GMP MANUFACTURING ENVIRONMENT
8. Commissioning, qualifi cation and maintenance
8.2 Qualifi cation
8.2.1 Validation is a many-faceted and extensive activity and is beyond the scope of these guidelines. Qualifi cation and validation guidelines are included in: Expert Committee on Specifi cations for Pharmaceutical Prep- arations. Fortieth report. Geneva, World Health Organization, 2005 (WHO Technical Report Series, No. 937), Annex 4 (see also Fig. 28).
Full fresh-air system with energy recovery
CC RHC
Cooling coil Re-heat coil Supply air fan Secondary fi lter HEPA fi lter
Supply air-handling unit
Primary fi lterExhaust air fan HEPA fi lter Secondary fi lter Primary fi lter
Production facility Exhaust air-handling unit
Energy recovery wheel
HEPA, high-effi ciency particulate air.
79
Manufacturers should qualify HVAC systems using a risk-based approach.
The basic concepts of qualifi cation of HVAC systems are set out below.
8.2.2 The qualifi cation of the HVAC system should be described in a vali- dation master plan (VMP).
8.2.3 It should defi ne the nature and extent of testing and the test proce- dures and protocols to be followed.
8.2.4 Stages of the qualifi cation of the HVAC system should include DQ, IQ, OQ and PQ.
8.2.5 Critical and non-critical parameters should be determined by means of a risk analysis for all HVAC installation components, subsystems and controls.
8.2.6 Any parameter that may affect the quality of the pharmaceutical product, or a direct impact component, should be considered a critical parameter.
8.2.7 All critical parameters should be included in the qualifi cation process.
Note: A realistic approach to differentiating between critical and non- critical parameters is required, to avoid making the validation process unnecessarily complex.
Example:
• The humidity of the room where the product is exposed should be con- sidered a critical parameter when a humidity-sensitive product is being manufactured. The humidity sensors and the humidity monitoring system should, therefore, be qualifi ed. The heat transfer system, chemical drier or steam humidifi er, which is producing the humidity controlled air, is further removed from the product and may not require operational qualifi cation.
Figure 28
Qualifi cation is a part of validation
Equip 1 Equip 2 Equip 3 Equip 4 Equip 5 Equip 6
QUALIFICATION VALIDATION
Equip 7
System 2 System 1
Process
Equip, equipment.
TSR2006_Annexs1_5.indd 79
TSR2006_Annexs1_5.indd 79 4.5.2006 16:12:474.5.2006 16:12:47
Figure 29
System operating ranges
the room air change rates and HEPA fi lters should be critical parameters and require qualifi cation. Items such as the fan generating the airfl ow and the primary and secondary fi lters are non-critical parameters, and may not require operational qualifi cation.
8.2.8 Non-critical systems and components should be subject to GEP and may not necessarily require qualifi cation.
8.2.9 A change control procedure should be followed when changes are planned to the direct impact HVAC system, its components and controls that may affect critical parameters.
8.2.10 Acceptance criteria and limits should be defi ned during the design stage.
8.2.11 The manufacturer should defi ne design conditions, normal oper- ating ranges, operating ranges, and alert and action limits.
8.2.12 Design condition and normal operating ranges should be identifi ed and set to realistically achievable parameters.
8.2.13 All parameters should fall within the design condition range dur- ing system operational qualifi cation. Conditions may go out of the design condition range during normal operating procedures but they should remain within the operating range.
8.2.14 Out-of-limit results (e.g. action limit deviations) should be recorded and form part of the batch manufacturing records.
8.2.15 The relationships between design conditions, operating range and qualifi ed acceptance criteria are given in Fig. 29.
Action limit
Alert limit Alert limit
Action limit
Design condition
Normal operating range
Operating range – validated acceptance criteria
81
8.2.16 A narrow range of relative humidities coupled with a wide range of temperatures is unacceptable as changes in temperature will automatically give rise to variations in the relative humidity.
8.2.17 For a pharmaceutical facility, based on a risk assessment, some of the typical HVAC system parameters that should be qualifi ed may include:
— temperature
— relative humidity
— supply air quantities for all diffusers
— return air or exhaust air quantities
— room air change rates
— room pressures (pressure differentials)
— room airfl ow patterns
— unidirectional fl ow velocities
— containment system velocities
— HEPA fi lter penetration tests
— room particle counts
— room clean-up rates
— microbiological air and surface counts where appropriate
— operation of de-dusting
— warning/alarm systems where applicable.
8.2.18 The maximum time interval between tests should be defi ned by the manufacturer. The type of facility under test and the product level of protec- tion should be considered.
Note:Table 3 gives intervals for reference purposes only. The actual test periods may be more frequent or less frequent, depending on the product and process.
8.2.19 Periodic requalifi cation of parameters should be done at regular intervals, e.g. annually.
8.2.20 Requalifi cation should also be done when any change, which could affect system performance, takes place.
8.2.21 Clean-up or recovery times normally relate to the time it takes to
“clean up” the room from one condition to another, e.g. the relationship between “at-rest” and “operational” conditions in the clean area may be used as the criteria for clean-up tests. Therefore, the clean-up time can be expressed as the time taken to change from an “operational” condition to an
“at rest” condition.