MPPS Integral
9. Commissioning, qualification and validation 1621
1622
9.1. General 1623
9.2.
1624
9.2.1. The heating, ventilation and air-conditioning (HVAC) system plays 1625
an important role in the protection of the product, the personnel and the 1626
environment.
1627 1628
9.2.2. For all HVAC installation components, subsystems or parameters, 1629
critical parameters and non-critical parameters should be determined.
1630 1631
9.2.3. Some of the parameters of a typical HVAC system that should be 1632
qualified include:
1633
Working document QAS/15.639 page 63 1634
• room temperature and humidity;
1635
• supply air and return air quantities;
1636
• room pressure, air change rate, flow patterns, particle count and clean-up 1637
rates;
1638
• unidirectional flow velocities and HEPA filter penetration tests; and 1639
• critical alarms, etc.
1640 1641
9.3. Commissioning 1642
1643
9.3.1. Commissioning should involve the setting up, balancing, 1644
adjustment and testing of the entire HVAC system, to ensure that the 1645
system meets all the requirements, as specified in the user requirement 1646
specification, and capacities as specified by the designer or developer. The 1647
commissioning plan should start at the early stages of a project so that it 1648
can be integrated with qualification and verification procedures.
1649 1650
9.3.2. Acceptable tolerances for all system parameters should be specified 1651
and agreed by the user prior to commencing the physical installation.
1652
These tolerances should be specified in the User Requirement 1653
measured data should fall within the acceptance criteria.
1657 1658
9.3.4. System installation records should provide documented evidence 1659
of all measured capacities of the system.
1660 1661
9.3.5. The i n s t a l l a t i o n r e c o r d s should include items such as the 1662
design and measured figures for airflows, water flows, system pressures 1663
electrical amperages, etc. These should be contained in the operating 1664
and maintenance manuals (O & M manuals). The installation records of 1665
the system should provide documented evidence of all measured capacities 1666
of the system.
1667 1668
9.3.6. Typical information that should be contained in the O&M 1669
manuals is the following:
1670 1671
• system description;
1672
• operating instructions, 1673
• trouble shooting;
1674
Working document QAS/15.639 page 64
• commissioning data schedules;
1675
• maintenance instructions;
1676
• list of equipment suppliers;
1677
• spare parts lists;
1678
• equipment capacity and data schedules;
1679
• supplier’s literature;
1680
• control system operation;
1681
• electrical drawings;
1682
• as-built drawings;
1683
• maintenance records.
1684 1685
9.3.7. O & M manuals, schematic drawings, protocols and reports should 1686
be maintained as reference documents for any future changes and upgrades 1687
to the system. As-built drawings should be available and should be kept up 1688
to date with all the latest system changes. Any changes from the originally 1689
approved system should be covered by change control documentation and 1690
risk assessment studies where deemed necessary.
1691 1692
9.3.8. Training should be provided to personnel after installation of the 1693
system, and should include how to perform operation and maintenance.
1694 1695
9.3.9. Commissioning should be a precursor to system qualification and 1696
validation.
1697 9.4.
1698
9.5. Qualification 1699
9.6.
1700
9.6.1. Manufacturers should qualify HVAC systems using a risk-based 1701
approach. The basic concepts of qualification of HVAC systems are set out 1702
in Figure 35 below.
1703 1704 1705
Working document QAS/15.639 page 65 Figure 35
1706
Qualification is a part of validation 1707
1708
9.6.2. The qualification of the HVAC system should be described in a 1709
validation master plan (VMP), or a subsection of the VMP.
1710 1711
9.6.3. The validation master plan should define the nature and extent of 1712
testing and the test procedures and protocols to be followed.
1713 1714
9.6.4. Stages of the qualification of the HVAC system should include 1715
design qualification (DQ), installation qualification (IQ), operational 1716
qualification (OQ) and performance qualification (PQ). The relationship 1717
between the development stage of a project and the qualification/validation 1718
stage is given in the V-Diagram (Figure 36) below.
1719 1720
Working document QAS/15.639 page 66
Figure 36 1721
User Requirement Specification
Functional Design Specification
Detail Design and Configuration Specifications
Build & Project Implementation
V-Model for Direct Impact Systems
PQ Test Plan (incl. UAT)
OQ Test Plan (incl. FAT)
IQ Test Plan (incl. PDI)
Design Qualification
DQ Test Plan
1722
9.6.5. Critical and non-critical parameters for all HVAC installation 1723
components, subsystems and controls should be determined by means of a 1724
risk analysis.
1725 1726
9.6.6. Any parameter that may affect the quality of the pharmaceutical 1727
product should be considered a critical parameter.
1728
Note: A realistic approach to differentiating between critical and 1733
noncritical parameters, systems or components is required, to avoid 1734
making the validation process unnecessarily complex.
1735
Example 1736
• The humidity of the room where the product is exposed should be 1737
considered a critical parameter when a humidity-sensitive product 1738
is being manufactured. The humidity sensors and the humidity 1739
monitoring system should, therefore, be qualified. Components or 1740
equipment such as the heat transfer system, chemical drier or 1741
steam humidifier, which is producing the humidity-controlled air, is 1742
Working document QAS/15.639 page 67 further removed from the product and may not require operational 1743
qualification.
1744
• A room cleanliness classification is a critical parameter and, 1745
therefore, the room air-change rates and high-efficiency particulate 1746
air (HEPA) filters should be considered critical parameters and 1747
components, and therefore require qualification. Items such as the 1748
fan generating the airflow and the primary and secondary filters 1749
are considered non-critical components, and may not require 1750
operational qualification.
1751 1752
9.6.8. Non-critical systems and components should be subject to 1753
verification by good engineering practice (GEP) and may not necessarily 1754
require full qualification.
1755 1756
9.6.9. A change control procedure should be followed when changes are 1757
planned to the HVAC system, its components and controls, that may affect 1758
critical parameters.
1759 1760
9.6.10. The design condition, normal operating ranges, operating range 1761
and alert and action limits should be defined and be realistic. Alert limits 1762
should be based on system capability.
1763 . 1764
9.6.11. All parameters should fall within the design condition range 1765
during system operational qualification. Conditions may go out of the 1766
design condition range during normal operating procedures but they should 1767
remain within the operating range.
1768 1769
9.6.12. Out-of-limit results (e.g. alert or action limit deviations) should be 1770
recorded and form part of the batch manufacturing records, and their 1771
impact should be investigated.
1772 1773
9.6.13. The relationships between design conditions, operating range and 1774
qualified acceptance criteria are given in Figure 37. There should be SOPs 1775
to determine action to be taken when alert and action limits are reached.
1776 1777
Working document QAS/15.639 page 68
Figure 37 1778
System operating ranges 1779
1780 1781
9.6.14. A narrow range of relative humidities coupled with a wide range of 1782
temperatures is unacceptable as changes in temperature will automatically 1783
give rise to variations in the relative humidity.
1784 1785
9.6.15. Some of the typical HVAC system parameters, based on a risk 1786
assessment, that should be qualified for a pharmaceutical facility may 1787
include:
1788 1789
— temperature 1790
— relative humidity 1791
— supply air quantities for all diffusers 1792
— return air or exhaust air quantities 1793
— room air-change rates 1794
— room pressures (pressure differentials) 1795
— room airflow patterns 1796
— unidirectional flow velocities 1797
— containment system velocities 1798
— HEPA filter penetration tests 1799
— room particle counts 1800
— room clean-up or recovery rates 1801
— microbiological air and surface counts where appropriate 1802
— operation of de-dusting 1803
— warning/alarm systems where applicable.
1804 1805
9.6.16. The maximum time interval between tests and re-qualification 1806
should be defined by the manufacturer. The type of facility under test and 1807
the product level of protection should be considered.
1808 1809
Working document QAS/15.639 page 69 Note: Table 5 gives intervals for reference purposes only. The actual test 1810
periods may be more or less frequent, depending on the product and process 1811
and subject to risk assessment.
1812
Table 5 1813
Strategic tests to demonstrate continued compliance 1814
(Time intervals given for re-qualification are for reference purposes only.
1815
The actual tests required will depend on specific facility requirements) 1816
Test parameter Max. time interval between tests (all classes)
Test procedure
Particle count test (verification of cleanliness)
6 months (ISO 5) 12 months
(>ISO 5)
Dust particle counts to be carried out and result printouts produced.
No. of readings and positions of tests to be in accordance with ISO 14644-1 Annex B.2
Air pressure difference (to verify absence of cross- contamination)
12 months
Log of pressure differential readings to be produced - critical plants should be logged daily, preferably continuously. In accordance with ISO 14644-3 Airflow volume
(to verify air change
rates) 12 months
Airflow readings for supply air and return air grilles to be measured and air change rates to be calculated. In accordance with ISO 14644-3 Annex B.4
Airflow velocity (to verify
unidirectional flow or containment
conditions)
12 months
Air velocities for containment systems and unidirectional flow protection systems to be measured.
In accordance with ISO 14644-3 Annex B.4
Working document QAS/15.639 page 70
HEPA filter leakage tests
(to verify filter integrity)
12 months
Filter penetration tests to be carried out by a competent person to demonstrate filter media, filter seal and filter frame integrity.. In accordance with ISO 14644-3 Annex B.6
Containment leakage (to verify absence of cross-contamination)
12 months
Demonstrate that contaminant is maintained within a room by means of:
• airflow direction smoke tests
• room air pressures. In accordance with ISO 14644-3 Annex B.13
Recovery
(to verify clean-up time)
12 months
Test to establish time that a
cleanroom takes to recover from a contaminated condition to the specified cleanroom condition. In Room temperatures
(to verify temperature
tolerance adherence) 12 months
Demonstrate that room temperatures at determined locations comply with specified tolerances. In accordance with ISO 14644-3 Annex B.8.2 Warehouse and store
temperatures (to verify temperature mapping conditions)
36 months
Demonstrate that store
temperatures are uniform within specified tolerances
In accordance with WHO 45th report (WHO Technical Report Series, No. 961), Annex 9 and WHO 49th report (WHO Technical Report Series, No. 992), Annex 5 plus Supplements 1 to 16
Room Humidities (To verify humidity tolerance adherence)
12 months
Demonstrate that room humidities at determined locations comply with specified tolerances. In accordance with ISO 14644-3 Annex B.9.2
Working document QAS/15.639 page 71 9.6.17. Requalification should also be done when any change, which could 1817
affect system performance, takes place.
1818 1819
9.6.18. Room clean-up or recovery tests are performed to determine 1820
whether the installation is capable of returning to a specified cleanliness 1821
level within a finite time, after being exposed briefly to a source of 1822
airborne particulate challenge.
1823 1824
Room clean-up or recovery tests should demonstrate a change in particle 1825
concentration by a factor of 100 within the prescribed time (as per ISO 1826
14644-3 clause B.12) (3). The guidance time period for clean-up or 1827
recovery is about 15 to 20 minutes.
1828
In some instances it is not possible to increase the concentration by a 1829
factor of 100 (such as for an ISO 14644 Class 8 condition) as the high 1830
particle concentration can damage the particle counter. In this instance the 1831
particle decay method can be used as per ISO 14644-3 clause B.12.3.2.
1832
9.6.19. If energy-saving procedures such as reducing the airflow during 1833
non-production hours are used, precautionary measures should be in place 1834
to ensure that the systems are not operated outside the defined relevant 1835
environmental conditions.
1836 1837
These precautionary measures should be based on a risk assessment to 1838
ensure that there is no negative impact on the quality of the product.
1839
Qualification tests should be carried out to demonstrate that there are no 1840
flow reversals, loss of room pressurisation cascade, temperature, humidity 1841
excursions, etc.
1842
9.6.20. Additional documents that should be included in the qualification 1843
manuals should include system airflow schematics, room pressure cascade 1844
drawings, zone concept drawings, air-handling system allocation drawings, 1845
particle count mapping drawings, etc.
1846 1847 1848
Working document QAS/15.639 page 72
9.7. Supplementary notes on test procedures 1849
1850
9.7.1. General 1851
1852
9.7.1.1. Tests should be carried as described in ISO 14644-3.
1853
However below are some supplementary notes and aspects that provide 1854
additional guidance.
1855 1856
9.7.2. Airflow measurements 1857
1858
9.7.2.1. The ISO 14644 method - "B.4.3.3 Supply airflow rate 1859
calculated from filter face velocity" - should not be used to measure the 1860
airflow at diffuser outlets. The diffuser air directional blades or swirl 1861
outlets result in highly inaccurate measurements.
1862 1863
9.7.2.2. The cone and anemometer method is more accurate. Other 1864
methods can be used such as volume flow regulators with built in orifice 1865
and pressure differential ports, whereby airflow can be read off a graph 1866
from the corresponding pressure differentials.
1867 1868
9.7.3. Non-viable air particle counts 1869
1870
9.7.3.1. Particle count test results should be calculated using the 1871
UCL (upper confidence level) formulas as described in ISO 14644-3, if 1872
there are up to nine locations. The practice of using the average value of 1873
all particle count readings as the pass criteria is not acceptable.
1874 1875
9.7.3.2. Ensure that the test certificate states the condition under 1876
which the test was taken i.e. “as built”, “at-rest” or “operational”. The 1877
operational condition should be clearly defined for each room. (For 1878
example: number of staff, staff locations, manner of equipment operating, 1879
etc.) 1880
1881
9.7.3.3. ISO 14644-1 clause B.4.3.42 states that when only one test 1882
location is determined by formula, “take a minimum of three single sample 1883
volumes (B.4.2) at that location.” A more representative result would be 1884
obtained by taking a single sample at each of three different locations in 1885
that room. The actual locations should be based on a risk assessment.
1886 1887
9.7.3.4. In addition to determining the number of the sampling 1888
locations based on the area of the clean room, a risk assessment should 1889
Working document QAS/15.639 page 73 determine if additional sample locations are warranted. Consider aspects 1890
such as personnel and/or production activities and air flow dead spots.
1891 1892
9.7.3.5. Where a UDAF is located within a room the UDAF and its 1893
background environment should be considered separately in terms of 1894
sampling location calculations, and should be individually certified.
1895 1896
9.7.3.6. The mapping drawing indicating test location should be 1897
included with the test certificate, and the same mapping locations should 1898
be used for future tests for comparative purposes.
1899 1900
9.7.4. HEPA filter integrity tests 1901
1902
9.7.4.1. Filter media, frame and seal should be tested for each filter 1903
and results for media, frame and seal penetration reflected separately on 1904
the test certificates.
1905 1906
9.7.4.2. When HEPA filters are terminally mounted at the room, it 1907
should be possible to carry out filter integrity tests from within the room.
1908
The filter housings will therefore require ports for measuring appropriate 1909
upstream concentration and penetration concentration from within the 1910
room. In addition it should be possible to measure the filter pressure drop 1911
in individual HEPA filters, also preferably from within the room. These 1912
pressure drops should be recorded on the filter test certificate as an 1913
indication of the filter life. (The practice of measuring the appropriate 1914
upstream concentration from the ceiling void or at the air handling plant-1915
room, and then measuring the filter penetration concentration in the room 1916
is unacceptable. The time lag between measuring the upstream 1917
concentration and the penetration concentration could mean that by the 1918
time the room penetration is measured, the upstream concentration is no 1919
longer the required concentration.) 1920
1921
9.7.4.3. The test procedure should not compromise the quality of 1922
the product.
1923
10.1. Maintenance records, maintenance procedures and Operating &
1928
Maintenance Manuals should be sufficient to indicate that the company 1929
has control over the HVAC systems. There should be a planned 1930
preventive maintenance programme, procedures and records for the HVAC 1931
Working document QAS/15.639 page 74
system. Records should be kept for a sufficient length of time should they 1932
be required for any product defect analysis.
1933 1934
10.2. O&M manuals, schematic drawings, protocols and reports should be 1935
maintained as reference documents for any future changes and upgrades 1936
to the system. These documents should be kept up to date, containing 1937
any system revisions made.
1938 1939
10.3. The O&M manuals should typically contain the following information:
1940
system description, operating instructions, trouble shooting, 1941
commissioning data, maintenance instructions, list of equipment suppliers, 1942
spare parts list, equipment data/capacity schedules, supplier’s literature, 1943
control system description, electrical drawings and as-built drawings.
1944 1945
10.4. Maintenance personnel should receive appropriate training, and training 1946
records should be kept.
1947 1948
10.5. HEPA filters should be changed either by a specialist or a trained person, 1949
and then followed by installed filter leakage testing.
1950 1951
10.6. Any maintenance activity should be assessed critically to determine any 1952
impact on product quality including possible contamination.
1953 1954
10.7. Maintenance activities should normally be scheduled to take place outside 1955
production hours, and any system stoppage should be assessed with a view 1956
to the possible need for requalification of an area as a result of an 1957
interruption of the service.
1958
1. Good manufacturing practices for pharmaceutical products: main 1963
principles. In: WHO Expert Committee on Specifications for 1964
Pharmaceutical Preparations Thirty-seventh report. Geneva, World 1965
Health Organization, 2003 (WHO Technical Report Series, No. 908), 1966
Annex 4. http://whqlibdoc.who.int/trs/WHO_ TRS_908_eng.pdf;
1967
Quality assurance of pharmaceuticals. A compendium of guidelines 1968
and related materials. Volume 2, Second updated edition. Good 1969
manufacturing practices and inspection. Geneva, World Health 1970
Organization, 2007; and Quality assurance of pharmaceuticals. A 1971
compendium of guidelines and related materials. Geneva, World 1972
Health Organization, 2015 (CD-ROM) (in print).
1973 1974
2. Expert Committee on Specifications for Pharmaceutical 1975
Preparations.Fortieth report. Geneva, World Health Organization, 1976
2005 (WHO Technical Report Series, No. 937) 1977
Working document QAS/15.639 page 75 http://whqlibdoc.who.int/trs/WHO_TRS_937_eng.pdf.
1978 1979
3. Technical supplements to Model guidance for the storage and 1980
transport of time- and temperature-sensitive pharmaceutical 1981
products. WHO Expert Committee on Specifications for 1982
Pharmaceutical Preparations. Forty Ninth report. Geneva, World 1983
Health Organization, 2015 (WHO Technical Report Series, No. 992), 1984
Annex 5.
1985
4. Model guidance for the storage and transport of time- and 1986
temperature-sensitive pharmaceutical products (jointly with the 1987
Expert Committee on Biological Standardization). WHO Expert 1988
Committee on Specifications for Pharmaceutical Preparations.
1989
Forty-fifth report. Geneva, World Health Organization, 2011 (WHO 1990
Technical Report Series, No. 961), Annex 9.
1991
Further reading 1992
1993
Quality assurance of pharmaceuticals. A compendium of guidelines and 1994
related materials, Volume 1. Geneva, World Health Organization, 1997.
1995
Quality Assurance of Pharmaceuticals. A compendium of guidelines and 1996
related materials, Volume 2, Second updated edition. Good manufacturing 1997
practices and inspection. Geneva, World Health Organization, 2007.
1998
http://
1999
www.who.int/medicines/areas/quality_safety/quality_assurance/productio 2000
n/ en/index.html; and Quality Assurance of Pharmaceuticals. A 2001
compendium of guidelines and related materials. Geneva, World Health 2002
Organization, 2015 (CD-ROM) (in print).
2003 2004
World Health Organization. Supplements and updates available at:
2005
www.who.int/medicines.
2006 2007
ASHRAE handbook 1999. HVAC Applications, SI edition. Atlanta, GA, 2008
ASHRAE, 2007. http://www.ashrae.org/technology/page/548.
2009 2010
ASHRAE handbook 2000. HVAC Systems and Equipment. Atlanta, GA, 2011
ASHRAE, 2008. http://www.ashrae.org/technology/page/548.
2012 2013
Daly BB. Woods practical guide to fan engineering. Colchester, Woods of 2014
Colchester Ltd. Third impression, June 1985. Cambridge, Cambridge 2015
University Press. www.flaktwoods.com.
2016 2017
Working document QAS/15.639 page 76
2018
European Commission. The rules governing medicinal products in the 2019
European Community, Volume IV. Good manufacturing practice for 2020
medicinal products. European Commission, Brussels, 2005.
2021
http://www.cen.eu/cenorm/ sectors/sectors/healthcare/index.asp.
2022 2023
ISPE Baseline® pharmaceutical engineering guides, Volume 2. Oral solid 2024
dosage forms, Second Edition / November 2009, International Society for 2025
Pharmaceutical Engineering. http://www.ispe.org/.
2026 2027
ISPE Baseline® pharmaceutical engineering guides for new and 2028
renovated facilities, Volume 5. Commissioning and qualification, 1st ed.
2029
Tampa, Fl, International Society for Pharmaceutical Engineering, 2001.
2030
http://www.ispe.org/.
2031 2032
International Cleanroom Standards, ISO 14644. Geneva, International 2033
Organization for Standardization. http://www.iso.org/iso/standards_
2034
development.htm.
2035 2036
Luwa. Introduction to high efficiency filtration. Bulletin 50.10.10, Sheet 2037
020. Pharmaceutical Inspectorate Convention/Pharmaceutical Inspection 2038
Co-operation Scheme. Guide to Good Manufacturing Practice for 2039
Medicinal Products. PH 1/97 (Rev. 3), 15 January 2002.
2040 2041
PIC/s GMP Guide (PE 009) 2042
http://www.picscheme.org/publication.php?id=4.
2043 2044
ICH Q9: “Quality Risk Management”, November 2005 2045
http://www.ich.org.
2046 2047
World Health Organization. Guidelines on quality risk management, 2048
Geneva, World Health Organization, 2013 (WHO Technical Report Series, 2049
No. 981), Annex 2).
2050
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2051