PROCESS VALIDATION FOR INJECTABLES

Process validation
Acc. to FDA : “Process validation is establishing documented evidence, which provides a high
degree of assurance that a specific process will consistently produce a product meeting its
predetermined specifications and quality characteristics”

Scope of validation
The scope of validation is to ensure that quality is built into the system at every step, and not
just tested for at the end, as such validation activities will commonly include training on
production material and operating procedures, training of people involved and monitoring of the
system at time of production. In general, an entire process is validated; a particular object within
that process is verified. The regulations also set out an expectation that the different parts of the
production process are well defined and controlled, such that the results of that production will
not substantially change over time. Validation should be performed for 1. New premises,
equipment, utilities and systems, and processes and procedures, 2. At periodic intervals, and 3.
When major changes have been made. There should be a clear distinction between in-process
controls and validation. In process tests are performed during the manufacture of each batch
using specifications and methods devised during the development phase. The objective is to
monitor the process continuously.

Types of Process Validation

Validation Depending on the time when validation is performed relative to the production,
process validations can be classified as:

1. Prospective

2. Concurrent

3. Retrospective

4. Revalidation

Process flow of parenteral dosage form

In the preparation of parenteral dosage form mixing, filteration, filling & sealing are the most
critical step. Flow diagram shows the process flow of parenteral dosage form.

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Processing variables in parenteral

Dispensing

Dispensing is one of the critical factor which may lead to product contamination while
transferring or dispensing. There are also chances of dispensing more or less quantity of API.

Assay: The calculation for the amount to be dispensed is done with respect to the COA of the
material, the calculations are done as on dried basis only thus Assay value have great impact in
the quantity of material dispensed, which may affect the final product.

Approved vendors: All the materials used for the production should be procured from approved
vendors only. The vendors are approved by prior vendor audit. If the materials are procured from
approved vendors the standard of the materials should be validated. If materials are procured
from unapproved vendors the purity and standard of the materials cannot be assured.

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LAF∆P and room temperature and RH: Pressure differentials in a controlled environment is
important to ascertain that the correct degree of over pressure is maintained relative to the
adjacent areas of lower classifications in order to minimize the contamination drawn into the
controlled environment from its surroundings. The LAF ∆P should be maintained within limits to
maintain a controlled environment.

Temperature and RH: Temperature and RH of the dispensing area should be within the
specified limit since the products can be detoriated at extreme environmental conditions. The
temperature and RH are monitored regularly to verify whether the area is in controlled state. The
failure of AHU leads to changes in temperature & RH.

Balance calibration: All the balances used for dispensing should be calibrated before starting
the days work. Apart from this calibration by external party should be conducted for periodically.
If balances are not calibrated there are chances of dispensing wrong quantity of materials which
may affect the final product assay.

Sterilization

Sterilization is the process by which a product made free of viable organisms with a specified
probability. Sterilization is carried out in a sequence of defined operating parameters such as
time, temperature and pressure and conditions required to render an item sterile.

Validated load pattern: When a multiple products are processed using the same cycle, a
minimum lethality to be delivered for product specific loads. By a validated load pattern a safety
margin is built into the minimum F0 requirements. It assures that the lethality requirements are
constantly delivered to each load. During the load pattern study the exact physical nature of each
product and materials are studied and an appropriate sterilization process are selected.

Clean-in-place / Sterilize-in-place: Validation of these systems may be difficult because of the

potential incompatibilities in requirements for the design of CIP and SIP facilities. All systems
have dead legs to a greater or lesser extent and the required orientation of the dead legs differ for
CIP and SIP. The orientation for CIP dead legs is slightly sloping so that the cleaning solution
can enter and also drain away. The dead leg for SIP is vertically up so that steam can
downwardly displace the air. The CIP and SIP procedures should be validated as the containers
are not supposed to be cleaned manually and the parameters used during process should
consistently provide the acceptance limits.

Hold time for sterilized goods: The hold time for the sterilized goods should be validated to
determine the effectiveness of the sterility process. The time period until which the products
remain sterile if not opened from the pack is determined. The products that lapses the hold period
must be sterilized and used (provided the packs are not opened).

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Manufacturing process
LAF∆P, Temperature and RH in manufacturing area: These parameters should be
maintained within the limits throughout the process in all the stages of manufacturing, filling,
sealing and packing. To avoid the product failure, the possible defects are mentioned in the
earlier section.

Subdued light: The intensity of the light in different areas is qualified during area qualification.
In some cases the products which are light sensitive should not be dispensed at normal light. The
activity should be carried out in subdued light which are of less intensity than normal light. If the
product is not manufactured under subdued light it may leads to product detoriation.

Environmental monitoring: Measurement and determination of the number and size of

airborne particulate contamination is essential to ensure that a suitable environment is maintained
for preparation of asepticaly prepared products. If any changes from the normal acceptance limit
may lead to product failure due to product contamination. Acceptable methods for monitoring
the microbiological quality of the environment include:

A] Surface monitoring

B] Active air monitoring

C] Passive air monitoring (Settling plates)

Mixing time and RPM: The product processing is done by mixing of the active and excipients
together in the solution preparation tank with water for injection. Mixing time is the critical
parameter as the dissolution of the materials mainly depends on mixing time. The mixing time is
determined during the validation process. If mixing time is not followed it may lead to improper
dissolution of API thus leads to wrong assay results. Mixing is facilitated by using the stirrer.
The stirrer speed should be validated so that we can assure that proper mixing has occurred each
time. The validation is conducted at different speeds and the optimized.

pH: One of the main parameter used to chek the product quality is by checking the pH of the
solution prepared, since the parenterals solutions are being injected directly it should be adjusted
to the pH that is more or less equal to that of blood. In some cases due to drug solubility
characterestics the pH may be acidic or basic. The pH is checked by using a calibrated pH meter
in the manufacturing area. Before starting every day’s activity pH meter should be calibrated.

Volume make up: Volume make up for the solution can be done by two ways such as by
weighing or by dip stick. Dipstick method is done by using the calibrated dipstick present along
with the manufacturing vessel. The dip stick has a measuring scale. If volume make up is done
wrongly it may leads to increase or decrease in the assay values. It should be carried out at
ambient temperature (25°±2°C).

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Hold time study: The product manufactured aseptically should be subjected to hold time study
to confirm that the product produced remain sterile, without any chemical change. During hold
time study the product is frequently sampled to determine any change has ocurred in stability and
sterility aspects. This is carried out since there are chances of any of equipment failure during
process.

Filtration activity: In aseptic processing the product is sterilized only by filtration, thus the
filtration activity should be adequately validated. The integrity of the sterilization filter should be
verified before use and should be confirmed immediately after use by an appropriate method
such as a bubble point, or diffusive flow or pressure hold test etc. The integrity of critical gas and
air vent filters should be confirmed at appropriate intervals.

Vial washing and depyrogenation

LAF∆P (across the HEPA filter), Temperature and RH: These parameters should be
maintained within the limits throughout the process in all the stages of manufacturing, filling,
sealing and packing.

Water and compressed air pressure: The vials are washed first by series of water at a high
pressure. The pressure of the water should be maintained throughout the process as the pressure
is directly proportional to the effectiveness of the washing process. If the pressure is less than the
acceptable value it may lead to improper washing. Compressed air is used for drying the washed
vials before it reaches the tunnel. Thus any deviations in the pressure maintained will leads to
improper drying which will affect the depyrogenation of the vials.

Clarity check: The washed vials are checked manually for the effectiveness of the washing
process. The vials which are broken or containing any dirt can be identified during these check’s
which prevent the rejections after filling.

Depyrogenation temperature and conveyor belt speed: Vial depyrogenation is another critical
factor to be checked. Depyrogenation of vials can be achieved at a temperature between 280˚C to
350˚C. If the temperature is not maintained throughout the process it may affect the
depyrogenation of the vials. The tunnel should be qualified before starting the process. During
the qualification stage the depyrogenation temperature and the conveyor belt speed for the
different vial size are done and established. The validated limits should be followed during the
process.

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∆P (across the HEPA filter and across the zones & rooms): Pressure differentials in the
tunnel is important to ascertain that the correct degree of over pressure is maintained relative to
the adjacent areas of lower classifications in order to minimize the contamination drawn into the
controlled environment from its surroundings. The ∆P should be maintained within limits to
maintain a controlled environment. The difference in ∆P may be due to blocked or partially
blocked HEPA filters. The ∆P across various zones of tunnel and the ∆P between the tunnel
cooling area and vial receiving area should be maintained.

Vial filling and sealing

Gowning procedure: The persons entering the sterile area should not contaminate the area by
shedding contaminants from own body. The person should follow the gowning procedure
strictly. The gowning qualification is done by taking swabs from the gowned persons at the
commonly used parts of the body on consecutive three days and incubated for checking the
presence of any viable organism in it. The results showing less than the alert level is the criteria
for acceptance. Person without proper training may lead to product contamination, thus proper
training is given to all personnel entering sterile area.

LAF∆P (across the HEPA filter), temperature and RH: These parameters should be
maintained within the limits throughout the process in all the stages of manufacturing, filling,
sealing and packing, to avoid the product failure. The possible defects are mentioned in the
earlier section.

Filling speed and fill volume: The filling speed of the machine should be validated during the
machine qualification stage. The filling speed depends upon the size of the vial and volume of
the liquid filled. The fill volume may be altered due to increasing or decreasing the speed of the
machine and also depends on the product physical nature. The changes from the established
limits may leads to reduced extractable volume. Thus it should be frequently monitored by doing
fill volume checks by using calibrated syringes or measuring cylinders.

Filter integrity testing: Fiteration is the only process of sterilization in aseptically filled
products, thus to confirm the sterilization has achieved filter integrity should be done. The
integrity of the sterilization filter should be verified before use and should be confirmed
immediately after use by an appropriate method such as a bubble point, or diffusive flow or
pressure hold test.

Sealing of vials: The vials filled asepticaly should be closed and sealed immediately after filling
of the solution. The sealing gives the proper closing of the vials. The sealing activity can be
confirmed by doing leak testing for the sealed vials frequently. Sealing prevents the leakage of
the containers during the transporting or shipping.

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