Documentation and recording of changes during development.docx

1. 3.I Qualification of premises and air-conditioning (HVAC)
systems
Up22 Dr. Hans H. Schicht
Here you will find answers to the following questions:
● What is the objective of qualification of premises and air-conditioning systems?
● When is qualification required and when is a technical acceptance procedure -sufficient?
● Which regulatory and normative provisions are to be observed?
● What qualification stages are distinguished?
● How are qualification master plans, qualification plans and qualification reports for premises and air-conditioning
systems being developed?
● How can checklists for systematic handling of qualification activities be compiled?
● When is requalification of the air-conditioning system required?
3.I.1 Objectives of qualification
It is a requirement of Annex 15 to the EU GMP Guidelines that premises as well as equipment and utilities installed
there and devoted to manufacturing processes, which are of considerable relevance for the quality of medicinal
products, must be assessed for their suitability, i.e. be qualified.
The regulatory fundamentals of qualification, the necessary documentation, the responsibilities and procedures are
discussed exhaustively in Chapter 6 Qualification, which is mainly focusing on process equipment. The present chapter
will complement the matter discussed there with view to the qualification of premises and their infrastructure systems.
Elements of the infrastructure systems, also called utilities, are:
● the HVAC systems (heating, ventilating and air-conditioning systems) with their measurement and automatic control
systems, including the eventual connection to a facility management system (see Chapter 3.G Heating Ventilation Air
Conditioning (HVAC))
● the process media systems (purified water, water for injection, process gases, compressed air etc.), together with
their measurement and automatic control systems (see Chapter 5 Pharmaceutical Water and Chapter 3.H
Pharmaceutical gases)
● the pharma monitoring system (see Chapter 3.J Pharma monitoring of HVAC systems)
● the electrical installations (illumination, interlocking of doors, alarms etc.) (see Chapter 3.F Building services)
and many other elements.
The objective of the qualification of premises and building infrastructure systems is the systematic and documented
proof, based upon risk assessment, that they are adequate for the intended use, compliant with GMP requirements and
capable of meeting the specified performance criteria. This status must be maintained during the entire life cycle of the
production process. Doing so, they contribute substantially towards manufacturing the foreseen products safely and
reproducibly in the specified quality.
In cases where toxic or highly active products are manufactured or processed, the objective of the qualification of
premises and utilities beyond these GMP aspects is to ensure the required protection against risks to persons, i.e. to
protect the persons involved in the manufacturing process and the environment of the facility against health and
contamination risks caused by such substances.
The extent of the qualification activities for rooms and building infrastructure systems depends on the purpose of the
production facility and on the air cleanliness classes according to Annex 1 of the EU GMP Guidelines which may
eventually have to be met (see Chapter 3.C Air Cleanliness Classes and Grades and C.6.1 Annex 1). Careful risk
assessment is the appropriate point of departure for determining the details.
An investment object will not only comprise systems requiring qualification, but also many others, whose technically
flawless operation must also be ensured and verified. In the case of a compressed air circuit distinction is required
between compressed air coming into contact with the product and compressed air for technical purposes (see Chapter
3.H Pharmaceutical gases). The compressed air coming into contact with the product presents a potential
contamination risk to it. Therefore qualification is required here, in addition to the technical acceptance tests. On the
other hand, technical acceptance tests according to Good Engineering Practice are sufficient for technical compressed
air as it will not come into contact with the product anywhere. Qualification and technical acceptance tests therefore are
complementary. On drawings and functional diagrams the boundaries between sectors requiring qualification and those
where technical acceptance is sufficient have to be clearly identified.
Premises and the utilities integrated into them are designed and built individually for each investment object. From this
individual character results an increased risk of deficiencies which have to be identified and corrected in time, so that
they can't endanger the quality of the medicinal products manufactured therein.
3.I.2 Regulatory and normative fundamentals of qualification

2. The general regulatory principles for the qualification of premises and their infrastructure systems in the pharmaceutical
industry are laid down in Annex 15 Qualification and Validation to the EU GMP Guide (see C.6.15). In the case of
facilities for the manufacture of sterile medicinal products, Annex 1 Manufacture of sterile medicinal products to that
Guide also applies (see Chapter C.6.1).
For details regarding the air cleanliness classification of the premises reference is made in Annex 1 to ISO 14644-1. For
air cleanliness measurement procedures as well as for all other physical metrology topics in contamination controlled
areas reference should be made to ISO 14644-3. In this standard detailed guidance can be found regarding the
following physical measurement parameters important for qualification of pharmaceutical production facilities:
● Airborne particle count
● Airflow test
● Air pressure difference test
● Installed filter system leakage test
● Airflow direction test and visualization
● Temperature and humidity uniformity test
● Particle deposition test
● Recovery test
● Containment leak test
Beyond the guidance regarding the execution of tests, the minimum performance requirements for the instrumentation
are also specified in ISO 14644-3.
Practice-oriented guidance for qualification measurements can also be found in the guideline VDI 2083 Part 3 Metrology
and test methods which however – as published prior to ISO 14644-3 – is not completely harmonized with it.
Additional important guidance regarding qualification and the qualification parameters can be found in Annex C to ISO
14644-4 and in Chapter 7 of VDI 2083 Part 4.1.
The complete literature references regarding the documents mentioned above are compiled in Chapter 3.L References.
3.I.3 Project development and qualification
As already mentioned, the provisions laid down in Annex 15 to the EU GMP Guide represent the basis for the
qualification of premises and utilities (see Chapter C.6.15). A completely revised version of Annex 15 has been
published in March 2015, with 1 October 2015 as deadline for coming into operation.
Point of departure for designing premises and their utility systems is a functional specification, frequently called User
Requirement Specification (URS). This should remain, as stipulated in Annex 15, a prominent point of reference
throughout the entire life cycle of the facility, and should also be considered as the first step of all qualification activities.
Subsequently to URS, four qualification stagesare distinguished:
● Design qualification (DQ)
● Installation qualification (IQ)
● Operational qualification (OQ)
● Performance qualification (PQ)
Due to the project-specific design and realization of premises and their technical infrastructure there is considerable risk
for errors during the design phase, and important aspects may well be overlooked or decisions deferred until it is too
late. Such design deficiencies should be detected prior to realization and commissioning of the investment object:
corrections during the design and calculation stage are straightforward, fast and cost-effective. Thus, thorough design
qualification will contribute relevantly to reducing the risk of design deficiencies: all the participants in project
development are thus driven towards careful design and dimensioning. Discovering and correcting shortcomings at a
later stage, i.e. during construction and installation, will consume a lot of time and money. Frequently, conflicting
requirements between different infrastructure systems will then impede an optimal solution. Thus, design qualification is,
beyond the GMP and personnel safety aspects, also a highly effective tool for controlling costs and meeting deadlines.
After having taken the general decision for going ahead with an investment object, two stages of design development
are distinguished:
● basic design as basis for the invitations for tendering for the different elements of the realization of premises and
infrastructure systems, and for the selection of suppliers and contractors
● detail design subsequent to the decision regarding the contractors, as basis for the realization of the investment
object
In order to guarantee optimal design quality, it is advantageous to realize design qualification in two steps:
● Design Qualification 1 (DQ 1) as documented proof that the concept specified as result of the basic design for
premises and utilities
● is suitable for the intended use,
● complies with the GMP requirements and the performance and quality criteria established in the specified
standards and guidelines, and

3. ● is mature for the invitations for tendering to be emitted.
● Design Qualification 2 (DQ 2) as documented proof that the detail design meets the requirements established in the
basic design and that it is mature for realization.
3.I.4 Qualification master plan
It is good practice to elaborate a specific Qualification Master Plan (see also Chapter C.6.1) as baseline for all
qualification activities for premises and the building infrastructure. Among other things, it is the appropriate instrument
for clearly determining the delimitation between design elements requiring qualification activities subsequent to technical
acceptance, and those for which technical acceptance is sufficient. The Qualification Master Plan is a sub-module of the
Validation Master Plan required by Annex 15 to the EU GMP Guide. As far as the following items have not yet been
specified in the Validation Master Plan, the Qualification Master Plan for the premises and the utilities installed therein
could cover the following topics:
● Objective of the investment object and its localization on the company area or within a building
● Company policy regarding product quality, qualification and process monitoring
● Organizational structure for the qualification activities
● Requirement profile for structuring qualification reports
● Protection requirements of the project regarding product, process and personnel plus determinations regarding the
required air cleanliness classes or grades
● Applicable regulatory compendia, standards, guidelines and company-internal directives and procedures
● Definitions (if necessary)
● Conclusions from risk assessment as basis for
● determination of the requirements regarding premises and utilities relevant for ensuring product quality
● determination of the scope of the qualification tests
● Brief description of the contamination control system with emphasis upon its contributions for enhancing process and
product safety
● Outline of the qualification concept including the delimitation between qualification and technical acceptance tests
● Time schedule, responsibilities and signature requirements
● Identification of the qualification parameters and their acceptance limits as well as determination of requirements
regarding the associated metrology
● Outline of the process monitoring concept and identification of the parameters to be monitored including alarm and
action limits
● Determinations regarding requalification, i. e. periodical verification of compliance with the specified requirements
(see Chapter 6.H The qualification life cycle)
● Determinations of the change control and deviation management requirements and procedures (see Chapter 19.C
Change Management, Chapter 19.E Deviations and Chapter 6.H The qualification life cycle)
● Determination of the structure of the qualification files and assignment of the responsibility for file management
Under the item regulatory compendia of the Qualification Master Plan a determination is due whether in addition to the
EU GMP Guide also guidance documents from other authorities (e.g. FDA) require consideration.
Regarding change control, the Qualification Master Plan should establish, for example, the exact starting date. As
appropriate starting date, the conclusion of DQ 2 has proved to be practical, as design activities should then have
formally come to an end.
3.I.5 Qualification plans and qualification reports
The detailed qualification activities to be performed are defined in Qualification Plans. Separate plans will have to be
prepared for premises and each utility system, one each for each qualification step. Successful conclusion of each
qualification step is then recorded, again separately for the premises and each utility system, in a Qualification Report.
Qualification Plans and Qualification Reports should be structured identically, for instance as follows:
● Objective of the specific qualification plan/report
● Identification of the system to be qualified
● Applicable regulatory guidance, normative and company-internal directives and procedures
● Terms and abbreviations
● A detailed compilation of the required checks and tests, in which each single item requiring assessment is individually
addressed, together with (where applicable) standardized measurement forms including acceptance criteria
● Formal requirements for drawings and functional diagrams
● Signature lists
● Assignment of responsibilities
For further details regarding the Qualification Plan including examples see Chapter 6.C.3.1 Qualification plans.
The Qualification Report will summarize the results of all checks and tests and draw a conclusion on the outcome of the
qualification. It is recommended to incorporate as first item of the Qualification Report a summarized statement of the

4. qualification’s results expressed as either “passed” or “failed”. Subsequently, the results of all measurements and tests
should be presented in detail. Core elements of the Qualification Report are the fully completed checklists of the
Qualification Plans (see Chapter 3.I.6 Qualification checklists); supplementary information may be added to them.
Eventual omissions, deficiencies, missing data and gaps identified during the qualification step under consideration may
be consolidated in a list of actions. Only when all pending items have been successfully concluded, the qualification
step can be considered as terminated.
For additional information regarding the Qualification Report see Chapter 6.C.3.3 Qualification reports.
3.I.6 Qualification checklists
Basis for all qualification activities are the following documents:
● Qualification Plans
● Qualification Reports
● Updated layout and sectional drawings together with the corresponding air cleanliness zoning and pressurization
schemes
For the realization of qualification activities detailed checklists are very helpful: they favour a systematic and
comprehensive execution of all necessary tasks. It is recommended to incorporate such checklists into the respective
qualification plans and reports. The first set of the detailed sample checklists compiled below comprises the qualification
tasks required for the qualification stages DQ to OQ, and are devoted to the topics Premises and HVAC systems. After
successful termination of the OQ exercise the responsibility for the investment object will pass from the
designer/contractor team to the buyer/operator. The operator will then be responsible for the performance qualification
(PQ). In order to incorporate as many specific subject items as possible into these sample checklists, a technically
complex investment object has been selected as example, i.e. a facility for aseptic filling of liquid parenterals. In the
case of technically less ambitious investment objects the checklists can and should be simplified.
Items that are only subject to technical acceptance procedures have not been incorporated into the checklists. Chillers,
for example, supplying the air coolers of the HVAC system with cold water, are therefore not included in the checklists.
Subject to qualification here, and at the same time the qualification limit, will be the control valve feeding the cold water
into the air cooler.
3.I.6.1 Design Qualification 1 and 2 (DQ 1 and 2)
Design qualification is the documented verification that the proposed design of facilities, utility systems and equipment is
suitable for the intended purpose.
DQ 1 encompasses all documents with impact on process, product and personnel safety developed during basic design
and relevant for the invitations for tendering, e.g. those regarding premises and their utility systems. The compilation
in Figure 3.I-1 is limited to the items Premises and HVAC systems and does not claim to be exhaustive. On the other
hand, not all items listed may be needed in case of a less exacting investment object. The column „o.k. yes/no“ will state
whether a document has been accepted or not. A „no“ requires inclusion of the respective item in a list of actions. Only
after conversion of all „no“ answers into a „yes“, the qualification step can be considered as terminated.
Figure 3.I-1 DQ 1 checklist for premises and HVAC system
Document identification
Document no.,
revision, date
o.k.
yes/no Date Signature
Premises
DQ 1 plan, premises
Description of the basic design
Layout and sectional drawings -including reserve spaces
Area utilization concept
Cleanliness zoning concept
Pressurization concept

5. Design base and requirement -profiles for realization of the -construction
work
Enclosure: risk report
Realization concept
Specification for access control -system
Specification of the wall and ceiling system complete with integrated
features such as lighting elements, terminal filter cells, fan-filter units,
supply and return air cut-outs, -material pass-through units, etc.
Specification for the air-lock -control system
Determination of the radius of wall/floor and wall/wall fillets
Specification for flooring including electrical resistance requirements
Enclosure leakage: determination of limit values
GMP conformity statement regarding relevant specifications, especially:
● Wall and ceiling elements incl. doors, windows, etc.
● Air-lock door control system
● Furniture and material pass-throughs
● Floors, wall, ceilings, as well as furniture easy to clean and disinfect
● Compatibility of floor/wall/ceiling materials and furniture with cleaning
and disinfection fluids
● Sealing concept of ceiling panels
● Piping, cables and their floor/wall/ceiling penetrations
● Prevention scheme for backflow in sinks and drains
● Design concept of personnel and material airlocks
Room program and room book
Illumination concept
HVAC system
DQ 1 plan, HVAC system
Basic specification of general -requirements (cornerstones for -
calculations, performance requirements)
Functional diagram of HVAC -system
Description of HVAC system including operating and monitoring -concept
HVAC system: risk report
Cooling load calculations with -resulting air flow rates/air change rates
Redundancies, e.g. double fans (eventually with list of additional, so far
unapproved proposals)
Provisional layout of machine room for air handling units and related
technical equipment
Provisional layouts for supply air, return air, extract air ducts including
eventual connections to isolators, RABS units, safety work stations,
material pass-throughs etc.)
Provisional layout of work areas with unidirectional airflow (if integrated into
the HVAC system)

6. Specification of air handling units (including reserve requirements)
Specification of ductwork including maximum permitted leakage rates
Specification of components such as
● Constant and variable airflow control valves
● Filter housings and fan-filter-units (FFU's)
● Air filters including HEPA filters
● Motorized dampers
● Fire dampers
● Outside air capture units
● Supply air diffusers and return air capture elements
GMP conformity of the specifications for
● Room pressurization
● HVAC system concept
● Air flow rates sufficient for meeting recovery test requirements and
microbial limit values (where applicable)
● Airflow pattern requirements
● Alarm functions
● Pharma monitoring concept
Functional diagram and specification of automatic control system
Functional diagram and specification of pharma monitoring system
All qualification-relevant documents serving as base for the realization of the investment object have to be submitted to
DQ 2. The compilation shown in Figure 3.I-2 does not claim for completeness.
Figure 3.I-2 DQ 2 checklist for premises and HVAC systems
Document identification
Document
no,
revision,
date
o.k.
yes/no Date Signature
Premises
Qualification report DQ 1, premises
DQ 2 plan, premises
Layout plans and sectional drawings (updated)
Cleanliness zoning concept -(updated)
Pressurization concept -(updated)
Enclosure: risk report (only if updating is necessary)
Access control system design in agreement with specification
Wall and ceiling system: Conformity of contractor’s design with the specified
requirements
Arrangement drawings and side views of wall elements (with integrated
components, reinforcements etc.)

7. Coordination drawings of the wall and ceiling system (with windows, doors,
details of wall/wall and wall/floor fillets, cut-outs for materials pass-throughs as
well as for supply and extract air, incorporation of media channels into the wall
elements etc.
Arrangement drawings for ceiling systems (including cut-outs for filter housings,
fan-filter units and lighting elements, penetrations e.g. for sprinklers, etc.)
Coordination plan for ceiling with -installation drawings for -filter housings, fan-
filter units, lighting elements, penetrations etc.
GMP conformity of execution documentation for:
● Room enclosure incl. doors, -windows etc.
● Furniture and wall fittings (e.g. material pass-throughs)
● Sealing concept of ceiling panels
● Pipings and cables and their floor/wall/ceiling penetrations
● Provisions for preventing backflow in sinks and drains (where acceptable)
Wall and ceiling system:
● Installation manual
● Instructions for repair, modifications, cleaning and disinfection
● Confirmation of compatibility with chemicals, cleaning and disinfection media
● Certificates (e.g. fire resistance)
Penetrations for cables etc. through walls/ceiling/floor. cleanroom compatible
and airtight
Description of connections to adjacent building sectors (e.g. to walls)
Specification of floor system and confirmation of conformity with the User
Requirement Specification
Detail drawings of floor system
Floor systems:
● Installation manual
● Instructions for repair, modifications, cleaning and disinfection
● Confirmation of compatibility with chemicals, cleaning and disinfection media
● Certificates (e.g. fire resistance)
Updated room programme and room book
Description of airlock control system including alarms and provisions for
emergencies
Standard Operational Procedure for measuring leakage rates of room
enclosures
Template for change control logbook regarding room enclosures (if not supplied
by user)
Change proposal, approval and assessment form regarding room enclosures (if
not supplied by user)
HVAC system
Qualification report DQ 1, HVAC -system
DQ 2 plan, HVAC system
Updated functional diagram of air circulation system
Updated system description including operation and monitoring concept
HVAC system: risk report (only if -updating was necessary)

8. Confirmation by contractor of -correctness of cooling load and air flow rate
calculations
Detailed layout of machine room for air handling units and related technical
equipment
Ducts (supply, return, extract air):
● Detailed arrangement drawings
● Specification and drawings -regarding thermal insulation where required
● Updated functional diagrams of the supply, return and extract air system with
connections for isolators, RABS units, safety work stations, material pass-
throughs, location of sensors plus aerosol injection points for the installed
HEPA filter leak test where applicable
Updated layout plans and installation drawings for work areas with -
displacement airflow (if integrated into the HVAC system)
Air handling units: complete documentation with installation drawings,
component lists and technical data
Supplier documentation with technical data and component lists for:
● Volume flow valves (constant and variable)
● Filter housings and fan-filter-units (FFU's)
● Air filters including HEPA filters
● Motorized dampers
● Fire dampers
● Outside air capture units
● Supply air diffusers and return air capture elements
Specification for air duct cleaning -after installation and before commissioning
Updated description of the pharma monitoring strategy
Updated functional diagram of the pharma monitoring system plus material
specifications and wiring diagrams
Updated description of the automatic control system including, where
applicable, its incorporation into the building management system
Updated functional diagram of the automatic control system plus -material
specifications and wiring -diagrams
Component deviations from those specified in the invitations for -tendering
Standard operation procedure for testing air handling units and ductwork for
airtightness
Calibration plans for measuring -instruments
Templates for change control logbook, HVAC system (if not supplied by user or
the contractor for -premises)
Change proposal, approval and -assessment form (if not supplied by user or the
contractor for premises)
Competence and training certificates
Project and qualification manager for
● Premises
● HVAC system
Supervisors including substitutes for
● Civil construction work
● Wall and ceiling system installation
● Floor system installation

9. ● HVAC system installation
3.I.6.2 Installation Qualification (IQ)
Sophisticated equipment, such as isolators and barrier systems according to the RABS principles (see Chapter 3.E
Barrier systems, isolators and safety cabinets) may require, before delivery to the jobsite, a Factory Acceptance
Test (FAT). In such cases, following receipt of these units at the installation site, also a Site Acceptance Test (SAT)
may be recommendable. For the conventional key components destined for the premises such as wall, ceiling and
flooring systems as well as those for the utility systems, Factory and Site Acceptance Tests are, as a rule, not
necessary. After termination of the installation work and prior to commissioning, the time has come for Installation
Qualification (IQ).
The objective of IQ is the documented proof that the realization of the investment object, as installed or modified,
complies with the detail design approved through DQ 2. At that stage, checks are also due for verifying that all project
changes authorized by means of the change control procedure have been duly realized as specified and documented
accordingly. Figure 3.I-3 summarizes the documents to be submitted and approved during IQ.
Figure 3.I-3 IQ checklist for premises and HVAC system
Document identification
Document
no,
revision,
date
o.k.
yes/no Date Signature
Premises
Qualification report DQ 2, -premises
IQ plan, premises
Area delimitation to surrounding building areas correctly signposted and
labelled
Access control system installed as specified
Revision drawings for wall and ceiling systems updated and in conformity with
reality
Statement that the revision drawings incorporate all changes authorized
through the change control procedure
Statement that all interfaces with other supply areas have been duly assessed
and that there are no pending items any more
Statement that all connections to adjacent facility sectors (e.g. to existing walls)
have been executed correctly and are correctly shown in the revision drawings
Statement that the airlock control system has been installed correctly, tested
and shown to address -requirements (including alarm and emergency functions)
Statement that the floors have been installed and documented correctly as
specified
Statement, complete with test -report, that the electrical resistance of the floor is
within specification
Rooms correctly labelled
Statement that the rooms have been built, equipped and furnished according to
the requirements of the room program and, where applicable, room book

10. Statement, complete with test report, that the enclosure leakage test has been
successfully passed
Pipe and cable penetrations through walls/ceilings/floors executed as specified
and airtight
GMP conformity assessed of installed
● Walls with doors, windows etc. including sealing
● Door control system of personnel and material airlocks (incl. emergency
functions)
● Furniture and wall-integrated elements (e.g. material pass-throughs)
● Ceilings (especially airtightness)
● sinks and drains (where permitted)
Correct installation of piping and -cables and airtightness of their
floor/wall/ceiling penetrations
Change control logbook correctly filled-in, complete and up-to-date up to IQ
status
Change control forms correctly filled in, complete and up-to-date up to IQ status
Changes according to change control system correctly realized and those
requiring qualification completely qualified up to IQ status
HVAC system
Qualification report DQ 2, HVAC -system
IQ plan, HVAC system
Functional diagram updated and corresponding with as built status
Revision drawings of the HVAC -system corresponding with the as built status
All components installed and functional (checked by means of functional
diagram and component lists):
● Constant and variable air -volume flow valves
● Filter housings and fan-filter-units (FFU's)
● Air filters including HEPA filters
● Motorized dampers
● Fire dampers
● Outside air capture units
● Supply air diffusers and return air capture elements
Labelling of air handling units -correct and complete
Copy of as built functional diagram of HVAC system attached to air hand-ling
unit in prominent position
Air handling system components -installed and operating correctly
Flow direction and character of air (e.g. outside air, supply air) correctly and
well visibly marked on air ducts
Air duct insulation, where required, in place and undamaged
Leakage test of air handling units and air ducts successfully performed and
documented
Air handling units and air ducts -correctly cleaned
Operation and maintenance manuals provided, complete and approved
Maintenance plan complete and -approved

11. Spare parts list provided, complete and approved
Initial spare parts stock purchased and stored
Standard operational procedures for OQ measurements available, complete
and approved, e.g. for
● Installed filter leak test
● Pressure differences
● Room air classification
● Air flow rates
● Air velocities (areas with unidirectional airflow only)
● Air flow visualization
● Recovery time (if required)
● Room air temperature and relative humidity
● Noise level
Interfaces to other utility installations without conflicts and without pending items
Correct availability of media -required for operating the HVAC -system (chilled
water, cooling water, warm water, technical compressed air etc.)
Pharma monitoring system: statement regarding completeness, correct
installation and functionality
Automatic control system: statement regarding completeness, correct
installation and functionality plus, where applicable, statement of correct
incorporation into the building automation system
Measurement instrumentation -correctly installed, documented and calibrated
according to calibration plan
Calibration certificates and protocols in accordance with specification and
complete
Training manuals for operational personnel prepared and complete
Change control logbook correctly filled-in, complete and up-to-date up to IQ
status
Change control forms correctly filled-in, complete and up-to-date up to IQ status
Changes requiring qualification -correctly realized and qualified up to IQ status
Certificates (incl. personnel training)
Competence and training certificates for:
● Contractor’s commissioning personnel
● Qualification managers for facility and HVAC system
● Contractor’s or separately contracted qualification measurement team (where
applicable)
Maintenance personnel successfully trained, training certificates available
Valid factory test certificates for HEPA filters
Calibration certificates for instruments (where required)
Conformity declarations
3.I.6.3 Operational Qualification (OQ)
After terminating IQ, and prior to OQ, the HVAC system is to be commissioned and the room-specific air flow rates are
to be adjusted to the specified levels.
OQ is the documented verification that premises, utility systems and equipment, as installed or modified, perform as
intended throughout the anticipated operating ranges. Following technical acceptance, OQ is performed as final proof
that rooms and their infrastructural services are robust and fit for hand-over to the purchaser and user.

12. The objective of OQ is to prove that premises and the utilities installed therein meet the specified requirements within
the entire specified operational range. The many single elements for proving this are compiled in Figure 3.I-4. In order
not to impair the commissioning of the process equipment, single OQ steps for the premises can be tackled already
during the IQ stage. This is particularly indicated for the balancing of the air flow rates and for the installed filter leak test
for the terminal HEPA filters. Changing damaged HEPA filters at a later point in time might compromise the OQ of the
process equipment.
Figure 3.I-4 OQ checklist for premises and HVAC systems
Document identification
Document no.,
revision, date
o.k.
yes/no Date Signature
Premises
Qualification report IQ, premises
OQ plan, premises
Access control operating correctly
Airlocks completely furnished -according to specification
Airlock control system successfully tested including alarms and
emergency functions
Rooms completely furnished as -specified
Pictograms regarding standard operational procedures (e.g. garmenting,
hand washing and disinfection procedures) in place and correctly
positioned as specified
Room lighting after furnishing and -installation of process equipment in
agreement with specifications
Simulation of an electrical blackout: Required functions regarding
emergency lighting, emergency power (if required), uninterrupted
electricity supply successfully tested and documented
Change control logbook correctly filled-in, complete and up-to-date until
OQ status and ready for transfer of ownership
Change control forms correctly filled-in, complete, and up-to-date until OQ
status and ready for transfer of ownership
Changes according to change control system correctly realized and those
requiring qualification completely qualified until OQ status and ready for
transfer of ownership
Room cleaning and, where required, room disinfection before transfer of
ownership successfully completed
Room surface cleanliness (particles, microorganisms) according to
specifications
Qualification report, OQ for premises
Qualification documentation for premises (DQ 1 through OQ) complete
and ready for transfer of ownership
Transfer of ownership documentation for premises complete and ready for
signature

13. HVAC system
Qualification report IQ, HVAC system
OQ plan, HVAC system
Reserve capacities of air handling units tested for compliance with
specification
Room specific air flow rates/air change rates correctly adjusted and in
conformity with specifications
Qualification measurements in the at rest occupancy state successfully
performed and documented:
● Pressure differences across HEPA -filters
● Installed filter leak test (terminal HEPA filters only)
● Room pressurization during normal and reduced operation, including
transitory phases
● Air cleanliness classification at rest
● Air flow or air change rates during normal and reduced operation
correctly adjusted and in agreement with specifications
● Air velocity (only areas with unidirectional airflow)
● Air flow visualization documented through video/DVD (only areas with
unidirectional airflow)
● Recovery test where required
● Room air temperature and relative humidity (for specified outside air
summer and winter conditions)
● Noise level in working rooms
Worst case situations for air handling systems completely and successfully
checked
Simulation of an electrical blackout: Specified HVAC emergency operation
successfully tested
Test certificate confirming correct functioning of pharma monitoring system
including alarm and safety functions
Test certificate confirming correct function of automatic control and, where
applicable, its connection to the building management system including
alarm and emergency functions
Change control logbook correctly filled-in, complete and up-to-date until
OQ status and ready for transfer of ownership
Change control forms correctly filled-in, complete, and up-to-date until OQ
status and ready for transfer of ownership
Changes according to change control system correctly realized and those
-requiring qualification completely qualified up to and including OQ status
and ready for transfer of ownership
Standard operational procedures for -microbiological air and surface
measurements including sampling plans completed and approved (if
applicable)
Qualification report, OQ for HVAC -system
Proposal for PQ plan, HVAC system (if required)
Qualification documentation of the HVAC system (DQ 1 through OQ)
complete and ready for transfer of ownership
Transfer of ownership documentation for HVAC system complete and
ready for signature

14. Certificates (incl. personnel training)
Valid calibration certificates for:
● Optical particle counters
● Aerosol generators and dilution devices
● Other measurement instruments requiring periodical recalibration
Valid factory certificates for:
● Spare HEPA filters
● Other spare parts requiring -certificates
Competence certificates for OQ -qualification team
Training of newly contracted maintenance personnel successfully
completed
3.I.6.4 Performance Qualification (PQ)
Performance qualification (PQ) is the documented proof that premises and utilities, in harmony with the production
equipment, are suitable for manufacturing the product reproducibly in the specified quality. Performance qualification is
the responsibility of the user of the facility and is initiated immediately after the transfer of facility ownership from the
contractor to the user.
Regarding premises and the infrastructure systems installed therein, not many surprises are to be expected at that point
in time. During operational qualification, air cleanliness measurements have been performed in the at rest occupancy
state. During performance qualification, they are repeated in the in operation occupancy state, i.e. with the numbers of
persons present as foreseen for normal production.
During PQ, the infrastructure systems and the process equipment operate, for the first time, as an integrated entity. For
the first time, all machinery and other elements contributing to the heat load are now active in parallel. Therefore, only
now it is possible to assess whether the HVAC system is capable of meeting its performance requirements at the
extreme thermal load conditions regarding air temperature and air relative humidity specified for summer and winter as
calculation base for dimensioning.
In addition, during performance qualification the human being is present for the first time in the facility in his condition as
dissemination source for micro-organisms. Now, for the first time, is it possible to assess – where this is relevant –
whether the limits established for microbiological monitoring are met. For sterile manufacturing, they are stipulated in
Annex 1 to the EU GMP Guide (see Chapter C.6.1 and Chapter 3.C.2 GMP Requirements for Cleanrooms: Air
Cleanliness Grades). In all other cases where microbiological risks have to be taken into consideration, they have to be
specified case-specifically upon risk assessment considerations.
A selection of suggested PQ checks and tests is compiled in Figure 3.I-5. As now the manufacturing process and
everything related to it is considered as an entity and as all interferences between the different elements of the
premises, equipment, the HVAC system, process media and the human being are now fully effective, no longer a
distinction is made in this table between the different infrastructure systems now acting together.
Figure 3.I-5 Checklist for performance qualification (HVAC related topics only)
Document identification
Document no.,
revision, date
o.k.
yes/no Date Signature
PQ plan, production system -including utilities (HVAC related topics only)
Room air temperature and -relative humidity at full heat load (including full
operation of process equipment) as specified for the predetermined
outside air conditions per room, for the:
● Summer
● Winter
standardized limit values
Room-specific air cleanliness classification in the occupancy state in
operation
● in agreement with specified limits

15. ● performed with calibrated -instruments (with calibration certificates
attached to test -report)
Microbiological tests (if -required) regarding
● Airborne microorganisms
● Microbial sedimentation
● Surface cleanliness
● Glove test (5 fingers)
successfully passed
Air flow pattern visualization documented with video/DVD (where -
required), e.g.
● Unloading areas of autoclaves into room areas with unidirectional
airflow
● Transfer belts penetrating walls
Worst case situations regarding the interactions between infrastructure
and production systems simulated completely and successfully
Media fill, where required, successfully performed
Production operators successfully trained and qualified, e.g. -regarding
● Garmenting procedures
● Operation of equipment (contamination control aspects)
● Emergency actions
● Performing the media fill
3.I.7 Requirements for measurement and test reports
During qualification activities numerous measurements and tests are necessary which must be documented adequately.
Basic requirement in preparing measurement and test reports is that they are capable of showing
● who has tested
● what
● when
● how and with what instrumentation
● and with which results.
For that reason, test and measurement reports and the forms used for data registration must contain at least the
information compiled in Figure 3.I-6.
Figure 3.I-6 Documentation of test results
Necessary statements to be incorporated into test reports
● Name and address of organization contracted for the measurement and test task
● Identification of the test object
● Yes/no statement whether specified limits have been met
● Identification of the sampling locations (room identification and coordinates of the sampling positions)
● Identification of the measurement instrumentation (manufacturer, type, identification no.)
● Identification of the standards and guidelines in compliance of which measurements are performed
● Specified limits with tolerance band and – in air cleanliness measurements – indication of the occupancy state of the
room
● Measured values (raw data and subsequent calculations where necessary)
● Other information and data if necessary
● Name and signature of person in charge of measurement plus date of measurement
● Name and signature of author of the test report (if not identical with the person performing the measurement) plus
date of emission of the report
Copies of the valid calibration certificates and, where required, of the original measurement strips (e.g. of particle
measurements), duly identified, have to be added to the report.

16. 3.I.8 Requalification
During its entire life cycle, the production process is to be submitted, in periodical intervals, to a requalification and
revalidation procedure. According to Annex 15 of the EU GMP Guide, requalification of the facility and its utility systems
should be performed at an appropriate frequency to confirm that they continue to comply with the requirements
stipulated in the User Requirement Specification (URS) and the design developed from it. The frequency of
requalification should be justified.
This also implies the requalification of the HVAC systems. For requalification of cleanroom systems, two situations
should be distinguished:
● periodical requalification, normally performed once a year in the case of pharmaceutical cleanroom systems
● extraordinary requalification
Extraordinary requalification is performed after
● completion of remedial action implemented to rectify an out-of-compliance condition
● a significant change to the current performance specification, such as a change in operational use
● any significant interruption of air movement which affects the operation of the installation
● special maintenance which significantly affects the operation of the installation (e.g. change of final filters)
Periodical requalification should at least comprise:
● confirmation of the air cleanliness class (or air cleanliness grade)
● air pressure difference between rooms
● airflow velocity (in the case of unidirectional airflow) or air flow rate (in the case of turbulent airflow)
Requalification activities are, as far as physical parameters are concerned, normally performed in the at rest occupancy
state, and they are frequently contracted out to company-external specialized firms. Performing the tests in the at
rest occupancy state also permits evaluation of the physical performance para-meters with greater precision – without
influence of the human being as disturbance factor.
For HVAC systems having to meet the FDA requirements for aseptic manufacturing, the installed filter leak test of
terminally installed HEPA filters has to be performed twice a year. As recommended in PIC/S PI 032-2, such a test
should however be incorporated into the requalification program for each HVAC system protecting sterile manufacturing
operations and be performed at least annually.
If recommended as a result of risk assessment, in addition to the aforementioned tests, the following test parameters
may also be assessed during requalification:
● containment leakage
● airflow visualization
● recovery time
Eventual further parameters for requalification tests may be added on a case-by-case basis, if risk assessments or
special protection schemes (e.g. isolator technology) suggest this.
During periodical requalification, the microbiological status of air and surfaces should be checked where necessary in
addition to the measurement of physical data – in that case, of course, in the occupancy state in operation and with
personnel present as specified. The objective is to confirm that the limits established for microbiological monitoring as
stipulated in Annex 1 to the EU GMP Guide continue to be met (see Chapter 3.C.2, Figure 3.C-2).
The opportunity to incorporate a thorough trend analysis into the requalification program should not be missed. For
this, not only the data of previous qualifications and requalifications should be taken into consideration, but also the data
from process monitoring (see Chapter 3.J Pharma monitoring of HVAC systems). Conclusions resulting from trend
analysis are an effective point of departure for improving systems and their performance. In the trend report, untoward
events should be listed and assessed; any changes to systems and their mode of operation resulting from this should
be identified. They are to be incorporated into the change control logbook, and by means of the change assessment
forms be assessed as to the need for qualification (from DQ through to OQ). Thus, the change control documentation
remains in place and active throughout the entire life cycle of the production process.
3.I Summary:
Premises and the utilities serving them – of which the HVAC system is an important element – require qualification if
they are of considerable relevance for product quality. The objective of the qualification of premises and building
infrastructure systems is the systematic and documented proof, based upon risk assessment, that they are adequate
for the intended use, compliant with GMP requirements and capable of meeting the specified performance criteria.

17. Qualification should be restricted to the aspects relevant for product and/or personnel safety. For all other aspects and
parameters necessary for the correct operation of premises and their HVAC systems, technical acceptance tests are
sufficient.
The basic requirements for qualification are laid down in Annex 15 to the EU GMP Guidelines. Additional guidance is
provided by a number of standards.
Point of departure for complex qualification tasks is a Qualification Master Plan establishing the basic requirements to
be met by the detailed qualification plans for premises and the utilities installed therein. Subsequent to the preparation
of the User Requirement Specification (URS), four qualification stages (DQ, IQ, OQ, PQ) are distinguished. Where
complex technologies such as isolators or RABS units are involved, the qualification steps are complemented by
Factory (FAT) and frequently also Site Acceptance Tests (SAT). Successful completion of each qualification stage is
documented by means of a qualification report.
The extent of the qualification activities depends on the complexity of the investment project and on the product
requirements, for example, regarding air cleanliness. Detailed checklists are a powerful tool for establishing the exact
extent of qualification activities.
In order to ensure and document continued compliance with the capabilities and performance levels demonstrated
during initial qualification, HVAC systems require periodical requalification in appropriate intervals, where physical
parameters and, where necessary, also microbiological parameters are to be verified. It is recommended to include a
trend analysis exercise into the requalification activities. Change control procedures covering all modifications to
systems and their mode of operation continue to be in place throughout the entire life cycle of the facility and its utility
systems.