VALIDATION OF UTILITY ( HVAC , CLEANING VALIDATION,)

GOOD REGULATORY PRACTICES
Validation Of Utility
Submitted by: Sonal Sharma
Submitted to: Dr. Navneet Sharma
1
Amity Institute of Pharmacy

GRADE ‘A’ ACCREDITED BY NAAC AUUP HQ
TABLE OF CONTENT-
1. Introduction
2. Validation of HVAC system
3. Cleaning validation
4. Validation of water system
5. Validation of steam system
6. Validation of compressed air systems
7. bibiliography
2

Validation of HVAC
system
• HVAC stands for heating
ventilation and air conditioning
system.
• The HVAC system also known as
the air handling unit (AHU) system
are placed in the clean rooms for
thermal control.
3

Test performed for validation of HVAC system:
1. ACPH
2. Filter integrity test
3. Non-viable particle count
4. Air flow visualization
5. Recovery period study
6. Temperature / relative humidity/ differential pressure monitoring
7. Air borne viable particle monitoring
4

Air changes per hour
• If the supplied air by HVAC per hour
is equal to the volume of the room/
area, then it will be one ACPH.
• To determine the average filter face
velocity and uniformity, and the
average room airflow velocity and
uniformity within a clean room.
• Test apparatus: ANEMOMETER
• Anemometer is placed
approximately 6 inches beneath
the filter surface and take velocity
of filter from 5 corners.
5
V1 V2
V3 V4
V5

6
• Get average velocity ( V ) = V1 + V2 + V3 + V4 + V5
5
• Calculate the area of filter (A) : L ( Length of filter) x W ( width of filter )
• Calculate total air volume supplied ( T ): A (in square feet ) x V ( in minutes )
• Calculate total volume of room : L (Length) x W (width) x H ( height in feet)
• Calculate ACPH by: T x 60
Room volume
• As per ISO 14644 recommended ACPH for clean rooms are as:
ISO CLASS ACPH
ISO 5 240 – 600
ISO 6 150 – 240
ISO 7 60 – 150
ISO 8 5 - 60

Filter integrity test:
• Filter integrity test is carried out to
assure the integrity of HEPA (high
efficiency particle airflow system)
filters against filter failure due to
damage while transportation,
installation or operation.
• Test apparatus: AEROSOL
GENERATOR & PHOTOMETER
7
• Through aerosol generator we generate
particle of PAO (Poly alpha Olefin) of 0.5 to
0.7 micron and supply it to AHU.
• Scan the downstream aerosol concenteration
by keeping photometer at HEPA surface.
• Scanning rate should be approx. 10 CFM
(cubic feet/ minutes)
• Acceptance criteria: NMT(not more then)
0.01% of upstream aerosol concenteration.

Non - viable particle count
• To determine the concentration of non-viable
airborne particles, equal to and greater than the
specified sizes, at designated sampling locations.
• Test apparatus: LSAPC ( light scattering air born
particle counter )
8
• Prior to testing all relevant aspects of the clean room that contributes to its integrity are
complete and function in accordance with its performance qualification.
• Sampling shall be done at rest condition only.
• Sampling location shall determine as per total area of clean room.
• For areas larger then 1000 m² , NL = 27 x A NL = Minimum number of locations
1000 A = area of clean room in m².
• Sampling location must be evenly distributed to entire room.
• Through particle counter get particle size of 0.5 & 5.0µ ( per meter cube of air).

Area in Number of sampling
locations
Area in Number of sampling
locations
2 1 32 8
4 2 36 9
6 3 52 10
8 4 56 11
10 5 64 12
24 6 68 13
28 7 72 14
9
Sampling location chart:
The minimum sample volume should be atleast 2 liters. Air with a minimum sampling
time for 1 minute for each sample at each location.

Air flow visualization
• To confirm that the air flow direction and its
Uniformity confirm to the design and
performance specification.
• Test Apparatus: Video camera, Glycerin with
Rose water, Fogger (Previously TTC (Titanium
Tetra Chloride) was used to
produce smoke/fog).
• Generate fog with the help of fogger and expose
the fog at supply end of the system.
10
• Observe the smoke pattern and ensure that, it should be unidirectional, smoke must
move from supply to return duct. & from positive pressure area to negative pressure
area.
• Picturise the direction of fog by the help of a Video.

Recovery Period Study
• This test is performed to determine the amount of time necessary for the clean room and
its system to reach a steady state in means of environmental condition (temperature and
RH) & cleanliness level after a brief particle generation event within the clean space.
• Test Apparatus: PARTICLE COUNTER & DIGITAL HYGROMETER
• To verify the recovery of particles present in clean room generate and introduce particles
of size 0.5 & 5.0 micron through HVAC system by PAO and evaluate the recovery
through particle counter after starting the HVAC system.
• To verify recovery of environmental condition, increase the temperature and humidity of
area by spraying hot water upto 75%.After starting the HVAC system, monitor the
humidity and temperature to get stabilized and area comes within specified
11

Temperature/Relative Humidity/ Differential Pressure
Monitoring
• To demonstrate the capability of the HVAC System to consistently maintain
Differential Pressures, Temperatures and Relative Humidity in the control areas.
• After completion of all said activities in qualification, area should monitor for
Temperature, Relative Humidity and Pressure differential for at least for 8 hrs. with
interval of 1 hr. ± 15 minute.
• This should be lead by monitoring the same on daily basis, at least twice a day.
12

Air Borne Viable Particle Count
• To check and ensure that the
controlled area meets the desired
level of area classification with
respect to viable counts.
• Test Apparatus: PRE-
INCUBATED MEDIA PLATES.
• Viable particle count monitoring-
shall done for at least 3 days for
qualification and as per
schedule after that.
13

CLEANING VALIDATION
• Cleaning validation is documented evidence that an approved cleaning
procedure is being used that will make equipment suitable for processing of
required medicinal product.
• Cleaning validation should be performed in order to confirm the
effectiveness of any cleaning procedure for all product contact equipment.
CLEANING PRINCIPLE : Pharmaceutical products can be contaminated by
other pharmaceutical products or APIs, by cleaning agents, by micro-
organisms or by other material (e.g. air-borne particles, dust, lubricants, raw
materials, intermediates, auxiliaries etc.). In many cases, the same equipment
may be used for processing different products. To avoid contamination of the
following pharmaceutical product, adequate cleaning procedures are essential.
14

TYPE OF CLEANING :
• TYPE A (MINOR): This type of cleaning take place between two batches
of same product. For minor cleaning, cleaning validation is not required,
since cross contamination is not an issue.
• TYPE B (MAJOR): This type of cleaning take place between two
different products.
HARD TO CLEAN AREA:
• Area/spots in any equipment which were really hard to reach and clean
define as hard to clean area.
• Hard to clean area should consider as worst case and must capture
in sampling plan. 15

SELECTION OF WORST CASE THROUGH PRODUCT
MATRIX
• The Worst-Case product for cleaning should be selected based on the APIs
used in the formulation.
• Following approach should be considered for selection of worst case molecule:
1. Aqueous Solubility (Lower aqueous solubility = higher worst case)
2. Therapeutic Dose (Lower Therapeutic dose = higher worst case)
3. LD50 (Lower LD50 = higher worst case)
16

S. no. Product
name
Active
material
Strength
( in mg)
Solubility in water LDD
(in mg)
Batch size
(liters)
1 ABC XXXX 50 Slightly soluble in water 400 3000
XXXX 125 Practically insoluble in
water
500
2 DEF XXXX 50 Slightly soluble in water 400 2000
water
500
3 GHI XXXX 50 Slightly soluble in water 400 5000
XXXX 125 Practically in soluble in
water
500
4 JKL XXXX 4 Freely soluble in water 10 3000
XXXX 2.5 Freely soluble in water 700
5 MNO XXXX 20 Practically insoluble in
water
100 5000
XXXX 10 Insoluble in water 200
water
40
6 PQR XXXX 540 Insoluble in water 2000 5000
17
PRODUCT MATRIX

Sr.
no.
Equipment Make Equipment id Material of
construction
Surface
area
(cm²)
10% Extra
of Total
Surface
area (cm²)
1 Manufacturing
vessel
2 Storage vessel
3 Scoops
4 Filling &
sealing machine
5 Conveyor belt
6 Material
transfer pipes
7 Filter press
total
18
EQUIPMENT TRIAL

SAMPLING CRITERIA
• Before sampling the surface would be clean visually.
• SWAB (Direct Surface Sampling): When samples were taken through
direct surface of the equipment with the help of swab sticks.
• Rinse Sample: Rinse sample shall be collected from the hard-to-access
locations of the equipments. Equipment surface shall be rinsed with the
given quantity of rinse volume with purified water and the sample shall be
collected from the rinsate.
19

SEQUENCE OF
SAMPLING
1. Microbial Swab
2. Chemical Swab
3. Chemical Rinse
METHODOLOGY TO GET
SWAB SAMPLE
• Swab sample are taken with the
help of swab sticks, which are
initially soaked in Purified water
and after sampling put
into mother solvent.
20
• To get swab sample select an area of 5x5 or 10x10 cm with the help of
sampler, and apply swab stick in above shown manner.

CALCULATION (NOEL)
NO OBSERVED EFFECT LEVEL
• Is the amount of drug/substance in mg that does not have any effect on the
human health.
• NOEL is calculated by using LD 50
(Lethal Dose 50 is the amount of a material, given all at once, which cause the death
of 50% of a group of animals) of the drug.
NOEL = (LD 50 × 70 kg)
2000
Where: LD 50 = Lethal Dose, 70 kg = Average Adult weight & 2000 is a constant.
NOEL is determined to calculate the MACO in cleaning validation.
21

CALCULATION (MACO)
MAXIMUM ALLOWABLE CARRY OVER
• Mathematically calculated quantity of residue from a previous product
when carried out over into a different product that can cause potential
harm to the patient.
• Three criteria to calculate MACO:
1. Therapeutic Daily Dose criteria
2. NOEL criteria
3. PPM criteria
22

• THERAPEUTIC DAILY DOSE CRITERIA:
MACO = TDD(p) × MBS(n)
SF x TDD(n)
Where: TDD(p) = Therapeutic Daily Dose of previous product
MBS(n) = Minimum Batch Size of next product
TDD(n) = Therapeutic Daily Dose of next product
SF = Safety Factor (1000 for Oral, 100 for external Preparation,& 10 for
sterile preparations)
23

• NOEL CRITERIA:
MACO = NOEL (P) × MBS (n)
SF × TDD(n)
Where: NOEL(p) = No Observed Effect Level of previous product
MBS(n) = Minimum Batch Size of next product
TDD(n) = Therapeutic Daily Dose of next product
SF = Safety Factor (1000 for Oral, 100 for external Preparation,& 10 for
sterile preparations)
24

• PPM CRITERIA:
If MACO calculations result in unacceptably high or irrelevant carryover
figures, or toxicological data for intermediates are not known, the approach of
a general limit may be suitable. User preferable may choose to have such an
upper limit as a policy. The general limit is often set as an upper limit for the
maximum concentration (MAXCONC) of a contaminating substance in a
subsequent batch.
MACOppm = MAXCONCs x MBS
Where: MAXCONC = General limit for maximum allowed concentration
(kg/kg or ppm) of"previous" substance in the next batch.
MBS = Minimum batch size for the next products),(where
MACO can end up).
25

MICROBIAL/ENDOTOXINS CRITERIA
• Samples should be analyzed for microbial aspects in all the three runs
during cleaning validation. The following should be acceptance criteria for
Microbiological monitoring during cleaning validation / verification:
26
Parameter Non sterile formulation
equipments
Sterile formulation
equipment
Total CFU - Swab NMT 50 CFU /25cm² NMT 5 CFU /25cm²

ANALYTICAL METHOD VALIDATION
Any instrumental analytical procedures used to analyze cleaning validation
samples need to be specified and sufficiently sensitive to determine the low
levels of residues typically found in samples.The methods used to analyze
samples that allow the equipment to be released for manufacture of another
product shall be validated to ensure that it meets following requirements, but
not limited to:
• Specificity
• Linearity
• Precision
• Robustness
• LOQ and LOD Determination
• Sample recovery
• Stability of analytical solution 27

HOLD TIME STUDIES
• The objective of hold time study is for establishing time limit between
equipment cleaning and reuse. It is done to ensure that the equipment
remains clean till the nest use.
• Equipment Holding Studies prior to cleaning/ Un cleaned equipment hold
time study: The interval between the end of production and the beginning
of the cleaning process shall be established through equipment holding
studies prior to cleaning.
• Cleaned Equipment Hold Time Study : The interval between the initiation
of production and the completion of the cleaning process
shall be established.
28

Water system validation
• Water system validation is very
important in pharmaceuticals.
Water is used in the
manufacturing process in very
large quantities during different
stages of manufacturing. During
manufacturing, water is
continuously generated and
distributed and can not be tested
and analyzed for each and every
quantity used in production.
• To provide consistent quality
standards, It needs to validate for
treatment, generation, storage, and
distribution. So, there is a total of
3 phases for water system
validation.
29

3 Types of Water System Validation
• Water System Validation Phase 1
PHASE I: INVESTIGATION PHASE
• Duration: Phase 1 typically lasts 2-4 weeks.
• Focus: It primarily focuses on rigorous monitoring and testing of the system to
ensure it operates continuously without any failures or deviations from expected
performance.
• Goals: The main goals are to establish initial operating procedures, verify the
quality of incoming water, develop maintenance procedures, and demonstrate that
the system can consistently produce the required quantity and quality of water. 30

PHASE II: SHORT-TERM CONTROL
• Duration: Phase 2 also lasts 2-4 weeks.
• Focus: This phase continues intensive monitoring, but it places a stronger
emphasis on refining and finalizing the standard operating procedures (SOPs)
established in Phase 1. It also allows for the use of water for manufacturing
purposes.
• Goals: Phase 2 aims to demonstrate consistent operation within established
ranges, ensure the system consistently produces the required water quality and
quantity when following the refined SOPs, and verify that the system works
effectively in actual manufacturing processes.
31

Phase III: Long-Term Control
• Duration: Phase 3 is the longest, running for approximately one year.
• Focus: Unlike the previous phases, Phase 3 is more about extended and long-
term performance. It takes into account seasonal variations and involves less
frequent testing.
• Goals: The primary objectives in Phase 3 are to prove that the system can
reliably perform over an extended period, evaluate its performance in different
seasons, and establish a routine maintenance plan based on the lessons learned
in the earlier phases. Sampling and testing become less frequent but are based
on established procedures from Phases 1 and 2.
32

VALIDATION OF STEAM SYSTEMS
• Pure steam is used in various operations in pharmaceuticals but its use in
sterilization is very common in pharmaceutical sterile manufacturing.
• At the time of performance qualification of pure steam generation system, the
sample shall be taken from each steam user point and analyzed for three
consecutive days. The purified water system must be qualified before starting
the qualification of pure steam.
• The sampling of Pure Steam:
Sampling for Bacterial Endotoxin Test and chemical tests should be done
separately. De-pyrogenated tubes or bottles should be used for taking the sample
for bacterial endotoxin test. Allow the steam to drain for minimum one minute.
33

Open the cap of the bottle and fill the bottle with steam condensate by holding the
bottle in the holder. Gloves should wear into the hands while sampling the pure
steam. Tighten the cap of the bottle and mark with the sampling information. If
the sample is not analyzed within 2 hours of sampling, store the sample at 2-8 °C.
• Analysis of Pure Steam: Pure steam should be analyzed for following tests.
1. Non-condensable Gases: Non-condensable gases are air and carbon dioxide
those do not condense with the steam. These are generated due to their presence
in the purified water that continuously circulates in the water distribution system.
Non-condensable gases should not be more than 3.5%.
2. Steam Dryness Value: Dry steam has more energy than the wet steam. Wet
steam has water with it and does not have heat energy as dry steam. Dryness of
steam is determined by the latent heat. Dryness of the pure steam should not be
less than 90%. High moisture content can cause the loss in energy of steam and
that may cause the longer sterilization time. 34

3. pH: Steam condensate is analyzed for pH value at 25 ° C. It should be
between 5-7.
4. Conductivity: Conductivity should be tested with calibrated conductivity
meter at 20 °C. Conductivity should not be more than 1.3 µS/cm.
5. Microorganisms: Steam condensate is tested for microbial contamination
using pour plate method. There should not any microbial contamination in the
steam condensate.
6. Endotoxin Test: Determine the endotoxin in the pure steam condensate and
it should not be more than 0.25 EU/ml as in water for injection.
35

COMPRESSED AIR
• Definition : Air kept under a
pressure that is greater then
atmospheric pressure.
• Compressed air serves as an
important medium to transfer of
energy in industrial process and to
operate air cylinders for
automation.
• Used as:
 Cleaning and sterilization
 Packaging
 Tablet coating
 Pneumatic conveying
36
Main parts of compressed air
system:
1. Compressor
2. Reciever’s tank
3. Air dryer
4. Moisture seperator

Parameters To Specify The Quality Of Compressed Air:
• Dew point
• Moisture content
• Viable count
• Oil content
• Particulate matter
DEW POINT TEMPERATURE OR SATURATION TEMPERATURE
• Temperature at which water vapour begins to condense.
• Gas of unknown water vapour concentration is passed over a temperature-controlled
surface.
• The surface is cooled until condensate forms.
• The temperature at which condensate forms is called the "Dew Point temperature”.
37

• Dew point temperatures in compressed air range from ambient down to -112 °F.
• Dew point temperatures in nitrogen gas range from -40°F.
Moisture content
• All atmospheric air contains some water vapour which will begin to condense into
liquid water in the compressed air or gas system.
• The condensed moisture must be removed by a separator and trap.
• Moisture in compressed air used in a manufacturing plant causes problems.
• Before test air flow rate is adjusted to 100ml/min.
• Drain the air for one minute before sampling. 38

• Spectroscopy methods are involved to detect the water vapour content in the gaseos
systems.
• Moisture content should be less than <0.01% for Compressed AirSystem
• Moisture content should be less than < 67ppm v/v for Nitrogen Gas System.
Particulate matter
• The impurities that nitrogen/compressed air contain contaminates the product and might
result in change of colour, taste and reduced shelf life.
• Particle purity class is provided by ISO 8573-1.
• Laser particle counter (LPC): This test can be used on-site, which is a big advantage for
troubleshooting the source of contamination. It provides a count of particles at all three
size ranges specified by ISO 8573 and can be used to measure purity down to Class 1. 39

• Filter collection with microscopy: This method collects particulate on a filter,
which is later examined under a microscope to provide a particle count. It is
necessary to know the pressure and flow rate for sampling to get an accurate
estimate of particulate concentrations.
• Mass concentration: This method is typically used for air of Class 6 or above. It
provides a total mass of particulate in a certain volume of air, reported in mg/m³. It
does not provide particle counts or size distribution.
• Compressed Air has the Particulate Matter to a level less than 0.02 mg/m³.
• Nitrogen has the particulate matter of < 5 mg/m³.
40

Oil mist testing:
• Oil may be present in a sample as an aerosol (liquid droplets suspended in
air) or a vapor. Testing methods depend on the level of contamination and
the purity class requirement for the sample.
• Heavier concentrations of oil aerosols are typically measured using a
membrane system that separates the oil from the air. Oil concentrations are
determined by weighing the amount of oil captured by the membrane.
• Oil vapor and organic solvent content testing (usually used for purity
classes 1 and 2) is usually done using gas chromatography.
• Oil content of less than 0.01 mg/m³ is allowed for compressed air and
nitrogen both. 41

Viable count
• Analytic testing can be used to determine what types of microbes are present and in
what quantities. Testing is usually focused on microbes that cause particular problems,
such as foodborne illnesses or respiratory diseases. These may include bacteria such as
Listeria, E.Coli and Salmonella and fungal species such as Candida and various molds
and yeasts. Microbial testing may be either qualitative or quantitative.
• Qualitative testing simply reports the presence or absence of specific microbes.
• Quantitative testing tells us the number of microbes present in a specified volume. ISO
8573-7 requires quantitative results and provides guidance on validated sampling
methods.
• Microorganisms can be identified using a variety of analytical methods, including
visual macroscopic and microscopic identification and molecular methods.
42

• The sample is usually cultured, using a petri dish to allow organisms to grow into a
colony. Identification may be made by looking at both macroscopic characteristics
(colony shape, color, borders, etc.) and microscopic characteristics (physiology,
Gram staining reaction, etc.).
• Identification may be completed or confirmed using molecular methods. These
methods include genetic testing and other forms of molecular analysis that
“fingerprint” organisms based on various characteristics.
• For Compressed Air System, Viable count should be <100CFU/m3 (colony
forming unit).
• For Nitrogen Gas system, Viable count should be <1CFU/m3.(colony forming unit)
43

BIBLIOGRAPHY
1. https://www.youtube.com/watch?v=rNGiUvVjM80
2. https://www.pharmaguideline.com/2012/07/purified-water-system-
validation.html
3. https://www.who.int/docs/default-source/medicines/norms-and-
standards/guidelines/production/trs1019-annex3-gmp-validation.pdf
4. https://www.researchgate.net/publication/40542934_Validation_Of_Pharmace
utical_Water_System_-_A_Review
5. https://fluidairedynamics.com/blogs/articles/compressed-air-testing-make-sure-
your-air-is-clean-dry-and-oil-free 44

45
THANK YOU

VALIDATION OF UTILITY ( HVAC , CLEANING VALIDATION,)

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