introduced in assembling the system; Validated Procedures - Helium • Flaws introduced in running the system; Validated operations + Detection

– Detection: • Visual; • Conductivity; • Pressure drop?




Typical Single Use

Bags /

Containers







Matls.

Common Media Prep.

Common Buffer Prep


Cell Culture Line 1


Matls.

Materials

Personnel

Equipment

Waste

Typical

Bio-Reactor

SS or Single Use


Final Purification

Line 2

Matls. Matls.

Matls.

Matls. Matls.

Matls. Matls.

Cell Culture Line 2

Materials

Personnel

Equipment

Waste



• Flaws in manufacture; • Flaws introduced in assembling the system; • Flaws introduced in running the system;

– Detection: • Visual; Operator presence - webcams • Conductivity; Bunded pans + sensors • Pressure drop? Contact pressure sensors




Typical

Single Use Bags /

Containers







Matls.

Common



Cell Culture Line 1

Final Purification

Line 1

Matls.

Materials

Personnel

Equipment

Waste

Typical

Bio-Reactor SS or Single Use



Matls. Matls.

Matls.

Matls. Matls.

Matls. Matls.

Cell Culture Line 2

Materials

Personnel

Equipment

Waste


• Significant loss from single use reactor bag...

• What about Ingress? – Causes as above...

– Egress reduces risk;

– Detection more challenging: • Can one MAB be picked out?

• Endotoxins?

• Elements of the media?

– Chemical ‘sniffing’.


Typical

Single Use

Bags / Containers






Matls.

Common



Cell Culture Line 1

Final Purification

Line 1

Matls.

Materials

Personnel

Equipment

Waste

Typical

Bio-Reactor

SS or Single Use



Matls. Matls.

Matls.

Matls. Matls.

Matls. Matls.

Cell Culture Line 2

Materials

Personnel

Equipment

Waste

Upstream Downstream Cross-Contamination Risk

• The usual reason (excuse) for segregation: – Causes:

• Human error!???

– Detection: • Supervision;

– Mitigations: • Scheduling • Focus on Human Performance; • Poke Yoke:

– Change parts - barcoding; – Procedures; – Truly effective training.


Typical

Single Use Bags /

Containers






Matls.

Common Media Prep.

Common Buffer Prep


Cell Culture Line 1

Final Purification

Line 1

Matls.

Materials

Personnel

Equipment

Waste

Typical

Bio-Reactor

SS or Single Use


Final Purification

Line 2

Matls. Matls.

Matls.

Matls. Matls.

Matls. Matls.

Cell Culture Line 2

Materials

Personnel

Equipment

Waste

Breach Risks - Downstream

• Perforation of tubing within a peristaltic pump:

– Similar causes

– Less impact

– More likely to be detected

visually

– Or by pressure drop

– Easier to clear up


Typical

Single Use Bags /

Containers






Matls.

Common



Cell Culture Line 1

Final Purification

Line 1

Matls.

Materials

Personnel

Equipment

Waste

Typical

Bio-Reactor

SS or Single Use



Matls. Matls.

Matls.

Matls. Matls.

Matls. Matls.

Cell Culture Line 2

Materials

Personnel

Equipment

Waste

Sanitisation

• Recovery from Breach:

– Speed of the essence to prevent dry out;

– Personal Protective Equipment;

– Heat to 121 oC;

– Alter pH (NaOH aq);

– Aerosol detection;

– Sampling;


In Conclusion

The leading Biopharm companies via BPOG are collaborating to define appropriate area classification for multi-product ballroom operations by;

• Developing common definitions and sharing best practices

– Application of Quality and Scientific Risk Management approaches – Considerations for closed processes utilizing technical and procedural

advances – Guidance for Industry*

• Influence the environment – A work in progress

– Internal Quality and Regulatory – External Regulatory authorities

• FDA Meeting Highlights • New work streams to expand the concepts

* Chalk, S., et.al.; “Challenging the Cleanroom Paradigm for Biopharmaceutical Manufacturing of bulk Drug Substances,”

BioPharm. Intl., August, 2011 *Chalk, S., et.al.; “New Challenges to the Cleanroom Paradigm for Multi-Product Facilities”, BioPharm Intl., May 2013


Going Forwards – What If?

• Compliant;

• Low capital cost;

• Low running cost;

• Reliable;

• In country;

• Orphan drug manufacture.


Acknowledgements • Co-Authors

– Simon Chalk, BioPhorum Operations Group

– Scott Probst, Bayer Technology Services

– Ken Green, Pfizer Manufacturing Services

– Russell Moser, Janssen Biopharmaceuticals

– Frank Urbanski, Pfizer Global Engineering

– Matthew Zicaro, HVAC Engineer

– Larry Pranzo, Merck Global Engineering

– Liz Dooley, Janssen Supply Chain

– Phil McDuff, Biogen Idec Engineering

• Reviewers/Collaborators

– Marc Pelletier, CRB Engineers

– Steve Buchholz, Gallus Biopharmaceuticals

– Martyn Becker, GSK

– Joe Rogalewicz, GSK

– Beth Junker, Merck

– Teresa Feeser, BMS


Thank you for Listening

• Any Questions?

• Robin Payne - [email protected]

• www.biophorum.com


mailto:[email protected]

http://www.biophorum.com/

Considering the additional risks of operating bio tech processes in a ball room facility 2

Health & Medicine

manufacturing process

collaboration process

system processing

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