2011 CMCE HallinanFrank

Biopharmaceutical Multi-Product Facilities:
the Challenges and the Solutions.
Frank Hallinan
EBE Biopharmaceutical Manufacturing
& CMC Conference
Barcelona, March 21, 2011
Agenda:
The Past
The Business Case & Future.
The Challenges:
Technical;
Regulatory.
Approaches to Meet those Challenges:
Quality Risk Management;
Single Use Approaches;
EBE Multi Purpose Use Concept Paper.
Conclusions.
Questions.
1
The Past:
Dedicated, Stainless Steel rich Facilities for

Block Buster Drugs.
Typically Single Host Cell Type eg CHO or, E.

coli but not both.
Typically Dedicated Single purpose Suites

where Product Change over is slow and
Individual Products fully temporally
segregated.
Cost not a Core Issue!
The Business Case for MPF:
Bringing new medicines faster to the patient.

Less Capacity Needed:
Increasing Titers;
More Products but less Blockbusters;
Personalised Medicine.
Cost Issues:
Cost Pressures throughout the Supply Chain;

The High cost of Biopharmaceuticals;
The Introduction of Biosimilars.
Technology Issues:
Flexible, Modular Facilities;

Disposable Components & Facilities.
Tomorrows Facility:
Long-standing facility design paradigms are changing -
Host cell changeovers, multi-host and/or

biohazard levels in same facility;
Non-dedicated suites where product changeovers
can occur more often and more rapidly;
Sharing of suites to manufacture different products
concurrently in closed systems;
Sharing of suites between clinical and commercial
manufacturing;
Rolling changeovers, changeover out-of-place.
The Technical Challenges:
Operational Complexity:
Multi Product;
Multi Phase;
Multi Platform.
Engineering Complexity:
Hardware Issues;
Software & Automation Issues.
Toxicological Complexity of Contaminants:
Pharmacological Reactivity;
Immunological Reactivity.
The Regulatory Challenges I:
Focus on EU Requirements for simplicity. but

Key Objective in all jurisdictions is to ensure the quality of
each product is not compromised by the other(s) being comanufactured in the facility.
Definition: Draft Annex 2 - Multi-Product Facility: A facility
that manufactures, either concurrently or in campaign mode,
a range of different biological medicinal substances and
products and within which equipment train(s) may or may not
be dedicated to specific substances or products.
Manufacture in a multiproduct facility may be acceptable
where the following, or equivalent, considerations and
measures are shown to be an effective part of the control
strategy to prevent cross-contamination.see later.
Dedicated Facility requirements under review at moment.
The Regulatory Challenges II:
A Regulatory Perspective..Dr Lorcan Allen of IMB Member of the

EMA Safety WP re the review of Dedicated Facility
requirements.Great Summary.
Dedicated Facility Review commenced in 2005 and a 2009 Update
from EMA states:
for other products, manufacturers introducing a product into shared facilities

should carry out an assessment of all relevant product and process
characteristics to evaluate whether it is suitable for production in shared
facilities. This assessment should include input from a toxicologist. Where the
product has known sensitizing potential, or is highly potent or toxic, the
Supervisory Authority should be consulted to discuss the manufacturers risk
management measures. (EMA/INS/GMP/809387/2009).
Dr Allen described the Toxicologists approach in more detail:

Formula for defining acceptable residue level for different product
classes.no longer one size fits all.
Generic NOT Specific to Biopharmaceuticals but see new Annex 2
The Regulatory Challenges III:
Draft Annex 2 is Very Informative:

Provides a definition of a Multi-Product Facility.
Emphasises the central role of Quality Risk Management under the
Principles section where it states: quality risk management principles

are particularly important for this class of materials and should be
used to develop their control strategy across all stages of manufacture
so as to minimise variability and to reduce the opportunity for
contamination and cross-contamination.
Provides Specific Criteria (a) (f) that: Manufacture in a
multiproduct facility may be acceptable where the following, or
equivalent, considerations and measures are shown to be an effective
part of the control strategy to prevent cross-contamination
But must also consider Annex 18 which has a number of

relevant Sections.
Complex.needing cross functional detailed planning.
The Regulatory Challenges IV- Specific

Criteria:
When Manufacture in a multiproduct facility may be

acceptable:
(a) Knowledge of key characteristics of all organisms in
the same facility;
(b) Live organisms and spores are prevented from
entering;
(c) Control measures to remove the organisms and
spores before the subsequent manufacture of other
products. Cleaning and decontamination for the organisms
and spores should be validated including the HVAC system;
(d) EM specific for the organism conducted in adjacent
areas during manufacture and after completion of cleaning
and Decontamination;
(e) All items only moved within and removed from such
areas in a manner that prevents cross contamination;
(f) Campaign-based manufacturing.
9
The Importance of QRM:
Making multiple products in one facility requires QRM.if

it did not exist you would have to invent it.
QRM allows you to systematically evaluate all the issues
(the RA step) and come up with specific customised
solutions to those potentialities that you consider
unacceptable (the Risk Mitigation step)
It provides a framework for presenting those risks to the
Regulatory Agency
ICH Q7a Fermentation 18.38 Shared (multi-product)
equipment may warrant additional testing after cleaning
between product campaigns, as appropriate, to minimize the
risk of cross-contamination.
Reference: Briefing Pack ICH Q9 QRM for Facilities (2006).
10
II.4: QRM for facilities, equipment

and utilities EXAMPLE
Facility Needs: Risk Acceptance profile
EFPIA. TG
dedicated facilities, 2006
Disposables:
Internal Project within Pfizers Bio-process Plant of the
Future initiative:
Evaluate cost/benefit as well as compliance (quality and
regulatory) and technical feasibility of disposable equipment for

commercial bio-processing.
Multidisciplinary internal team for period Dec 08 to Dec 09.

Key Objectives were around better understanding of:
Our current usage of disposables?

Opportunities for a coordinated disposables approach in Company
The challenges (technical, regulatory, quality, procurement, engineering etc)
Key themes
cost.
included increased operational flexibility and reduced
Single Use Time Line in Bio-Manufacturing Industry

1985
1990
Up To
750L
Storage
1995
Solid/LiquidSeparation
2005
Steamable
Connections
Sterile
Connectors
Sartorious
Pall
(Centrifugation,NormalFlow
orTFF)
Millipore
Hyclone
Chromatography
Roller Bottles
Unifuge
Lev
Tech
HyNetics
Mixing
CellCulture
2010
Up To
10,000L
Stedim
Tubing
Welders
Connections
2000
WAVE
Xcellerex
Hyclone
GE
Healthcare
EBE Multi-Purpose Use of Plants:

Published July 2010
Team from Sanofi-Aventis,

Centocor, Roche, Abbott,
Amgen, NovoNordisk,
Biogen Idec and Baxter
EBE Concept Paper - Table of Contents:
References
Purpose
Scope
Regulatory Aspects
Methodology:
Segregation of Products
Risk Assessment:
Material
Environment
Equipment
Methods
People
Cleaning
Change-Over
15
EBE Concept Paper References:
References include EU GMPs, CFR and ICH.

Therefore Scope of Applicability is Global.
Scope states: .applicable to any
(bio)pharmaceutical manufacturing facility
manufacturing commercial APIs in which additional
API (commercial or, clinical) manufacturing
processes are introduced.
16
EBE Concept Paper Purpose:
Guidance on design and operational requirements

to be considered when a new product enters the
facility, in particular transition from a single product
operation to a Multi product operation.
A methodology described to control the
associated risks.
The risks will be unique to each transfer and
governed by the specific combination of
product(s), process(es) and site design features
Therefore, approach is to describe all the points
that should be considered
17
EBE Concept Paper - Regulatory Aspects:
Complex, consider Early Communication.

Consider Manufacturing AND Marketing
Authorisations:
May be a Major Change (Type II in EU/CBE 30 in US);

May trigger Pre-approval GMP inspection.
Type and Scope of Variation depends on:

Current Operating model for Facility (Single V Multi
Product/Host);
Nature of new Product/Process;
Any Facility/Equipment Changes Being made.
Must consider MAs of all products in Facility not only

New Product.
Generally no Comparability Exercise required.
18
EBE Concept Paper - Methodology I:
1. Segregation of Products:
..appropriate controls to prevent cross
contamination
Segregation is due to a combination of Soft (ie
Procedural Controls) and Hard (ie Physical
controls) Boundaries which together minimise
risk of cross contamination.
2. Risk Assessment
3. Cleaning
4. Change-Over
19
EBE Concept Paper - Methodology II:
1. Segregation of Products:
2. Risk Assessment:
Risk Assess Overall Operating Model:
Campaign/Parallel Processing
Select appropriate Operating Model
Risk Assess Each of the Operating Steps
Consider Categories of
Materials/Environment/Equipment/Methods/People
3. Cleaning
4. Change-Over
20
EBE Concept Paper - Risk Assessment Equipment I:
Closed Systems:
Single Use/Disposable equipment:
Dedicated Vs Shared Equipment

Shared Equipment
qualification/maintenance/calibration
Automation
Equipment Identification Practices
NOT an Exhaustive List..Should trigger further

thinking relevant to your facility.
21
EBE Concept Paper - Methodology III:
3. Cleaning:
Risk Assess Cleaning Processes/Validation
Cleaning Validation Strategy for New product based on
data with this product.
Intervals for monitoring of cleaning and revalidations
reassessed
4. Change-Over:
Clearly document processes and Procedures.
22
Conclusions:
The Future is Flexible Multi Product Facilities;

Requires experienced, skilled staff at all levels with
broad understanding;
QRM is a proven tool in documenting that all concerns
have been adequately controlled;
EBE Concept Paper provides an effective framework for
using QRM as a Central Tool for achieving biotech
manufacturing facility flexibility.
Level of achieved flexibility is a function of:
The rigor of your risk management;
The effectiveness of your prospective engagement with BoH;
Single Use Systems offers major benefits but with

challenges around assuring consistent quality.
Questions:
Acknowledgements & References:
EBE Concept Paper Multi Purpose Use of Plants (2010).

Kristin Murray & Stephen Reich (Pfizer):
Paul McCormac (Pfizer):
Kristin Murray & Stephen Reich (2010) Enabling Flexible Manufacturing

Facilities Using Quality Risk Management Approaches at IBC 6th International
BMD Summit, Boston, MA
Paul McCormac (2010) The Plastics Factory -Disposables and The Bioprocess
Plant of the Future at IBC 6th International BMD Summit, Boston, MA
Lorcan Allen (IMB):
Dr Lorcan Allen (2010) Contamination Control in MultiProduct Facilities Cleaning

Validation The Toxicological Approach at IMB Manufacturers Information
Day.
Stephan Ronninger (Roche):
Stephan Ronninger (2008) Case Study of Implementation of Quality Risk

Management Manufacturing Facilities at PDA/EMEA Conference, Budapest
ISPE Risk Based Manufacture of Pharmaceutical Products A Guide

to Managing Risks associated with Cross Contamination (2010).

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Biopharmaceutical Multi-Product Facilities:

the Challenges and the Solutions.

Dedicated, Stainless Steel rich Facilities for

Typically Single Host Cell Type eg CHO or, E.

Typically Dedicated Single purpose Suites

Cost not a Core Issue!

The Business Case for MPF:

Bringing new medicines faster to the patient.

Cost Pressures throughout the Supply Chain;

Flexible, Modular Facilities;

Host cell changeovers, multi-host and/or

The Technical Challenges:

Toxicological Complexity of Contaminants:

The Regulatory Challenges I:

Focus on EU Requirements for simplicity. but

The Regulatory Challenges II:

A Regulatory Perspective..Dr Lorcan Allen of IMB Member of the

for other products, manufacturers introducing a product into shared facilities

Dr Allen described the Toxicologists approach in more detail:

The Regulatory Challenges III:

Draft Annex 2 is Very Informative:

Principles section where it states: quality risk management principles

But must also consider Annex 18 which has a number of

The Regulatory Challenges IV- Specific

When Manufacture in a multiproduct facility may be

The Importance of QRM:

Making multiple products in one facility requires QRM.if

II.4: QRM for facilities, equipment

Evaluate cost/benefit as well as compliance (quality and

regulatory) and technical feasibility of disposable equipment for

Multidisciplinary internal team for period Dec 08 to Dec 09.

Our current usage of disposables?

included increased operational flexibility and reduced

Single Use Time Line in Bio-Manufacturing Industry

EBE Multi-Purpose Use of Plants:

Team from Sanofi-Aventis,

EBE Concept Paper - Table of Contents:

EBE Concept Paper References:

References include EU GMPs, CFR and ICH.

EBE Concept Paper Purpose:

Guidance on design and operational requirements

EBE Concept Paper - Regulatory Aspects:

Complex, consider Early Communication.

May be a Major Change (Type II in EU/CBE 30 in US);

Type and Scope of Variation depends on:

Must consider MAs of all products in Facility not only

EBE Concept Paper - Methodology I:

EBE Concept Paper - Methodology II:

EBE Concept Paper - Risk Assessment Equipment I:

Dedicated Vs Shared Equipment

NOT an Exhaustive List..Should trigger further

EBE Concept Paper - Methodology III:

The Future is Flexible Multi Product Facilities;

Single Use Systems offers major benefits but with

Acknowledgements & References:

EBE Concept Paper Multi Purpose Use of Plants (2010).

Paul McCormac (Pfizer):

Kristin Murray & Stephen Reich (2010) Enabling Flexible Manufacturing