This document provides an overview of HVAC systems in pharmaceutical manufacturing from a regulatory perspective. It discusses: 1) The relationship between pharmaceutical manufacturing processes, cleanrooms, and HVAC systems and how they must be designed and integrated to control airborne particles and ensure product quality. 2) Key factors the FDA inspectors examine when evaluating HVAC systems, including design documentation, operating procedures, maintenance records, environmental monitoring data, and how systems address failures. 3) Two case studies where issues with water systems and inability to control contamination during construction led to failures like pyrogenic reactions in patients and product recalls. 4) A third case study where poor container closure practices allowed tap water contamination of sealed vials

1. HVAC & Water in Pharmaceutical Manufacturing
From Theory to Application
A Regulatory Perspective
Roohi B. Obaid Jan 19th 2019
Part 2

3. It reflects the views and understanding of presenter
& may not be construed to represent the views or
policies of organization or association to which
speaker has ties
Documents of US-FDA, Papers from
Pharmaceutical Technology & Review Scientific
Articles are used to construct presentation
Disclaimer
Reference

4. Lets understand
relationship
Pharmaceutical Manufacturing
Process & HVAC

5. Manufacturing Process
DS / DP
HVAC

6. Reaction
Separation
Crystallization
Purification
Drying
Drug
Substance

7. Tablets
Liquids
Injections
Creams
Patches
Drug Product

8. Air borne
Particles

9. Air borne
Particles
Solid suspended in air

10. Air borne
Particles
Solid suspended in air
Diameter of human hair is about 75 – 100 microns

11. Air borne
Particles
Solid suspended in air
Diameter of human hair is about 75 – 100 microns
The target is 0.5 micron

12. Bacterial and particulate
Vehicle
Air

13. Men, Material,
Movement
Construction
Design

14. External
Outside make-up air
introduced into the room
Infiltration through
doors, windows & other
penetration through
cleanroom barriers
Control Action
Make-up air
filtration
Room
Pressurization
Sealing of all
penetrations in
space

15. Internal
People Control Action
Cleanroom Surface
Shedding
Process Equipment
Material Ingress
Manufacturing Process
Use of air
showers
1/4

16. Internal
People
Cleanroom Surface
Shedding
Process Equipment
Material Ingress
Manufacturing Process
Designing
airflow path
Control Action
2/4

17. People
Cleanroom Surface
Shedding
Process Equipment
Material Ingress
Manufacturing Process
Use of non-
porous materials
Internal
Control Action
3/4

18. Internal
People
Cleanroom Surface
Shedding
Process Equipment
Material Ingress
Manufacturing Process
Efficient gowning
procedures
Control Action
4/4

19. A room in which the concentration of
airborne particles is controlled
?

20. A room in which the concentration of
airborne particles is controlled
CLEAN ROOM

21. Stopper
Bowls
Filling
Zone
Open
filled
vials
Aseptic
working
Vial
making
for filling
Vial
washing
Aseptic
change
room
Material
Receiving
Solution
preparati
on room
Material
entry locks
Exit
Packaging
room
Aseptic
Injections

22. Stopper
Bowls
Filling
Zone
Open
filled
vials
Aseptic
working
Vial
making
for filling
Vial
washing
Aseptic
change
room
Material
Receiving
Solution
preparati
on room
Material
entry locks
Exit
Packaging
room
Aseptic
Injections

23. Series of
integrations
To match with the requirement of
manufacturing process

24. 15 + 3 20 + 3

25. 15 + 3
12 to 18
20 + 3
17 to 23

26. 15 + 3
12 to 18
20 + 3
17 to 2317 & 18

28. Pharmaceutical
quality demands
Increased air supply HEPA filter
Air flow pattern Room pressurization

29. Lets Design a System

30. 1
Building
construction &
Layout Design

31. Layout & Construction HVAC Performance

32. Layout & Construction HVAC Performance
Air conditioning
need varies with
mfg process &
operations

33. So

34. Proper
Design
Flow
Cleanliness
So

35. So
Proper building design
and planning of the flow of
personnel, material and
equipment is essential for
achieving and maintaining the
design levels of cleanliness
and pressure gradients.
Proper
Design
Flow
Cleanliness

36. 2
Defining the HVAC requirement
System wise & Room wise
Cleanliness level Temp. & Humidity
Pressure Flow Pattern

37. 3
Cooling Load
&
Air Flow
Compilation

38. 4
Selection of air
flow pattern

39. 5
Pressurization of
rooms

40. 6
Air Handling
System

41. 7
Duct System
design &
construction

42. 8
Selection, location
& mounting of
filtration system

43. 9
De-fumigation
requirement

44. 10
Commissioning,
Performance,
Qualification &
Validation

45. 11
Testing &
Validation

46. 12 Documentation

47. Product EnvironmentPersonnel
Protection

48. Temperature Humidity Air Pressure Air borne
particles
1 2 3 4

49. 1 2
Contaminated may not be
cleaned by HVAC
Human aptitude & unqualified
interventions cannot be
substituted by HVAC

50. The way Inspector inspects HVAC
Does manufacturer investigate failures or breakdown to
improve knowledge
Does manufacturer investigate to simply build argument
to continue manufacturing
OR

51. Remember
Information is
not knowledge
Don’t confuse
with each other

52. Contamination

53. Contamination
Transfer of material from one
process to another process

54. Contamination
Transfer of material from one
process to another process
How would you demonstrate that this
movement will not contaminate
product

55. Contamination

56. Contamination
If your dust extraction system fails or
malfunction during manufacturing
of atenolol

57. Contamination
If your dust extraction system fails or
malfunction during manufacturing
of atenolol
Please explain chain of events that
may create unreasonable potential
contamination

58. Remember

59. Remember
The dust extractor must be easy to clean

60. Remember
The dust extractor must be easy to clean
It should possess a trap to prevent
revert back flow

61. Contamination

62. Contamination
Use of old equipment that is
difficult to clean

63. Contamination
Use of old equipment that is
difficult to clean
Interest on you demonstration will be
loose. Remember easy to clean is a
regulatory requirement

64. Contamination

65. Contamination
Use of open tray dryer
for potent class of drugs in multiple
drug manufacturing facility

66. Contamination
Use of open tray dryer
for potent class of drugs in multiple
drug manufacturing facility
It generates and build up
contamination and difficult to prove
containment of product

67. Remember

68. Remember
Re-circulated air should be
proven clean

69. Remember
Re-circulated air should be
proven clean
Filter efficiency needs to be
proved in multiple drug
manufacturing facility

70. The way Inspector inspects HVAC
Verification of design documentation including
description of installations & functions, requirements
and specifications
Standard operating procedures

71. The way Inspector inspects HVAC
Maintenance / calibration program and records
Training files (program, records, evaluation)

72. The way Inspector inspects HVAC
Environmental data, records and trend.
Evaluation of OOS, OOT.

73. Case Study 1

74. Parenteral Grade Drug Substance
Pyrogenicity
Ref: Richard. L. Friedman,
US-FDAApril 2005 (PDA)

75. Pyrogenic
Shock
One API used by two different
manufacturers for their own drug
products
Both caused numerous adverse
drug reactions including pyrogenic
reactions

76. API
Used to manufacture both
injectable and oral dosage forms
All tests prescribed in USP are
routinely followed & compliant

77. API
Produced by a multistep process
Fermentation, Purification
& Isolation

78. API Deionized Water used for
Equipment cleaning
Dissolution step
As washing solvent

79. Unsuitable water in final
processing step
Validation was not done upon scale up & multiple
significant changes implemented

80. The equipment usage log for spray dryer was
not maintained
Same person signed as operator & checker for a
batch step in many instances

81. Record was rewritten without
explanation
Possible contributor of endotoxin had
not been evaluated

82. Potential capability of the process to destroy
or remove endotoxin had not been evaluated
Opportunity for endotoxin reduction in
the process did not exist

83. Composite testing was used to keep
endotoxin in acceptance limit
Laboratory failed to perform endotoxin control
required by the USP - BET

84. Water used for purification step & final rinse
was not tested for total microbial count
No procedure exist to characterize
the microorganisms

85. Impurity tests of the finished API were
not validated
Interestingly, HPLC system suitability test was
performed monthly

86. Complaint of ADR was not
adequately scrutinized
Strength of root cause analysis & CAPA
was questionable

87. Multiple quality system elements of
API manufacturer were objectionable
Manufacturer’s material system
became questionable by default
Inadequate raw material is often named
as root cause of product quality failure

88. The origin of product
problemRaw Material
Variability
Defects, product loss,
rejection or recall

89. The material system should
provide on going assurance
of acceptable
Compliant
Quality System
Raw Material Quality

91. Fundamental failure of GMP at API site &
Material System at FG Manufacturer site
Same manufacturing approach adopted by the
API manufacturer for parenteral & oral dosage
forms
1
2

92. Little assurance of process or
laboratory control
Unacceptable water system & standards
3
4

93. Greatest amount of endotoxin was contributed
during the final wash of crude active
Additional contribution of endotoxin might
have occurred during other steps
5
6

94. Rinse water with
significant endotoxin
load was used to wash
(clean) product contact
surface

95. Pyrogenic test &
endotoxin test found
positive by the FDA in
some samples picked
from discrete part of
drums

96. Some samples found
non-pyrogenic &
significant potential of
intrabatch variation
due to lack of process
control

97. About 200 ADE were
reported by the
medical practitioner
upon administration of
the contaminated drugs

98. Recalls & market
withdrawal of API and
Finished product

99. Import detention for
multiple years unless
reaches minimal
compliance with GMP

100. New owners,
assistance of
consultants & major
changes brought back
the company & it took
not days but years &
end up with change of
management

101. Case Study 2

102. Migration of Contamination liberated
during Facility Construction
Ref: Richard. L. Friedman,
US-FDAApril 2005 (PDA)

103. Major
Construction In a clean room next to the
personnel entry air lock e.g.
gowning area
Production & construction
continued simultaneously

104. MFT
Contaminated
Practice unrelated to the
construction was likely the source
of contamination
Another MFT failure occurred
Bacillus specie identified

105. MFT
Contaminated
Spore forming bacteria …
Bacillus specie identified
?

106. Firm did not adequately assess the
risk posed by the construction
activities
Production system was the
most deficient
Failure of QMS to evaluate impact of
change in normal & qualified condition

107. Moving of wall is a common culprit
in the location of spore formers into
the clean room environment
Many sterility failures & MFT failures
have been attributed to contamination
from nearby construction
Evaluate carefully, move carefully, be
vigilant always

108. Assuring Container Closure Integrity throughout
Manufacturing
Case Study 3
Recall of multiple lots under Class I

109. Background
Contamination
found
Enterobacter
colacae
Other micro-
organisms also
found
Xanthomonas
maltophilia
Adverse drug
events
Septicemia

110. cGMP Issue
Container closure integrity problem identified Finished product dropped
Cleaning of floor with uncontrolled shower of tap water done
Sealed vials exposed to tap water ? ? ?

111. Quality System
Packaging &
labeling system
deficient
Poor handling
sealed glass
Rough
handling
Sub-visible
hairline cracks
Contamination
confirmed
Same organism
found in water
tank

112. Quality System
Critical GMP
concept required
to be reinforced
Every production
phase through
packaging must
be robust
Assure proper
design of
manufacturing
operations
Assure proper
control of
manufacturing
operations
Assure proper
maintenance of
manufacturing
operations
Continuous
learning
throughout the
life cycle

113. Poor & rough handling
Caused septicemia to several patients
Case Study
Outcome

114. Fragile System to respond to Failures
Case Study 4
A story of Fertile Recall

115. Failed to:
1. Respond to critical
deviation
2. Determine RC
3. Respond CAPA
Ability to Investigate

116. Microbes in your water
25 batches of alert level or
action level for CFU
Bulkholderia cepacia was
known in your system
Forgot that it forms biofilm
Failed to consider

117. Did not establish root cause
(25)
Alleged with sampling error
without any proof (16)
Left several (09) unattended
Ignored

118. Vulnerable for:
Regulatory actions
Complaints & recalls
Manufacturing closure
Fragile System

119. Thank You