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QUALIFICATION AND VALIDATION

MANUAL FOR STERILE DRUG
MANUFACTURING
Version 00

Das, Palash Chandra 3/4/23 PRES(USCGMP) publication

 Das, Palash Chandra

QUALIFICATION AND VALIDATION MANUAL FOR STERILE DRUG MANUFACTURING

Table of Contents
Introduction................................................................................................................. 3
Qualification and Validation Definition ......................................................................... 4
How to establish requalification or validation frequency ? .......................................... 4
Lyophiliser ................................................................................................................... 5
Working Principle ..................................................................................................... 5
Performance Qualification (PQ) ................................................................................ 6
Performance verification run with Mannitol: .......................................................... 7
Autoclave/ Steam Sterilization ..................................................................................... 7
Working Principle ..................................................................................................... 7
Performance Qualification (PQ) ................................................................................ 8
Aseptic Filling Isolator.................................................................................................. 9
Working Principle ..................................................................................................... 9
Performance Qualification (PQ) .............................................................................. 10
Difference between Aseptic Filling Isolator and Sterility Testing Isolator .................. 11
Filling, bunging, and sealing Machine......................................................................... 11
Working Principle ................................................................................................... 11
Performance Qualification (PQ) .............................................................................. 12
Washer ...................................................................................................................... 13
Working Principle ................................................................................................... 13
Performance Qualification (PQ) .............................................................................. 14
Depyrogenation and Sterilization tunnel ..................................................................... 14
Working Principle ................................................................................................... 14
Performance Qualification (PQ) .............................................................................. 15
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Laminar Air flow hood /Biosafety cabinet .................................................................... 16

Working Principle ................................................................................................... 16
Performance Qualification (PQ) .............................................................................. 16
PFS (Pre-fill syringe) machine .................................................................................... 17
Benefits of PFS over conventional filling method ..................................................... 17
How PFS machines work: ....................................................................................... 18
Performance Qualification (PQ) .............................................................................. 18
HVAC ........................................................................................................................ 19
Working Principle ................................................................................................... 19
Performance Qualification (PQ) .............................................................................. 20
Computer System Validation Requirements ............................................................... 21
Process validation...................................................................................................... 22
Critical Steps: ......................................................................................................... 22
Importance: ........................................................................................................... 22
Digital Technology Arena ........................................................................................... 23
Regulatory Recommendation ..................................................................................... 24
Conclusion ................................................................................................................ 25

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QUALIFICATION AND VALIDATION MANUAL FOR STERILE DRUG MANUFACTURING

Introduction
Qualification and validation are essential processes in the manufacturing of sterile
pharmaceuticals to ensure that the equipment, systems, and facilities used are fit for
their intended purpose. Sterile pharmaceuticals are sensitive to contaminants and must
be produced in a controlled and sterile environment to ensure their safety and efficacy.
Qualification and validation processes provide assurance that the equipment, systems,
and facilities used in the manufacturing process are appropriately designed, installed,
and operating correctly to produce a safe and effective product.

The qualification process involves testing and documenting that the equipment,
systems, and facilities meet their intended design specifications and operate correctly.
The validation process involves testing and documenting that the manufacturing
process consistently produces a product of the required quality.

Qualification and validation for sterile pharmaceutical equipment, systems, and facilities
are critical to the pharmaceutical industry and are required by regulatory authorities
such as the FDA (Food and Drug Administration) and EMA (European Medicines
Agency). Failure to comply with these requirements can result in costly product recalls,
regulatory action, and damage to the company's reputation.

In summary, qualification and validation are essential processes that ensure the safety
and efficacy of sterile pharmaceutical products. They provide assurance that the
equipment, systems, and facilities used in the manufacturing process are appropriately
designed, installed, and operating correctly to produce a safe and effective product.

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Qualification and Validation Definition

In the context of manufacturing, qualification and validation are two related but distinct
concepts.

Qualification refers to the process of demonstrating that equipment, facilities, systems,

and processes are suitable for their intended use and meet the necessary requirements.
This involves a series of tests and procedures to ensure that the equipment, facilities,
systems, and processes are functioning correctly and consistently, and that they can
produce the desired results. Qualification can include installation qualification (IQ),
operational qualification (OQ), and performance qualification (PQ).

Validation, on the other hand, refers to the process of establishing documented

evidence that a process or system will consistently produce a product or result that
meets the predetermined specifications and quality attributes. This involves a series of
tests and procedures to ensure that the process or system is capable of producing the
desired results consistently, and that the results meet the necessary quality standards.
Validation typically includes process validation, which involves establishing the
appropriate parameters for a specific process, and product validation, which involves
testing the final product to ensure that it meets the necessary quality standards.

In summary, qualification is the process of demonstrating that equipment, facilities,

systems, and processes are suitable for their intended use, while validation is the
process of establishing documented evidence that a process or system will consistently
produce a product or result that meets the predetermined specifications and quality
attributes. Both qualification and validation are critical components of ensuring that
manufacturing processes and products meet the necessary quality standards.

How to establish requalification or validation frequency ?

The frequency for requalification or validation in pharmaceutical manufacturing should
be established based on a risk-based approach that considers the criticality of the
equipment, facilities, systems, and processes involved.

Here are some general guidelines that can be followed:

a) Determine the criticality: First, determine the criticality of the equipment,

facilities, systems, and processes involved in the manufacturing process. This
can be done by assessing the impact of any failures or deviations on the quality,
safety, or efficacy of the final product.
b) Define the requirements: Based on the criticality assessment, define the specific
requirements for requalification or validation. This can include the frequency of

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requalification or validation, the types of tests and procedures that need to be

conducted, and the acceptance criteria that need to be met.
c) Develop a risk-based approach: Develop a risk-based approach that considers
the likelihood and impact of any failures or deviations. This can include factors
such as the complexity of the equipment or process, the frequency of use, and
the historical performance data.
d) Establish a schedule: Based on the risk-based approach, establish a schedule for
requalification or validation. This should be documented in a master validation
plan (MVP) or equivalent document.
e) Monitor and review: Monitor the performance of the equipment, facilities,
systems, and processes on an ongoing basis, and review the requalification or
validation schedule periodically to ensure that it remains appropriate.

It's worth noting that the specific frequency for requalification or validation may vary
depending on the organization and the requirements involved. It's important to follow
the relevant regulations and guidelines, as well as any internal procedures or guidelines
that are in place.

Lyophiliser
Working Principle
A pharmaceutical Lyophiliser, also known as a freeze dryer, is a specialized piece of
equipment used in the pharmaceutical industry to remove moisture from
pharmaceutical products while preserving their integrity. The primary function of a
Lyophiliser is to convert a liquid product into a dry and stable form, which can be stored
and transported more easily.

The working principle of a pharmaceutical Lyophiliser is based on a process called

sublimation, which involves the conversion of water from a solid (ice) to a gas (water
vapor) without passing through a liquid state. The Lyophiliser works by lowering the
temperature of the product to be dried and then applying a vacuum to create a low-
pressure environment. This process causes the frozen water in the product to sublimate,
or evaporate, directly from a solid to a gas, without passing through a liquid state.

The Lyophiliser is typically made up of three main components: a condenser, a vacuum

chamber, and a drying chamber. The product to be dried is placed in the drying
chamber and frozen to a very low temperature using a refrigeration system. The vacuum
is then applied to the chamber, which lowers the pressure and allows the water
molecules in the product to vaporize and sublimate.

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The water vapor is then drawn out of the drying chamber and directed to the condenser,
where it is converted back into a liquid state and collected. The remaining dry product is
left in the drying chamber, where it can be stored and transported without the risk of
degradation due to moisture.

Overall, the pharmaceutical Lyophiliser works by using a combination of low

temperature and vacuum to remove moisture from pharmaceutical products, preserving
their integrity and stability. This process is particularly important for sensitive drugs or
biologics, which can be easily degraded by exposure to moisture or high temperatures.

Performance Qualification (PQ)

Performance Qualification (PQ) is a critical stage in the validation process of a
pharmaceutical Lyophiliser. During PQ, the equipment is tested to ensure that it
consistently performs within the specified limits and produces products of consistent
quality. The following are some of the tests that may be performed during the PQ of a
pharmaceutical Lyophiliser:

a) Temperature Mapping: Temperature mapping is done to ensure that the

Lyophiliser maintains a consistent temperature throughout the chamber. This is
done by placing temperature sensors at various locations inside the chamber and
monitoring the temperature over time.
b) Vacuum Integrity Testing: Vacuum integrity testing is performed to ensure that
the vacuum level inside the Lyophiliser is consistent and within the specified
range. This is typically done by performing a pressure decay test.
c) Condenser Capacity Testing: Condenser capacity testing is done to ensure that
the Lyophiliser condenser has sufficient capacity to handle the load being
processed. This is done by measuring the amount of ice that forms on the
condenser during a cycle.
d) Product Uniformity Testing: Product uniformity testing is done to ensure that the
Lyophiliser produces products of consistent quality. This is typically done by
analyzing samples of the lyophilized product for attributes such as moisture
content, particle size, and appearance.
e) Container Closure Integrity Testing: Container closure integrity testing is
performed to ensure that the vials or other containers used to hold the lyophilized
product are sealed properly and do not leak.
f) Cycle Time Optimization: Cycle time optimization is done to determine the
optimal cycle time for the Lyophiliser. This is done by varying the cycle time and
monitoring the product quality at each time point.

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These are some of the tests that may be performed during the performance qualification
of a pharmaceutical Lyophiliser. The specific tests may vary depending on the
Lyophiliser design and intended use.

Performance verification run with Mannitol:

Mannitol can be used as a surrogate material to challenge the performance of a
Lyophiliser during performance qualification. The following steps can be taken to
challenge the Lyophiliser with mannitol:

a) Prepare the mannitol solution: Prepare a mannitol solution with a concentration

of 5-10% (w/v) in distilled water. The solution should be filtered through a 0.22
μm filter to remove any particulate matter.
b) Fill the vials: Fill the vials with the mannitol solution, ensuring that each vial is
filled to the same level.
c) Load the Lyophiliser: Load the vials onto the Lyophiliser shelves, ensuring that
they are evenly distributed and balanced.
d) Start the lyophilization cycle: Start the lyophilization cycle according to the
Lyophiliser standard operating procedures.
e) Monitor the process: Monitor the lyophilization process, including the
temperature, pressure, and time. Record the critical parameters, such as the
shelf temperature and vacuum pressure.
f) Evaluate the product: After the lyophilization cycle is complete, evaluate the
product for critical attributes such as dryness factor and cake density.
g) Analyze the results: Analyze the results and compare them to the acceptance
criteria established for the Lyophiliser. If the results are within the acceptance
criteria, the Lyophiliser can be considered qualified for use.

In terms of critical attributes, the dryness factor and cake density are important
parameters to evaluate during performance qualification. The dryness factor can be
calculated by dividing the initial weight of the vial and product by the weight of the dried
product. The cake density can be determined by measuring the weight of the dried
product and the volume of the vial. The critical values for these parameters will depend
on the specific product being lyophilized and should be established in advance.

Autoclave/ Steam Sterilization

Working Principle
Moist heat sterilizers are commonly used in pharmaceutical manufacturing to ensure
that equipment, instruments, and other materials are free from microbial
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contamination. The working principle of a moist heat sterilizer involves exposing the
materials to high temperature and pressure to kill any microorganisms present.

The basic steps in the working of a moist heat sterilizer are as follows:

a) Loading: The items to be sterilized are placed in the sterilization chamber. The
chamber is then sealed to prevent any air from escaping or entering.
b) Air Removal: The sterilizer is then filled with steam, which displaces the air in the
chamber. The air removal process is important as it ensures that steam can
penetrate all areas of the materials to be sterilized.
c) Sterilization: The chamber is heated to a temperature of around 121°C (250°F)
and the materials are exposed to the steam for a specific period of time. The
exposure time depends on the type and amount of material being sterilized.
During this process, the heat and pressure cause the destruction of
microorganisms.
d) Cooling: After the sterilization cycle is complete, the chamber is cooled down
slowly to prevent any damage to the materials. The cooling time can vary
depending on the size and type of materials being sterilized.
e) Unloading: Once the cooling cycle is complete, the chamber is opened, and the
sterilized materials are removed. The materials are now considered to be sterile
and can be used in the manufacturing process.

Moist heat sterilization is a widely used method in the pharmaceutical industry due to its
effectiveness in killing microorganisms and its ability to penetrate materials to be
sterilized. It is important to follow the manufacturer's guidelines for operation and
maintenance to ensure that the sterilizer is functioning properly and producing reliable
results.

Performance Qualification (PQ)

Performance Qualification (PQ) is a critical stage in the validation process of a
pharmaceutical steam sterilizer or autoclave. During PQ, the equipment is tested to
ensure that it consistently performs within the specified limits and produces products of
consistent quality. The following are some of the tests that may be performed during the
PQ of a pharmaceutical steam sterilizer or autoclave:

a) Temperature Mapping: Temperature mapping is done to ensure that the sterilizer

maintains a consistent temperature throughout the chamber. This is done by
placing temperature sensors at various locations inside the chamber and
monitoring the temperature over time.
b) Steam Quality Testing: Steam quality testing is performed to ensure that the
steam used in the sterilization process is of sufficient quality. This is typically

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done by analyzing the steam for attributes such as moisture content and non-
condensable gases.
c) Bowie-Dick Test: The Bowie-Dick test is performed to ensure that the sterilizer is
functioning properly and that air is being removed from the chamber before
sterilization. This is typically done by placing a test pack containing a chemical
indicator inside the chamber and monitoring the results.
d) Biological Indicator Testing: Biological indicator testing is performed to ensure
that the sterilization process is effective in killing microorganisms. This is
typically done by placing a test pack containing a biological indicator inside the
chamber and monitoring the results.
e) Load Configuration Testing: Load configuration testing is performed to ensure
that the sterilizer can handle the load being processed. This is typically done by
running a cycle with a load that represents the maximum load the sterilizer is
expected to handle and monitoring the results.
f) Cycle Time Optimization: Cycle time optimization is done to determine the
optimal cycle time for the sterilizer. This is done by varying the cycle time and
monitoring the product quality at each time point.

These are some of the tests that may be performed during the performance qualification
of a pharmaceutical steam sterilizer or autoclave. The specific tests may vary depending
on the sterilizer’s design and intended use.

Aseptic Filling Isolator

Working Principle
A pharmaceutical aseptic processing isolator is a highly specialized containment system
used in the pharmaceutical industry to create a sterile environment for the production of
sterile drugs or biologics. The primary function of an isolator is to isolate the drug
product from the surrounding environment, including airborne particles,
microorganisms, and human contact.

The working principle of a pharmaceutical aseptic processing isolator is based on the

use of a highly controlled and closed environment. The isolator is usually designed as a
closed system with a double-layered structure. The outer layer acts as a barrier to
protect against environmental contaminants, while the inner layer is where the sterile
product is produced. The isolator has a positive air pressure differential, which prevents
air and contaminants from entering the chamber.

The isolator is equipped with a series of HEPA (high-efficiency particulate air) filters that
remove airborne particles as small as 0.3 microns. These filters are typically placed at
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the inlet and outlet of the isolator, as well as within the isolator itself. The isolator also
features a series of sterilization systems, such as vaporized hydrogen peroxide, which
are used to sterilize the inner environment and surfaces.

Operators working within the isolator typically wear sterile gowns, gloves, and masks to
prevent any human-borne contaminants from entering the sterile environment. The
materials used to construct the isolator are also selected for their ability to withstand
sterilization methods and their low particle generation properties.

Overall, the pharmaceutical aseptic processing isolator works by providing a highly

controlled and sterile environment for the production of sterile drugs and biologics,
preventing environmental contaminants and human contact from contaminating the
final product.

Performance Qualification (PQ)

Performance qualification of a pharmaceutical aseptic filling isolator or sterility testing
isolator typically involves several tests to ensure that the isolator is operating as
intended and is capable of maintaining a sterile environment. Some of the tests that
may be performed during performance qualification include:

a) Airflow velocity and pattern testing: This test evaluates the airflow patterns and
velocities within the isolator to ensure that the air is flowing properly and creating
a clean environment.
b) Leak testing: This test checks for any leaks in the isolator that could compromise
the sterile environment.
c) Pressure decay testing: This test measures the pressure changes within the
isolator over time to detect any leaks or breaches in the system.
d) Microbial challenge testing: This test involves introducing a known concentration
of microorganisms into the isolator to evaluate the effectiveness of the
sterilization processes and the ability of the isolator to maintain a sterile
environment.
e) Sterilization cycle validation: This test evaluates the effectiveness of the
sterilization process to ensure that it is capable of killing all microorganisms
within the isolator.
f) Particle counting: This test measures the concentration of particles within the
isolator to ensure that it meets the specified cleanroom classification.
g) Temperature and humidity mapping: This test evaluates the temperature and
humidity distribution within the isolator to ensure that it is consistent throughout
the system.
h) Recovery testing: This test evaluates the ability of the isolator to recover from a
potential breach in the sterile environment.

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The specific tests performed during performance qualification may vary depending on
the specific requirements of the isolator and the regulations governing its use.

Difference between Aseptic Filling Isolator and Sterility Testing

Isolator
An aseptic filling isolator and a sterility testing isolator are both types of isolators used in
pharmaceutical manufacturing. However, their functions and purposes are different.

An aseptic filling isolator is designed to provide a sterile environment for the filling of
sterile products, such as injectable drugs, to prevent contamination. The isolator is
designed to maintain a positive pressure to prevent external contamination from
entering the isolator, while also filtering the air that enters the isolator to remove any
particles or microorganisms. Personnel working in the isolator wear sterile clothing and
gloves, and the equipment used in the isolator is sterilized prior to use.

On the other hand, a sterility testing isolator is designed for the testing of finished
pharmaceutical products for sterility. The isolator provides a controlled environment for
testing, with a negative pressure to prevent the escape of any contaminants. The
isolator also has HEPA filters to prevent any external contamination from entering the
isolator during testing. Personnel working in the isolator wear sterile clothing and gloves,
and the equipment used in the isolator is sterilized prior to use.

In summary, while both isolators are designed to maintain sterile environments, the
aseptic filling isolator is used for filling sterile products, while the sterility testing isolator
is used for testing finished pharmaceutical products for sterility.

Filling, bunging, and sealing Machine

Working Principle
An aseptic injection filling, bunging, and sealing machine is used for filling and
packaging sterile liquid products, such as pharmaceuticals, biologics, and sterile food
products, into vials or other containers.

The working principle of an aseptic injection filling, bunging, and sealing machine
involves several steps, including:

a) Sterilization: The machine components that come into contact with the product
or the container are sterilized using various methods, such as steam, hydrogen
peroxide, or irradiation.
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b) Filling: The sterile liquid product is pumped into the container through a needle
or nozzle, which is inserted into the container under sterile conditions.
c) Bunging: A sterile stopper or bung is inserted into the container, sealing the
product inside and preventing contamination from external sources.
d) Sealing: The container is sealed using a cap, crimp or snap-on closure, or other
sealing mechanism to maintain the sterility of the product.

The entire process is carried out in a controlled environment, such as a cleanroom or

isolator, to prevent any contamination from entering the product or the packaging. The
machine is designed to minimize the risk of contamination by incorporating various
features, such as laminar airflow, HEPA filters, and sterile barriers.

In summary, the working principle of an aseptic injection filling, bunging, and sealing
machine involves the use of sterile components and a controlled environment to fill and
package sterile liquid products into containers.

Performance Qualification (PQ)

The performance qualification of a pharmaceutical liquid injection filling, bunging, and
sealing machine involves several tests to ensure that the machine is operating as
intended and is capable of producing safe and effective pharmaceutical products. Some
of the tests that may be performed during performance qualification include:

a) Accuracy and precision testing: This test evaluates the accuracy and precision of
the machine's liquid filling process to ensure that it dispenses the correct volume
of liquid consistently.
b) Container closure integrity testing: This test checks for any leaks or defects in the
container closure system to ensure that it is capable of maintaining a sterile
environment and protecting the product from contamination.
c) Sterilization process validation: This test evaluates the effectiveness of the
sterilization process used to prepare the machine for use to ensure that it is
capable of killing all microorganisms that may be present.
d) Linearity and range testing: This test evaluates the machine's ability to
accurately fill a range of container sizes and volumes.
e) Bunging and sealing performance testing: This test evaluates the machine's
ability to properly insert bungs and seals onto containers to ensure that they are
secure and leak-free.
f) Cleaning and sanitization validation: This test evaluates the effectiveness of the
cleaning and sanitization processes used to maintain the machine's cleanliness
and prevent contamination.
g) Particle counting: This test measures the concentration of particles within the
filling area to ensure that it meets the specified cleanroom classification.

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h) Process capability analysis: This test evaluates the machine's ability to

consistently produce pharmaceutical products that meet the specified quality
requirements.

The specific tests performed during performance qualification may vary depending on
the specific requirements of the machine and the regulations governing its use.

Washer
Working Principle
Pharmaceutical glass bottle (vial) and ampoule washing machines operate on the
principle of mechanical washing and sterilization. These machines use a combination of
water, detergent, and high-pressure air to clean and sterilize glass vials or ampoules
before they are filled with pharmaceutical products.

The working principle of a typical vial washing machine involves several steps:

a) Loading and Sorting: The vials or ampoules are loaded onto the machine's
conveyor system and sorted to ensure they are properly aligned and spaced
apart.
b) Pre-Washing: The vials or ampoules are rinsed with water to remove any loose
particles or debris.
c) Main Washing: The vials or ampoules are subjected to a series of wash cycles
that involve the use of detergent and water. The machine uses high-pressure jets
to direct the cleaning solution onto the inside and outside of the vials or
ampoules, removing any residual contaminants.
d) Rinsing: After the main washing cycle, the vials or ampoules are rinsed with water
to remove any remaining detergent or debris.
e) Sterilization: The vials or ampoules are subjected to a sterilization cycle, which
typically involves heating the vials or ampoules to a high temperature using hot
air or steam. This process ensures that any remaining microorganisms are killed.
f) Drying: Finally, the vials or ampoules are dried using hot air before they are
removed from the machine and sent for filling.

The entire process is carried out automatically and is designed to ensure that the vials or
ampoules are thoroughly cleaned and sterilized before they are filled with
pharmaceutical products. This helps to prevent contamination and ensures the safety
and efficacy of the final product.

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Performance Qualification (PQ)

The PQ testing for a washing machine typically includes:

a) Cleaning Efficiency: This involves testing the washing machine's ability to remove
soil from vials, stoppers, and other equipment. This is typically done by visual
inspection, particulate analysis, or chemical testing.
b) Rinse Efficiency: This involves testing the washing machine's ability to remove
residual cleaning agents from vials, stoppers, and other equipment. This is
typically done by chemical testing or conductivity testing.
c) Sanitization Efficiency: This involves testing the washing machine's ability to
reduce or eliminate microorganisms from vials, stoppers, and other equipment.
This is typically done by microbial challenge testing.
d) Cycle Time: This involves testing the washing machine's ability to perform the
cleaning and sanitization process within a predetermined time frame.
e) Reproducibility: This involves testing the washing machine's ability to
consistently achieve the predetermined level of cleanliness over multiple runs.
f) Capacity: This involves testing the washing machine's ability to clean and sanitize
the required number of vials, stoppers, and other equipment per cycle.
g) Changeover: This involves testing the washing machine's ability to switch from
one product effectively and efficiently to another.

By performing these PQ testing, it can be ensured that the washing machine is qualified
and validated for use in the manufacture of sterile injectable drugs.

Depyrogenation and Sterilization tunnel

Working Principle
Pharmaceutical depyrogenation and sterilization tunnels are important pieces of
equipment used in the manufacturing of sterile injectable drugs. These tunnels work by
subjecting the containers, such as vials or ampoules, to high temperatures and/or
exposure to dry heat, in order to remove pyrogens (substances that can cause fever)
and microorganisms.

The depyrogenation process typically involves the use of high-temperature dry heat to
remove pyrogens from the surface of containers. This is typically done in a tunnel-like
chamber, where containers are transported on a conveyor belt through the chamber
while being exposed to hot air at a temperature of around 300°C for a set period of time.

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Sterilization, on the other hand, involves the complete destruction or removal of all
microorganisms from the containers. This can be done using various methods, such as
steam, dry heat, or chemical sterilization. In the case of a sterilization tunnel, containers
are typically subjected to a high-temperature dry heat treatment, where they are
exposed to hot air at a temperature of around 250-300°C for a set period of time.

Both depyrogenation and sterilization are critical steps in the manufacturing of sterile
injectable drugs, as they help to ensure that the final product is free from harmful
contaminants that could cause harm to patients. The use of depyrogenation and
sterilization tunnels helps to ensure that these processes are carried out efficiently and
effectively, in a controlled and validated environment, with the ultimate goal of
producing safe and effective medicines.

Performance Qualification (PQ)

The performance qualification of a pharmaceutical depyrogenation and sterilization
tunnel used in sterile injectable drug manufacturing involves several tests to ensure that
the tunnel is operating as intended and is capable of producing sterile and pyrogen-free
products. Some of the tests that may be performed during performance qualification
include:

a) Temperature mapping: This test evaluates the temperature distribution within

the tunnel to ensure that it is consistent and meets the specified requirements.
b) Airflow mapping: This test evaluates the airflow patterns within the tunnel to
ensure that they are consistent and meet the specified requirements.
c) Sterilization process validation: This test evaluates the effectiveness of the
sterilization process used to sterilize the products passing through the tunnel.
d) Depyrogenation process validation: This test evaluates the effectiveness of the
depyrogenation process used to remove endotoxins from the products passing
through the tunnel.
e) Biological indicator testing: This test uses biological indicators to monitor the
sterilization process and ensure that it is effective in killing all microorganisms.
f) Endotoxin testing: This test evaluates the level of endotoxins in the products
passing through the tunnel to ensure that they meet the specified requirements.
g) Cleaning and sanitization validation: This test evaluates the effectiveness of the
cleaning and sanitization processes used to maintain the tunnel's cleanliness
and prevent contamination.

The specific tests performed during performance qualification may vary depending on
the specific requirements of the tunnel and the regulations governing its use.

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Laminar Air flow hood /Biosafety cabinet

Working Principle
Pharmaceutical Laminar Air Flow Hood/Biosafety Cabinet is an important equipment
used in sterile injectable drug manufacturing to provide a sterile work environment and
protect the product and operator from contamination. The working principle of these
cabinets involves the use of high-efficiency particulate air (HEPA) filters to purify the air.

In a Laminar Air Flow Hood, the air is drawn from the surrounding area and passed
through a pre-filter and then a HEPA filter. The HEPA filter removes particles as small as
0.3 microns, including bacteria, viruses, and other contaminants, from the air. The
purified air is then passed through the cabinet in a laminar flow, which means the air
flows in a smooth, uniform manner without turbulence, creating a clean air environment
in the work area.

In a Biosafety Cabinet, the air is also drawn from the surrounding area and passed
through a pre-filter and a HEPA filter. However, in addition to the HEPA filter, the
cabinet also has a front opening with a sash that can be adjusted to provide a barrier
between the work area and the operator. The air flows in a laminar flow across the work
surface, and any potential contaminants are captured by the HEPA filter.

Both Laminar Air Flow Hoods and Biosafety Cabinets have different classes based on
the level of protection they provide. The cabinets are tested and certified to meet
specific standards by regulatory authorities to ensure their performance.

In summary, Laminar Air Flow Hoods and Biosafety Cabinets work by filtering the air in
the surrounding environment, removing contaminants, and creating a clean and sterile
work area for the manufacturing of sterile injectable drugs.

Performance Qualification (PQ)

During the performance qualification (PQ) of a Pharmaceutical Laminar air flow hood or
Biosafety cabinet used in sterile injectable drug manufacturing, the following tests should be
performed:

a) Airflow Velocity Test: This test measures the velocity of the air flowing through
the laminar air flow hood or biosafety cabinet. The test is performed using an
anemometer and ensures that the air flow is within the range specified in the
design qualification (DQ).

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b) Airflow Pattern Test: This test ensures that the air flow is uniform and the air is
not re-circulating within the cabinet. Smoke or tracer gas can be used to visualize
the airflow pattern.
c) Particulate Count Test: This test measures the number of airborne particles of a
certain size within the laminar air flow hood or biosafety cabinet. The test should
be performed in accordance with ISO 14644-1 or other relevant standards.
d) Filter Integrity Test: This test ensures that the HEPA filters are functioning
correctly and are not allowing particles to pass through. The test should be
performed in accordance with ISO 14644-3 or other relevant standards.
e) Noise Level Test: This test measures the noise level produced by the laminar air
flow hood or biosafety cabinet and ensures that it is within the specified limits.
f) Lighting Intensity Test: This test measures the intensity of the light inside the
laminar air flow hood or biosafety cabinet and ensures that it is within the
specified limits.
g) Microbial Contamination Test: This test measures the level of microbial
contamination inside the laminar air flow hood or biosafety cabinet. The test
should be performed using appropriate methods and standards, such as ISO
14698-1.

These tests ensure that the laminar air flow hood or biosafety cabinet is operating within
the specified parameters and is suitable for use in sterile injectable drug manufacturing.

PFS (Pre-fill syringe) machine

Benefits of PFS over conventional filling method
Pre-Fill Syringe (PFS) machines are used in the pharmaceutical industry to fill syringes
with sterile injectable drugs. They offer several benefits over traditional vial filling
methods, including increased product safety, reduced risk of contamination, and
improved patient convenience. Here are some of the key benefits of PFS machines and
how they work:

a) Reduced risk of contamination: PFS machines are designed to be a closed

system, which reduces the risk of contamination during the filling process. This is
particularly important for sterile injectable drugs, which need to be free from any
contaminants that could cause harm to the patient.

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b) Increased product safety: PFS machines offer improved product safety because
they allow for precise dosing of the drug. This reduces the risk of over or under-
dosing, which can lead to adverse effects or ineffective treatment.
c) Improved patient convenience: PFS machines offer improved patient
convenience because they allow for self-administration of drugs. This is
particularly important for patients who require frequent injections or have
difficulty with traditional vial and syringe methods.
d) Cost-effective: PFS machines can be a cost-effective solution for pharmaceutical
companies because they eliminate the need for vials, stoppers, and seals, which
can be expensive to produce and sterilize.

How PFS machines work:

PFS machines work by automatically filling syringes with a precise amount of drug and
then sealing them. The process involves the following steps:

a) Syringe feeding: The machine feeds empty syringes into the filling station.
b) Filling: The machine fills the syringes with a precise amount of drug.
c) Plunger insertion: The machine inserts the plunger into the syringe to create a
seal.
d) Stopper insertion: The machine inserts a stopper into the syringe to create a
second seal.
e) Capping: The machine caps the syringe with a sterile cap.
f) Inspection: The filled syringes are inspected for quality and integrity before being
released for distribution.

Overall, PFS machines offer several benefits over traditional vial filling methods and are
an important tool for pharmaceutical companies to ensure the safety, convenience, and
cost-effectiveness of their sterile injectable drugs.

Performance Qualification (PQ)

During the performance qualification (PQ) of a pharmaceutical pre-filled syringe (PFS) machine
used in sterile injectable drug manufacturing, the following tests should be performed:

a) Dose Accuracy Test: This test verifies that the PFS machine dispenses the
correct dose of the drug into each syringe. The test is performed using a
precision scale and/or analytical methods to measure the weight or volume of the
drug dispensed.
b) Particle Count Test: This test measures the number of particles of a certain size
in the drug solution filled in the syringes. The test should be performed in
accordance with ISO 14644-1 or other relevant standards.

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c) Leak Test: This test ensures that the syringe is properly sealed and prevents any
leakage of the drug solution. The test is performed by visually inspecting the
syringe for any signs of leakage or by performing a pressure decay test.
d) Sterility Test: This test verifies that the PFS machine is capable of producing
sterile products. The test should be performed using appropriate methods and
standards, such as USP (United States Pharmacopeia) <71>.
e) Compatibility Test: This test determines the compatibility of the drug product
with the syringe materials and ensures that the drug does not react with the
syringe or cause any degradation of the drug or syringe materials.
f) Functionality Test: This test ensures that the PFS machine is operating correctly
and all components are functioning properly. This includes verifying that the
syringe is properly loaded, the drug solution is properly filled, and the syringe is
properly sealed.
g) Cleaning Validation: This test verifies that the cleaning process used for the PFS
machine is effective and ensures that there is no cross-contamination between
different drug products.

These tests ensure that the PFS machine is operating within the specified parameters
and is suitable for use in sterile injectable drug manufacturing.

HVAC
Working Principle
HVAC (Heating, Ventilation, and Air Conditioning) systems play a crucial role in
maintaining a controlled environment in drug manufacturing facilities and clean rooms.
The working principle of an HVAC system used in such facilities involves the following
steps:

a) Air intake and filtration: The HVAC system takes in outside air and filters it to
remove any contaminants or particles that could compromise the clean
environment inside the facility.
b) Conditioning: The air is then conditioned by adjusting its temperature, humidity,
and pressure to meet the specific requirements of the facility. This is important
because different drug manufacturing processes may require different
environmental conditions to ensure product quality and safety.
c) Distribution: The conditioned air is distributed throughout the facility using a
network of ducts and vents. In clean rooms, the air is typically distributed in a
laminar flow pattern to minimize the buildup of particles and contaminants.

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d) Exhaust: As the conditioned air circulates in the facility, it picks up contaminants

and particles. The HVAC system then exhausts this contaminated air to maintain
a clean environment inside the facility.
e) Monitoring and control: The HVAC system is equipped with sensors and controls
to continuously monitor the temperature, humidity, pressure, and particle levels
inside the facility. The system automatically adjusts the conditioning and
distribution of air to maintain the desired environment.

Overall, the working principle of an HVAC system used in drug manufacturing facilities
and clean rooms is to create a controlled environment that meets the specific
requirements of the facility and ensures the safety and quality of the products being
manufactured.

Performance Qualification (PQ)

During the performance qualification (PQ) of a pharmaceutical HVAC (heating,
ventilation, and air conditioning) system, specifically the air handling units (AHUs) used
in the manufacturing of sterile injectable drugs, the following tests should be performed:

a) Airflow Velocity Test: This test measures the velocity of air moving through the
AHUs and ensures that it meets the specified limits. The test is performed using
an anemometer and should be performed at different points along the air path.
b) Air Change Rate Test: This test measures the rate at which the air is changed
within the cleanroom and ensures that it meets the specified limits. The test
should be performed in accordance with ISO 14644-3 or other relevant
standards.
c) Differential Pressure Test: This test measures the pressure differential between
the cleanroom and adjacent areas and ensures that it meets the specified limits.
The test should be performed at different points along the air path.
d) Temperature and Humidity Test: This test measures the temperature and
humidity within the cleanroom and ensures that it meets the specified limits. The
test should be performed at different points along the air path.
e) Airborne Particle Count Test: This test measures the number of particles of a
certain size in the air and ensures that it meets the specified limits. The test
should be performed in accordance with ISO 14644-1 or other relevant
standards.
f) Recovery Test: This test measures the time taken by the AHUs to recover the
cleanroom to its specified environmental conditions after a disruption, such as a
door opening. The test should be performed at different points along the air path.
g) Filter Integrity Test: This test ensures that the filters used in the AHUs are
working properly and are not allowing any particles to pass through. The test

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should be performed in accordance with relevant standards, such as ASTM

F3150.
h) Microbial Air Sampling: This test measures the level of microorganisms in the air
and ensures that it meets the specified limits. The test should be performed
using appropriate methods and standards, such as USP <1116>.

These tests ensure that the HVAC system, specifically the air handling units, are
functioning correctly and providing the required environmental conditions for the
manufacturing of sterile injectable drugs.

Computer System Validation Requirements

The specific tests that need to be performed for computer system validation (CSV) of
critical pharmaceutical equipment will depend on the equipment and the specific
requirements of the regulatory authority overseeing the validation. However, some
common tests that may be included in the CSV process are:

Installation Qualification (IQ) testing: This involves testing the installation of the
equipment to ensure it meets the manufacturer's specifications, is properly installed
and configured, and has been installed in an appropriate environment.

Operational Qualification (OQ) testing: This involves testing the equipment's operational
functions to ensure that it operates within its specified parameters and meets the
regulatory requirements. This includes testing the equipment's performance under
different operating conditions and ensuring that it can perform the required tasks.

Performance Qualification (PQ) testing: This involves testing the equipment's

performance in a simulated or real-world environment to ensure that it meets the
regulatory requirements and performs as expected. This may involve testing the
equipment's reliability, accuracy, precision, and repeatability.

a) Security testing: This involves testing the equipment's security features to ensure
that it meets the regulatory requirements for data privacy and security. This may
include testing access controls, data encryption, and data backups.
b) User Acceptance testing (UAT): This involves testing the equipment's user
interface and user experience to ensure that it is intuitive and easy to use. This
testing is typically performed by end-users to ensure that the equipment meets
their needs and is fit for purpose.
c) Data Integrity testing: This involves testing the equipment's ability to capture,
store, and retrieve data accurately and securely, ensuring that the data
generated by the equipment is complete, consistent, and accurate.
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d) Change Control testing: This involves testing the equipment's ability to manage
changes in the system, including software and hardware upgrades, and ensure
that the equipment continues to meet regulatory requirements.

Overall, the validation process should ensure that the equipment meets the regulatory
requirements for safety, efficacy, and quality, and that it is fit for its intended use in the
pharmaceutical manufacturing process.

Process validation
Process validation is a critical requirement for pharmaceutical sterile drug
manufacturing. It involves establishing documented evidence that a manufacturing
process consistently produces products that meet the required quality and safety
standards. In this context, the critical steps and importance of process validation are
discussed below,

Critical Steps:
a) Process Design: The first step in process validation is to design the
manufacturing process, including the equipment, raw materials, and personnel
involved. The process should be designed to ensure that the product is
manufactured consistently, and any critical quality attributes are addressed.
b) Process Qualification: Once the process design is established, the next step is
process qualification, which involves determining the critical process parameters
and their acceptable ranges. The critical parameters are monitored and
controlled during manufacturing to ensure consistent product quality.
c) Process Validation: The third step in process validation involves testing the
manufacturing process under normal operating conditions to establish that it
consistently produces products that meet the required quality and safety
standards.

Importance:
a) Ensures Product Quality: Process validation is essential to ensuring that
pharmaceutical sterile drug products are of high quality and free from
contaminants. It helps to identify critical process parameters that affect the
product's quality and establishes their acceptable ranges.
b) Regulatory Compliance: Process validation is a regulatory requirement for
pharmaceutical sterile drug manufacturing. Compliance with these requirements
is necessary to obtain regulatory approvals for marketing and selling
pharmaceutical sterile drugs.

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c) Cost Reduction: Process validation can help identify inefficiencies in the

manufacturing process and reduce the risk of product failures, which can lead to
product recalls and additional costs.
d) Continuous Improvement: Process validation is not a one-time event. It is an
ongoing process that allows for continuous improvement of the manufacturing
process. By monitoring critical process parameters, the manufacturing process
can be optimized to improve product quality and reduce costs.

Pharmaceutical manufacturers must follow the process validation requirements to

ensure that their products are safe and effective for use.

Digital Technology Arena

Digital technological advancements in pharma manufacturing using AI and machine
learning have revolutionized the way drugs are developed, tested, and manufactured.
Machine learning (ML) and artificial intelligence (AI) have the potential to revolutionize
sterile drug manufacturing by enabling continuous process improvement and critical
process control. Here are some ways in which ML and AI can be used in this context:

a) Predictive maintenance: ML algorithms can be used to analyze real-time data

from equipment sensors and predict when maintenance is required. This can
help reduce downtime and prevent costly equipment failures.

b) Quality control: AI can be used to analyze large volumes of data from quality
control tests and identify patterns that could indicate issues with the
manufacturing process. This can help improve the quality and consistency of the
final product.

c) Process optimization: ML algorithms can be used to analyze data from the

manufacturing process and identify areas where improvements can be made. For
example, the algorithms can identify variables that affect yield or product quality
and suggest changes to the process to optimize these variables.

d) Risk assessment: AI can be used to analyze data on the manufacturing process

and identify potential risks to product quality or safety. This can help
manufacturers proactively identify and address potential issues before they
become problems.

e) Supply chain optimization: ML algorithms can be used to analyze data from the
supply chain, including raw materials and shipping logistics, and identify areas
where improvements can be made to increase efficiency and reduce costs.
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f) Overall, the use of ML and AI in sterile drug manufacturing can help improve the
efficiency, quality, and safety of the manufacturing process, while also reducing
costs and improving profitability for manufacturers.

Regulatory Recommendation
The pharmaceutical and healthcare industry is highly regulated, and there are several
guidelines and regulations that need to be followed to ensure the quality, safety, and
efficacy of critical equipment, systems, instruments, and computer systems used in
these industries. Some of the best available guidelines and regulations for qualification
and validation of critical equipment, systems, instruments, and computer systems in
pharmaceutical and healthcare industries are:

a) Current Good Manufacturing Practices (cGMP): The cGMP regulations provide

minimum requirements for the methods, facilities, and controls used in
manufacturing, processing, and packing of pharmaceutical products.
b) International Council for Harmonization (ICH) Guidelines: The ICH guidelines
provide a unified approach to the development, implementation, and registration
of pharmaceutical products worldwide. ICH guidelines cover various aspects of
pharmaceutical manufacturing, including validation and qualification.
c) United States Pharmacopeia (USP): The USP provides standards for the quality
of medicines, dietary supplements, and healthcare products, including
guidelines for validation and qualification.
d) Food and Drug Administration (FDA) Regulations: The FDA regulations provide
guidance on the requirements for validation and qualification of critical
equipment, systems, instruments, and computer systems used in the
pharmaceutical and healthcare industries.
e) European Medicines Agency (EMA) Regulations: The EMA regulations provide
guidance on the requirements for validation and qualification of critical
equipment, systems, instruments, and computer systems used in the
pharmaceutical and healthcare industries in Europe.
f) ISO Standards: The International Organization for Standardization (ISO) provides
standards for the development, implementation, and maintenance of quality
management systems, including guidelines for validation and qualification.

It is important to note that the specific guidelines and regulations applicable to a

particular critical equipment, system, instrument, or computer system will depend on
the country or region where it is being used, as well as the specific requirements of the
pharmaceutical or healthcare industry. It is essential to consult with regulatory

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authorities and seek expert advice to ensure compliance with all relevant guidelines and
regulations.

Conclusion
In conclusion, qualification and validation are fundamental processes in the
pharmaceutical and healthcare industries to ensure that products and processes are
safe, effective, and of high quality. These processes involve verifying and documenting
that equipment, facilities, and systems are installed and operated according to their
intended design and purpose, and that processes consistently produce results that
meet predetermined quality specifications.

It is crucial for pharmaceutical and healthcare companies to adhere to regulatory

guidelines and standards when conducting qualification and validation activities. These
guidelines help to ensure that products and processes are consistent, reliable, and meet
regulatory requirements. Companies that fail to comply with these guidelines risk
significant consequences, including product recalls, regulatory sanctions, and damage
to their reputation.

By conducting thorough qualification and validation processes and maintaining up-to-

date documentation, pharmaceutical and healthcare companies can ensure the safety,
efficacy, and quality of their products, which ultimately benefits patients and the
healthcare industry as a whole.

-x-

Author Bio link

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