Cross Contamination in a multi-products plant
CTP approach
S. Orlandini
Cross Contamination in a Multi-Products Plant – CTP Approach
Page 1
CONTENT OF THE PRESENTATION
• Foreword
• The Pharmaceutical lay-out
• General Concepts
• Constraints and compromises
• Differential Pressures
• HVAC
• Recirculation or full fresh air
• Examples
• Summary
S. Orlandini
Cross Contamination in a Multi-Products Plant – CTP Approach
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Foreword
In the last Century, the GMP evolvement, had focused about innovative
concepts:
 Risk Assessment & Management
 Process Analytical Technologies
 Continuous Improvement
 Quality By Design
Product
Process
Plants & Production structures
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Cross Contamination in a Multi-Products Plant – CTP Approach
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Foreword
Following the “Quality by design” concept, the pharmaceutical
production Facility has to be designed and constructed to
prevent the product contamination risk and the consequent,
negative, impact on its quality
CHAPTER 3 - PREMISES AND EQUIPMENT
Principle
Premises and equipment must be located,
designed, constructed, adapted and maintained to
suit the operations to be carried out. Their layout
and design must aim to minimise the risk of errors
and permit effective cleaning and maintenance in
order to avoid cross-contamination, build up of dust
or dirt and, in general, any adverse effect on the
quality of products.
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Cross Contamination in a Multi-Products Plant – CTP Approach
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The Pharmaceutical lay-out
The pharmaceutical department lay-out is a complex problem,
that it’s affected by many factors and requirements:
Manufacturing
Process
GMP & Rules
Building shape
Budget
People
management
Construction
timeline
LAYOUT
Ergonomics
Environmental
requirements
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Flows
Process
Equipments
Technological
plants
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The Pharmaceutical lay-out
Concepts to be applied:
 Linear and logical flows, avoiding crossing the path of the operating
personnel and materials
3.7 Premises should preferably be laid out in such a way as to allow the production to take
place in areas connected in a logical order corresponding to the sequence of the
operations and to the requisite cleanliness levels. (EU GMP Part.1 Ch.3)
The design of the lay-out of the production
department should start from the study of
flows (materials, personnel, products, mobile
equipment, rejected and waste, etc..), which
must be adapted and planned to the specific
manufacturing process, to the expected
equipment and to the need of products
protection from contamination.
Flows must be studied in order to avoid, as far
as possible, intersections that may constitute a
possibility of error or contamination.
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Raw
Materials
Packaging
Materials
Finished
Products
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The Pharmaceutical lay-out
Concepts to be applied:
 Process operations in dedicated rooms
3.5
Steps should be taken in order to prevent the entry of unauthorised people.
Production, storage and quality control areas should not be used as a right of way by
personnel who do not work in them.
3.38
Equipment should be installed in such a way as to prevent any risk of error or of
contamination.(EU GMP Part.1 Ch.3)
3.1.3 To ensure protection against cross contamination the following technical and
organizational measures should be considered in OSD facility design:
• Physical segregation and separation of manufacturing areas and production systems
handling different products
• ….
(ISPE Baseline Vol.2 – OSD Forms)
It is an essential condition for being able to work lots of different products in the same
department.
It is a system to mitigate the risk of oversight and error, allowing staff to focus all its
attention on the work in progress in that room, in particular, it is important to avoid transit
through the operating room.
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Cross Contamination in a Multi-Products Plant – CTP Approach
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The Pharmaceutical lay-out
Concepts to be applied:
 In case of multi-product manufacturing departments, dedicated and
confined rooms (with airlocks) for exposed product operation
3.14 In cases where dust is generated (e.g. during
sampling, weighing, mixing and processing
operations, packaging of dry products), specific
provisions should be taken to avoid crosscontamination and facilitate cleaning.(EU GMP
Part.1 Ch.3)
3.1.3 To ensure protection against cross contamination the
following technical and organizational measures
should be considered in OSD facility design:
• Physical segregation and separation of
manufacturing areas and production systems
handling different products
• ….
• Personnel clothing and footwear change regimes
(ISPE Baseline Vol.2 – OSD Forms)
This concept allows to create a differential
pressure to avoid the spread of products in the
department, outside the room where is the
specific processing.
It is the most appropriate solution to work lots
of different products in the same department
minimizing the risk of cross-contamination.
Allows you to easily maintain an adequate level
of cleanliness in the operating environments.
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The Pharmaceutical lay-out
Differential Pressure
53. A filtered air supply should maintain a positive pressure and an air flow relative to surrounding areas of a
lower grade under all operational conditions and should flush the area effectively. Adjacent rooms of different
grades should have a pressure differential of 10 – 15 pascals (guidance values). (EU GMP Annex 1)
3.1.3 To ensure protection against cross contamination
the following technical and organizational
measures should be considered in OSD facility
design:
• ......
• HVAC systems, which protect against cross
contamination through use of differential
pressure regimes to control air flow direction
(ISPE Baseline Vol.2 – OSD Forms)
(ISPE Good Practice Guide - HVAC – Appendix 2)
The insertion of airlock between rooms at a different degree of cleanliness (or protection)
allows to mitigate the risks of product contamination, cross-contamination between different
products or to create conditions of containment in the event of processing of dangerous
products, through the creation of a suitable sequence of differential pressures.
The adoption of the model sequence most appropriate to the specific situation (cascade,
bubble, sink) depends from the goal you want to achieve (avoid product contamination,
cross-contamination, build a containment situation).
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Cross Contamination in a Multi-Products Plant – CTP Approach
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Source: WHO QAS/15.639, draft (WHO TR 961, Annex 5)
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The Pharmaceutical lay-out
Concepts to be applied:
 Separation between dirty and clean materials and components
3.36 Manufacturing equipment should be designed so that it can be easily and
thoroughly cleaned. It should be cleaned according to detailed and written
procedures and stored only in a clean and dry condition. (EU GMP Part.1
Ch.3)
5.2.2 Key design criteria associated with the material flow and building
arrangement include:
• ….
• Provision of logical flow of dirty and clean equipment and components
and avoid common staging areas
(ISPE Baseline Vol.2 – OSD Forms)
Aseptic preparation
31. Components after washing should be handled in at least a grade D
environment. (EU GMP Annex 1)
The separation of clean and dirty equipment, achieved either in flows that in the
spaces of temporary storage, reduces the risk of cross-contamination and errors.
It allows to create the distinction between the staff dedicated to cleaning operations
by the one that uses the clean equipment for process operations.
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Cross Contamination in a Multi-Products Plant – CTP Approach
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Recirculation System
There should be no risk of contamination or cross-contamination
(including by fumes and volatiles) due to recirculation of air.
Depending on the airborne contaminants in the return-air system it
may be acceptable to use recirculated air, provided that HEPA
filters are installed in the supply air stream to remove contaminants
and thus preventing cross-contamination. The HEPA filters for this
application should have an EN1822 classification of H13.
HEPA filters may not be required where the air-handling system is
serving a single product facility and there is evidence that crosscontamination would not be possible.
Recirculation of air from areas where pharmaceutical dust is not
generated such as secondary packing, may not require HEPA
filters in the system.
WHO TRS 961 Annex 5
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Cross Contamination in a Multi-Products Plant – CTP Approach
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Recirculation System
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Recirculation System
Air containing dust from highly toxic processes should never be recirculated to the HVAC
system.
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Cross Contamination in a Multi-Products Plant – CTP Approach
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Full Fresh Air Systems
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Full Fresh Air Systems
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Full Fresh Air Systems
Energy-recovery wheels should normally not be used in multiproduct
facilities. When such wheels are used they should not become a
source of possible contamination (see Fig. 25). Note: Alternatives to
the energy-recovery wheels, such as crossover plate heat
exchangers and watercoil heat exchangers, may be used in
multiproduct facilities.
The potential for air leakage between the supply air and exhaust air
as it passes through the wheel should be prevented. The relative
pressures between supply and exhaust air systems should be such
that the exhaust air system operates at a lower pressure than the
supply system.
WHO TRS 961 Annex 5
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Cross Contamination in a Multi-Products Plant – CTP Approach
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Heat Recovery Measures
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Full Fresh Air Systems
ΔP
ΔP
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Heat Recovery Measures
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Cross Contamination in a Multi-Products Plant – CTP Approach
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Heat Recovery Measures
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Cross Contamination in a Multi-Products Plant – CTP Approach
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Heat Recovery Measures
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Heat Recovery Measures
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Examples
Forewords
As already mentioned, the layout must first be adapted to the
production processes: the next slides show some examples,
taken from projects carried out or in progress, in which we
believe the current GMP requirements have been correctly
applied (paying attention to a future development, that is nearly
always to be expected in a restrictive sense of the standard),
the adopted engineering and technology solutions
corresponding to the current state of the art.
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Cross Contamination in a Multi-Products Plant – CTP Approach
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Examples
Multipurpose Oral Solid Dosage forms department
In this case, the most important criticality, for the GMP, is constituted by
the cross contamination between different products and by a product
contamination from external factors: the solutions adopted to mitigate the
risk mainly concern:
 Flows linearity,
 Powder containment and suction,
 Cleaning easiness,
 The containment, with airlocks and appropriate differential pressure,
in the room where product exposure,
 The paths separation of clean and dirty materials and equipment,
 The physical separation of the primary and secondary packaging,
 The possible mix-up prevention.
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Cross Contamination in a Multi-Products Plant – CTP Approach
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Examples
Multipurpose Oral Solid Dosage forms department
Another primary facility and equipment risk for product contamination is product crosscontamination….
OSD facilities are susceptible to this type of contamination as most facilities handle multiple
products during manufacture in the form of dry granules or powder. Handling and processing may
generate airborne dusts, which can escape from their designated area of manufacture.
To ensure protection against cross contamination the following technical and organizational
measures should be considered in OSD facility design:
•
Physical segregation and separation of manufacturing areas and production systems handling
different products
•
Effective process containment, including equipment wash-in-place and clean-in-place, where
practicable
•
HVAC systems, which protect against cross contamination through use of differential pressure
regimes to control air flow direction
•
Efficient dust capture, collection, and extraction systems, where required
•
Personnel clothing and footwear change regimes
(ISPE Baseline Vol.2 – OSD Forms)
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Cross Contamination in a Multi-Products Plant – CTP Approach
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Summary
The speech outlines the current requirements related to the protection
of the product against the cross-contamination and the lines of design
development followed by CTP to prevent - effectively and efficiently the risks.
Usually we can say that, for this type of process, we sometimes note
a tendency – unjustified in our view – towards an interpretation of the
GMP more excessive than the expressed requirements: these
"OVERDESIGN" situations often evolving in lay-out solutions that
cause unnecessary procedural complications (leading to an increased
risk), induce diseconomies caused by an unjustified number of
controls, excessive pressure differentials (stress on the architectural
finishes of the premises).
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References

Eudralex Vol. 4 – Good manufacturing practices – European commission (EU
GMP)

WHO TRS 961 Annex 5

ICH Q9 – Quality Risk Management

ISPE Good practice Guide – Good Engineering Practice

ISPE Good Practice Guide - HVAC

ISPE Baseline Guide – Vol. 2 – OSD Forms

ISPE Baseline Guide – Vol. 5 – Commissioning and Qualification
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Thank you for your kind attention
S. Orlandini
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