Pharmaceutical Facility Design

Pharmaceutical Facility Design

Session 1-7

Process Clean Utilities

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 Pharmaceutical Facility Design

Table of Contents
1 Process Support and Utilities .................................................................... 3
1.1 System Impact Descriptions ............................................................... 3
1.2 System Layout and Routing ................................................................ 5
1.3 Design Considerations ........................................................................ 5
2 References .............................................................................................. 10

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1 Process Support and Utilities

(Based on Section-7 from ISPE Baseline Guide 1 ‘Active Pharmaceutical Ingredients’ (2007))

Process support and utility systems supporting the manufacture of APls

include:
• Nitrogen, process air, and other process gases
• Instrument, breathing, and plant air
• Heating/cooling medium
• Clean steam
• Steam and hot water systems
• Process vacuum
• Mechanical seal systems
• CIP Systems
• Solvent supply (including process water)
• Solvent recovery
• Bulk storage liquid
• Vents
• Drains
• Waste handling
• HVAC
• Electric power
• Firewater sprinklers

Good Engineering Practice (GEP) is a satisfactory approach for Indirect or No

Impact systems. Where engineering systems may have a Direct Impact on
product quality, supplementary qualification practices (in addition to GEP and
commissioning) are required fully to address pharmaceutical industry
demands.

1.1 System Impact Descriptions

The FDA suggests that manufacturers understand the ultimate risk to the
patient and focus on areas to reduce that risk. During the facility design, there
should be an awareness of which areas represent the greatest risk to the API,
and therefore, the greatest risk to the patient. Process support and utility
systems may be categorized as Direct Impact, Indirect Impact, or No Impact
systems. The design, construction, commissioning, and documentation
requirements for the systems should be reviewed

Direct Impact Systems

Direct Impact Systems should be designed, constructed, commissioned, and
qualified to provide a service that meets a defined specification (considering
product quality requirement) and prevents product contamination or
deterioration.

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The materials of construction should be non-additive, non-reactive, non-

absorptive, and resistant to the conditions and media handled. For systems
that require regular sanitization/sterilization (e.g., purified water), care should
be taken with regard to the sanitization/sterilization chemicals used.

General Guidance for Typical System Classifications

Direct Impact
(D) Documentation
NormallyGMP
System Indirect Impact and
Important
(I) Commissioning
No Impact (N)
Process Air, Nitrogen
and other Process D Yes Enhanced
Gases
Instrument Air N No GEP
Breathing Air N (note 3) No GEP
Plant Air N No GEP
Heating/Cooling
I In part only GEP
Mediums
Clean Steam D Yes Enhanced
Steam and Hot Water
N No GEP
Systems
Process Vacuum In part only
I GEP
Systems (note 1)
Mechanical Seal
I Yes GEP
Fluids
CIP Systems D Yes Enhanced
Solvent Supply (incl.
D Yes Enhanced
Process Water)
Bulk Storage I (note 2) In part only GEP
Vents N No (note 1) GEP
Drains N No (note 1) GEP
Waste Handling N No GEP
Notes:
1. Shared services not dedicated to one process are a potential source of
cross contamination and the implications of this should be considered.
2. Bulk storage of liquid intermediates, or materials going into later stages
can be Direct Impact.
3. Breathing air that will be exhausted into a classified room may be treated
as an indirect system with the initial quality matching that of the
classification.
4. The selection of process, instrument, or plant air is important, as the
potential for product contact needs to be included in the thought process to
select the type of air.
(Based on table 7.1 from ISPE Baseline Guide 1 ‘Active Pharmaceutical Ingredients’ (2007))

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Indirect and No Impact Systems

Indirect and No Impact systems should be designed and constructed in
construction will depend primarily upon the service requirements. If any of
these services or their points-of-use should be located in classified areas, the
materials of construction should be non-additive, non-reactive, non-
absorptive, and able to withstand room sanitization, as required. Therefore, it
is common for the materials of construction of both Indirect Impact and No
Impact systems to change to a higher specification when used in classified
areas.

1.2 System Layout and Routing

Care should be taken to locate service components and piping outside the
Level III manufacturing areas, where possible. Care also should be taken to
locate components requiring maintenance outside the Level III space.

1.3 Design Considerations

Design concepts for specific API support systems and how those systems
might affect reliable and consistent production of quality API products are
considered. It is important to identify and account for any parts of the control
system that may affect product quality. The specification of materials
contacting the system may change within the system as the process moves
toward becoming a bulk sterile. In this case, the ability to clean easily and to
sterilize becomes a key requirement.

Nitrogen, Process Air, and Other Process Gases

The gas quality should meet product specification and be sampled to assure
conformity. The materials of construction should be consistent with the quality
specification. For nitrogen and process air, typical materials of construction
are 304 Stainless Steel and 316 Stainless Steel. Copper can be used with
point of use filters; as a minimum stainless steel would be used downstream
of the point of use filters.

Filtration used is usually to 1.0

micron; however, where product
purity for low bio burden or aseptic
manufacture is required, 0.2 micron
may be used. The number and
location of the filters may vary, but
upgraded materials of construction
should be used downstream of the
filter for the piping system, e.g., 316
Stainless Steel. The nitrogen
distribution system design should
allow for sampling the nitrogen Redundant filters at point of use
stream.

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If process air has direct contact with the product, the consequence of
exposing the product to oxygen also should be considered. If the impact of the
air is deemed to be critical then pump selections should take this into account.
For example, the use of barriers, etc., on diaphragm pumps should be
considered rather than increasing a utility specification.

Instrument Air
As it is unlikely that instrument air would be in direct contact with the product,
these systems normally should be designed in accordance with GEP.
However, consideration should be given to the need for filtration of exhaust air
to protect classified areas.

Breathing Air

Breathing air should not contact the

product, but it is important to worker
safety. Regulations, e.g.,
Occupational Safety and Health and
EU standards, state the maximum
allowable contaminant levels.

Breathing Air System

Plant Air
As plant air is normally used to power hydraulic tools, etc., it should not be in
direct contact with the product and these systems should normally be
designed in accordance with GEP. However, consideration should be given to
the need for filtration of exhaust air to protect classified areas.

Heating/Cooling Mediums
Heating and cooling systems,
including steam, cooling and chilled
water, glycol systems, and thermal
fluid systems, normally will not
contact the product and should be
designed in accordance with GEP.
Selection of the heat transfer media
should consider the potential risk of
leakage. Monitoring for system
leakage should be considered. Temperature control module

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Clean Steam
Clean steam will usually have a direct impact
on product quality and should be designed,
constructed, commissioned, and qualified to
meet a defined specification. The required
steam quality should be chosen to ensure no
product contamination. Materials of
construction should be 316 Stainless Steel,
having appropriate surface roughness.
Pipework should be passivated prior to use.
The potential for microbial growth should be
eliminated and steam traps should be
minimized; where used they should be of a
hygienic design. However, the distribution
pipe work and equipment to be sanitized
should ensure condensation is removed
adequately to ensure all areas reach the
required temperature for sanitization.
Purified water should be used as feed for the
Clean steam generator clean steam generator.

Steam and Hot Water Systems

Steam and hot water systems are not usually used in applications where there
is exposure to the product and should be designed in accordance with GEP.
Steam and hot water may be used to wash down and clean off-line
equipment. In this case, the contaminants introduced may be removed by
subsequent steps in the wash down or cleaning SOPs, such as final
equipment wash-down using treated water. The cleaning procedure should be
verified.

Process Vacuum System

Vacuum systems not dedicated to one process system are a potential source
of cross contamination. A Risk assessment should be carried out to confirm
that the potential risk for cross contamination is acceptable. Vacuum systems
are a potential source of contamination coming from the outside and
protection against backflow in case of power outage is required. Care should
be taken to determine operational pressure ranges, as abnormal pressure
ranges increase the possibility of cross contamination. Exceeding vacuum
design limits could cause the process to be unstable and the design should
consider ways of limiting the number of simultaneous users.

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Mechanical Seal Fluids

For mechanical seals in product
application, the use of food grade
materials are recommended. If seal
fluid is likely to leak into the product
during a critical step, its impact on
product quality should be addressed.
Dry-running gas barrier seals can be
an effective alternative to
mechanical seals, preventing the
need for a compatible liquid seal
fluid. In this case, filtered nitrogen is
often used. Consideration should be
given during seal selection to the
nitrogen specification, particularly
Fluid mechanical seal humidity.

CIP Systems
The CIP system should ensure no product contamination could occur.
Cleaning chemicals (e.g., detergents) should be removed by subsequent
steps in the cleaning cycle, such as final rinsing using treated water. For multi-
product API facilities, the CIP system should not introduce contamination from
previous cleaning cycles. The materials of construction should be consistent
with the quality specification. The CIP distribution system design should allow
sampling of the CIP stream for qualification and operational purposes.

Solvent Supply (including Process Water)

Solvents are added directly to the process
and the quality should meet product
specification. Materials of construction
should be consistent with the quality
specification, and acceptable materials
normally include 304 Stainless Steel and
316 Stainless Steel; for soft goods (e.g.,
seals), materials should be non-absorptive.
The supply distribution systems design
should allow sampling for qualification and
Multipurpose solvent recovery
operational purposes.

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Bulk Storage Liquids

The bulk storage system should be designed to
GEP. However, bulk storage of liquid
intermediates, or materials going into later stages
may be direct impact. The storage design should
ensure that the quality requirements are
maintained and not compromised during storage.
Consideration should be given to materials of
construction, blanketing of the headspace (for
safety and/or degradation issues), and prevention
of ingress of atmospheric air during emptying of a
tank. Tank farm

Vents
Vents not dedicated to one process are a potential source of cross contamination.
The potential for backflow in both normal and abnormal processing conditions should
be given careful consideration to prevent contamination from the environment. This
can occur, e.g., when depressurizing a reactor into a common header system.
Materials of construction for the vent line should be suitable for the service and
resistant to the various vent gases and vapors that may be encountered.

Drains
Drains should be designed to GEP and the appropriate standards. Materials of
construction for drain lines should be suitable for the service and resistant to the
various waste steams the drains will see. It is preferable to design-out the need for
drains in cleanrooms. However, should drains be required, it is typical to have sealed
drains, which are opened only during times of clean down or firewater release.
Where drains are provided in Level III areas, there will be a requirement to sterilize
these as necessary.

Waste Handling
Waste handling systems not dedicated to one process are a potential source of cross
contamination. The potential for backflow in both normal and abnormal processing
conditions should be given careful consideration. Materials of construction for the
waste handling system should be suitable for the waste being handled.

Fire Water Sprinklers

Facility design needs to incorporate adequate provision to handle the firewater
drainage, and avoid a cGMP impact in the eventuality of the sprinklers being
activated.

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2 References

ISPE Baseline Guide-1

(second edition)

Active Pharmaceutical Ingredients

International Society for

Pharmaceutical Engineering, Tampa,
FL 33607, USA

(2007)

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