Working document QAS/10.342
January 2010
RESTRICTED
SUPPLEMENTARY GUIDELINES ON
GOOD MANUFACTURING PRACTICES FOR HEATING,
VENTILATION AND AIR-CONDITIONING SYSTEMS FOR
NON-STERILE PHARMACEUTICAL DOSAGE FORMS
PROPOSAL FOR REVISION
______________________________________________________________________________________________________________
© World Health Organization 2010
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Please send any request for permission to:
Dr Sabine Kopp, Medicines Quality Assurance Programme, Quality Assurance and Safety: Medicines, Department of Essential
Medicines and Pharmaceutical Policies, World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) 791 4730;
e-mail: kopps@who.int.
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Please address comments on this proposal, by 10 April 2010 to Dr S. Kopp, Medicines Quality
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Working document QAS/10.342
page 2
SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT QAS/10.342:
SUPPLEMENTARY GUIDELINES ON GOOD MANUFACTURING PRACTICES
FOR HEATING, VENTILATION AND AIR-CONDITIONING SYSTEMS FOR
NON-STERILE PHARMACEUTICAL DOSAGE FORMS
PROPOSAL FOR REVISION
WHO Supplementary guidelines on good manufacturing practices
for heating, ventilation and air-conditioning systems for non-sterile
pharmaceutical dosage forms. In. WHO Expert Committee on
Specifications for Pharmaceutical Preparations. Fortieth report
(WHO Technical Report Series, No. 937, Annex 2), 2006.
The need for an update of the above-mentioned supplementary
guidelines was identified during the meeting of inspectors
collaborating in the WHO Prequalification Programme.
2006
2-3 April 2009
Recommendation regarding update made by the WHO Expert
Committee on Specifications for Pharmaceutical Preparations
12-16 October 2009
A first draft proposal for revision was prepared by Mr D. Smith,
South Africa
November-December
2009
The above-mentioned proposal reviewed by the WHO
Prequalification Inspection team
January 2010
Mailing (wide distribution) of document for comments February 2010
Discussion during informal consultation on Quality assurance
systems, medicines and risk analysis, Geneva
4-6 May 2010
Review of comments received and further mailing of working
document
June 2010
Further review of comments received August-September
2010
Discussion during WHO Expert Committee on Specifications for
Pharmaceutical Preparations
18-22 October 2010
Any follow-up action, as needed …
Working document QAS/10.342
page 3
c World Health Organization
WHO Technical Report Series, No. 937, 2006
Annex 2
Supplementary guidelines on good manufacturing
practices for heating, ventilation
and air-conditioning systems for
non-sterile pharmaceutical dosage forms
Proposal for revision
1. Introduction
2. Scope of document
3. Glossary
4. Protection
4.1 Products and personnel
4.2 Air filtration
4.3 Unidirectional airflow
4.4 Infiltration
4.5 Cross-contamination
4.6 Temperature and relative humidity
5. Dust control
6. Protection of the environment
6.1 Dust in exhaust air
6.2 Fume removal
7. HVAC Systems and components
7.1 General
7.2 Air distribution
7.3 Recirculation system
7.4 Full fresh air systems
7.5 Additional system components
8. Commissioning, qualification and maintenance
8.1 Commissioning
8.2 Qualification
8.3 Maintenance
9. Premises
References
1. Introduction
Heating, ventilation and air-conditioning (HVAC) play an important role in ensuring the
manufacture of quality pharmaceutical products. A well designed HVAC system will also
provide comfortable conditions for operators.
These guidelines mainly focus on recommendations for systems for manufacturers of
solid dosage forms. The guidelines also refer to other systems or components which are
Working document QAS/10.342
page 4
not relevant to solid dosage form manufacturing plants, but which may assist in providing
a comparison between the requirements for solid dosage-form plants and other systems.
HVAC system design influences architectural layouts with regard to items such as airlock
positions, doorways and lobbies. The architectural components have an effect on room
pressure differential cascades and cross-contamination control. The prevention of
contamination and cross-contamination is an essential design consideration of the HVAC
system. In view of these critical aspects, the design of the HVAC system should be
considered at the concept design stage of a pharmaceutical manufacturing plant.
Temperature, relative humidity and ventilation should be appropriate and should not
adversely affect the quality of pharmaceutical products during their manufacture and
storage, or the accurate functioning of equipment.
This document aims to give guidance to pharmaceutical manufacturers and inspectors of
pharmaceutical manufacturing facilities on the design, installation, qualification and
maintenance of the HVAC systems. These guidelines are intended to complement those
provided in Good manufacturing practices for pharmaceutical products (1) and should be
read in conjunction with the parent guide. The additional standards addressed by the
present guidelines should therefore be considered supplementary to the general
requirements set out in the parent guide.
2. Scope of document
These guidelines focus primarily on the design and good manufacturing practices (GMP)
requirements for HVAC systems for facilities for the manufacture of solid dosage forms.
Most of the system design principles for facilities manufacturing solid dosage forms also
apply to other facilities such as those manufacturing liquids, creams and ointments. These
guidelines do not cover requirements for manufacturing sites for the production of sterile
pharmaceutical products.
These guidelines are intended as a basic guide for use by pharmaceutical manufacturers
and GMP inspectors.
They are not intended to be prescriptive in specifying requirements and design
parameters. There are many parameters affecting a clean area condition and it is,
therefore, difficult to lay down the specific requirements for one particular parameter in
isolation.
Many manufacturers have their own engineering design and qualification standards and
requirements may vary from one manufacturer to the next. Design parameters should,
therefore, be set realistically for each project, with a view to creating a cost-effective
design, yet still complying with all regulatory standards and ensuring that product quality
and safety are not compromised. The three primary aspects addressed in this manual are
the roles that the HVAC system plays in product protection, personnel protection and
environmental protection (Figure 1).
Working document QAS/10.342
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These guidelines do not cover the specific requirements relating to facilities handling
hazardous products. Guidelines for hazardous product facilities are covered in a separate
WHO guideline.
Figure 1
The guidelines address the various system criteria according to the sequence set out
in this diagram
3. Glossary
The definitions given below apply to terms used in these guidelines. They may have
different meanings in other contexts.
acceptance criteria
Measurable terms under which a test result will be considered acceptable.
action limit
The action limit is reached when the acceptance criteria of a critical parameter have been
exceeded. Results outside these limits will require specified
action and investigation.
air changes per hour (ACH)
The volume of air supplied to a room, in m3/hr, divided by the room volume, in m3.
air-handling unit (AHU)
The air-handling unit serves to condition the air and provide the required air movement
within a facility.
airlock
An enclosed space with two or more doors, which is interposed between two or more
rooms, e.g. of differing classes of cleanliness, for the purpose of controlling the airflow
between those rooms when they need to be entered. An airlock is designed for and used
by either people or goods (PAL, personnel airlock; MAL, material airlock).
alert limit
The alert limit is reached when the normal operating range of a critical parameter has
been exceeded, indicating that corrective measures may need to be taken to prevent the
action limit being reached.
as-built
Condition where the installation is complete with all services connected and functioning
but with no production equipment, materials or personnel present.
at-rest
Condition where the installation is complete with equipment installed and operating in a
manner agreed upon by the customer and supplier, but with no personnel present.
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central air-conditioning unit (see air-handling unit)
change control
A formal system by which qualified representatives of appropriate disciplines review
proposed or actual changes that might affect a validated status. The intent is to determine
the need for action that would ensure that the system is maintained in a validated state.
clean area (clean room)1
An area (or room) with defined environmental control of particulate and microbial
contamination, constructed and used in such a way as to reduce the introduction,
generation and retention of contaminants within the area.
commissioning
Commissioning is the documented process of verifying that the equipment and systems
are installed according to specifications, placing the equipment into active service and
verifying its proper action. Commissioning takes place at the conclusion of project
construction but prior to validation.
containment
A process or device to contain product, dust or contaminants in one zone, preventing it
from escaping to another zone.
contamination
The undesired introduction of impurities of a chemical or microbial nature, or of foreign
matter, into or on to a starting material or intermediate, during production, sampling,
packaging or repackaging, storage or transport.
critical parameter or component
A processing parameter (such as temperature or humidity) that affects the quality of a
product, or a component that may have a direct impact on the quality of the product.
cross-contamination
Contamination of a starting material, intermediate product or finished product with
another starting material or material during production.
design condition
Design condition relates to the specified range or accuracy of a controlled variable used
by the designer as a basis for determining the performance requirements of an engineered
system.
1 Note: Clean area standards, such as ISO 14644-1 provide details on how to classify air cleanliness
by means of particle concentrations, whereas the GMP standards provide a grading for air cleanliness
in terms of the condition (at-rest or operational), the permissible microbial concentrations, as
well as other factors such as gowning requirements. GMP and clean area standards should be used
in conjunction with each other to define and classify the different manufacturing environments.
Working document QAS/10.342
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design qualification (DQ)
DQ is the documented check of planning documents and technical specifications for
conformity of the design with the process, manufacturing, GMP and regulatory
requirements.
direct impact system
A system that is expected to have a direct impact on product quality. These systems are
designed and commissioned in line with good engineering practice (GEP) and, in addition,
are subject to qualification practices.
facility
The built environment within which the clean area installation and associated controlled
environments operate together with their supporting infrastructure.
good engineering practice (GEP)
Established engineering methods and standards that are applied throughout the project
life-cycle to deliver appropriate, cost-effective solutions.
indirect impact system
This is a system that is not expected to have a direct impact on product quality, but
typically will support a direct impact system. These systems are designed and
commissioned according to GEP only.
infiltration
Infiltration is the ingress of contaminated air from an external zone into a clean area.
installation qualification (IQ)
IQ is documented verification that the premises, HVAC system, supporting utilities and
equipment have been built and installed in compliance with their approved design
specification.
no-impact system
This is a system that will not have any impact, either directly or indirectly, on product
quality. These systems are designed and commissioned according to GEP only.
non-critical parameter or component
A processing parameter or component within a system where the operation, contact, data
control, alarm or failure will have an indirect impact or no impact on the quality of the
product.
normal operating range
The range that the manufacturer selects as the acceptable values for a parameter during
normal operations. This range must be within the operating range.
Working document QAS/10.342
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operating limits
The minimum and/or maximum values that will ensure that product and safety
requirements are met.
operating range
Operating range is the range of validated critical parameters within which acceptable
products can be manufactured.
operational condition
This condition relates to carrying out room classification tests with the normal production
process with equipment in operation, and the normal staff present in the room.
operational qualification (OQ)
OQ is the documentary evidence to verify that the equipment operates in accordance with
its design specifications in its normal operating range and performs as intended
throughout all anticipated operating ranges.
oral solid dosage (OSD)
Usually refers to an OSD plant that manufactures medicinal products such as tablets,
capsules and powders to be taken orally.
pass-through-hatch (PTH) or pass box (PB)
A cabinet with two or more doors for passing equipment or product, whilst maintaining
the pressure cascade and segregation.
performance qualification (PQ)
PQ is the documented verification that the process and/or the total process related to the
system performs as intended throughout all anticipated operating ranges.
point extraction
Air extraction to remove dust with the extraction point located as close as possible to the
source of the dust.
pressure cascade
A process whereby air flows from one area, which is maintained at a higher pressure, to
another area at a lower pressure.
qualification
Qualification is the planning, carrying out and recording of tests on equipment and a
system, which forms part of the validated process, to demonstrate that it will perform as
intended.
relative humidity
The ratio of the actual water vapour pressure of the air to the saturated water vapour
pressure of the air at the same temperature expressed as a percentage. More simply put, it
Working document QAS/10.342
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is the ratio of the mass of moisture in the air, relative to the mass at 100% moisture
saturation, at a given temperature.
standard operating procedure (SOP)
An authorized written procedure, giving instructions for performing operations, not
necessarily specific to a given product or material, but of a more general nature (e.g.
operation of equipment, maintenance and cleaning, validation, cleaning of premises and
environmental control, sampling and inspection). Certain SOPs may be used to
supplement product-specific master and batch production documentation.
turbulent flow
Turbulent flow, or non-unidirectional airflow, is air distribution that is introduced into the
controlled space and then mixes with room air by means of induction.
unidirectional airflow (UDAF)
Unidirectional airflow is a rectified airflow over the entire cross-sectional area of a clean
zone with a steady velocity and approximately parallel streamlines (see also turbulent
flow). (Modern standards no longer refer to laminar flow, but have adopted the term
unidirectional airflow.)
validation
The documented act of proving that any procedure, process, equipment, material, activity
or system actually leads to the expected results.
validation master plan (VMP)
VMP is a high-level document which establishes an umbrella validation plan for the
entire project, and is used as guidance by the project team for resource and technical
planning (also referred to as master qualification plan).
4. Protection
4.1 Products and personnel
4.1.1 Areas for the manufacture of pharmaceuticals, where pharmaceutical starting
materials and products, utensils and equipment are exposed to the environment, should be
classified as “clean areas”.
4.1.2 The achievement of a particular clean area classification depends on a number of
criteria that should be addressed at the design and qualification stages. A suitable balance
between the different criteria will be required in order to create an efficient clean area.
4.1.3 Some of the basic criteria to be considered sh
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