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69Process Validation
VALIDATION TEAM
Process Validation is one of many signicant activities that is performed under the
umbrella of Quality Assurance. Basically, validation is the fundamental part of
Quality Assurance that induces the quality in the product by controlling each and
every manufacturing step. It is a step-by-step procedure that is designed to ensure that
a manufacturing process can consistently produce quality products. The pharmaceuti-
cal company’s Quality Assurance department must establish a validation team com-
prising of a member each from Product development, Production, engineering and
Quality Assurance itself, led by a QA personnel, preferably the Validation Manager.
Process validation starts as early as the pilot batches manufacturing. This means it
has to be done before releasing a new product, when applying any change on an exist-
ing product, and for periodically verifying the process. Established at the onset, a
protocol should specify how the validation process will be carried out, including the
parameters to be monitored, the samples to be taken, and the results to be accepted.
Process Validation comprises of the following steps:
1. Process Design: During this stage, the manufacturing process is dened in a
way that it can reproduce the delivery of a medicinal product that meets pre-
determined specications and quality attributes. To achieve this, the valida-
tion team should have a clear grasp of how the process actually works. In
short, the process design can be further categorized into the following steps.
• Risk assessment is carried out to identify the critical process and qual-
ity attributes of the product.
• Protocols are written, reviewed, and approved.
• Pilot batches and when appropriate, scale-up batches are manufactured.
• Process is validated under the approved protocol using the sampling
and testing criteria which were derived during the risk assessment step.
•
Report is written where critical quality attributes of the product and
critical process parameters are dened to be monitored in the next
phase which is process qualication.
2. Process Qualication: In the process Qualication stage, process design
evaluation is performed to determine the effectiveness for quality production.
The following steps will be taken in the process Qualication stage:
• Ensure that the manufacturing facility was designed as per the require-
ments of current good manufacturing practice (CGMP).
• Secondly, all utilities and equipment associated with the manufactur-
ing should be qualied and validated to ensure that they are built and
installed in compliance with design specications.
•
Finally, process performance qualication should be executed through
a protocol and documented in a report.
Validation Protocol: A validation protocol must cover the following
aspects;
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70 Basics of Pharmaceutical Manufacturing and Quality Operations
a. Introduction of the product and process, Objectives of the valida-
tion, and Scope of the validation
b. Dene the responsibilities of Production, Quality Assurance (QA),
and Quality Control (QC) and Prerequisites (e.g., manufacturing
re c o rds)
c. Process Validation Study Plan based on Quality Risk Management
(QRM)
d. Establish a Validation Team that may be comprised of a person each
from Research and Development, Engineering, Production, QA,
and QC
e. List of Materials and Master Formula
f. List of Equipment
g. Process Flow Chart
h. Describe briey the Manufacturing Process and identication of
critical process parameters
i. In-process Test and Specications or critical quality attributes
j. Sampling, Testing Plan, sample sizes, and Acceptance Criteria
k. Yield Details for at least three consecutive batches
l. Analytical Method Validation
m. Packaging process
n. Finished Product Specication
o. Review of Out-of-Specication Test Results, Deviation, and Change
Control
p. Revalidation Criteria (if applicable)
q. Summary and Conclusion
3. Process Verication: Process verication is a continued process that comes
after process design and process qualication. This stage deals with contin-
uous monitoring of the validated process to ensure that the process remains
in a state of control and within the validated parameters.
Continued process verication often incorporates the use of statistical
process control, the continuous monitoring and sampling of process param-
eters and quality attributes, and the scheduled maintenance of the facility,
utilities, and equipment.
Types of Process Validation:
There are four types of process validation:
1. Prospective validation
2. Retrospective validation
3. Concurrent validation
4. Revalidation
Prospective Validation: Prospective validation is implemented when a new product
is planned to be manufactured for the rst time. This could be with a new formula or
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71Process Validation
within a new facility. Prospective validation is always carried out before beginning
commercial production batches. Prospective validation is actually the base of any
new product that will be released under new conditions.
Retrospective Validation: This type of validation study is conducted only when
at the time of launching a new product; a documented validation has not been car-
ried out. This study is then fullled with the use of historical data and trend analysis
to provide evidence that the process, despite not formally validated, is still at a state
that it is intended to be in. This approach, however is no longer acceptable to process
validation because it’s a regulatory requirement that all new products should have
already been validated before their commercial distribution.
Concurrent Validation: Concurrent validation is done under special circum-
stances during regular pharmaceutical production. Though, the approach is not
widely practiced yet still acceptable under certain conditions. For example, manufac-
turing medically necessary drugs in coordination with the USFDA to prevent a short
supply or a smaller batch size required immediately in the market and a prospective
validation with three batches may result in scrapping the product unused, etc. Health
regulators nevertheless continue to emphasize that it should only be used rarely.
Revalidation: Revalidation is more widely used for medical devices than drug
products. It is executed when prospective validation reaches a conclusion that the
manufacturing process is unable to produce the product consistently. Moreover, a
criterion for revalidation may be indicated in the original validation protocol. The
revalidation process may not be as comprehensive as the initial validation, especially
if the situation only calls for some aspects to be repeated.
QUESTIONS AND ANSWERS
1. Dene process validation
Answer: PROCESS VALIDATION is establishing documented evidence
which provides a high degree of assurance that a specic process consistently
produces a product meeting its predetermined specications and quality.
2. Dene and explain Process Design
Answer: Process design is the rst stage of process validation. In this stage,
the manufacturing process is dened in a way that it can reproduce the
delivery of a medicinal product that meets predetermined specications and
quality attributes.
3. How many steps are there in the process Design
Answer: The process design is further categorized into the following ve
steps.
• Risk assessment is carried out to identify the critical process and quality
attributes of the product.
•
Protocols are written, reviewed, and approved.
• Pilot batches and when appropriate, scale-up batches are manufactured.
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72 Basics of Pharmaceutical Manufacturing and Quality Operations
• Process is validated under the approved protocol using the sampling and
testing criteria which were derived during the risk assessment step.
• Report is written where critical quality attributes of the product and
critical process parameters are dened to be monitored in the next phase
which is process qualication.
4. What is process Qualication stage?
Answer: Process Qualication is a stage where process design evaluation is
performed to determine the effectiveness for quality production.
5. How many steps are there in the process qualication stage?
Answer: The following steps will be taken in the process Qualication
stage:
• Ensure that the manufacturing facility was designed as per the require-
ments of current good manufacturing practice (CGMP).
• Secondly, all utilities and equipment associated with the manufacturing
should be qualied and validated to ensure sure that they are built and
installed in compliance with design specications.
• Finally, process performance qualication should be executed through a
protocol and documented in a report.
6. What step follows the Process Qualication?
Answer: Process verication follows process qualication which is a con-
tinued process.
7. What is the signicance of Process Verication?
Answer: Process verication is a continued process which deals with
continuous monitoring of the validated process to ensure that the process
remains in a state of control and within the validated parameters.
8. How does Prospective validation differ from Concurrent validation?
Answer: Prospective validation is implemented when a new product is
planned to be manufactured for the rst time with a new formula or within
a new facility. This type of validation is carried out before beginning com-
mercial production batches. Whereas, concurrent validation is allowed only
under special circumstances such as manufacturing medically necessary
drugs in coordination with the USFDA to prevent a short supply or when
a smaller batch size is required immediately in the market. However, a
concurrent validation strategy is not encouraged by health regulators and
should only be used rarely.
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7.1
Protocol Generation
The process validation protocol is actually a written plan that describes the process
to be validated. It further includes the list of production equipment and the entire
approach as to how validation will be conducted. A validation protocol is necessary
to dene the specic items and activities that will constitute a validation study.
The validation protocol must be written by a qualied person of the concerned
department and approved by appropriate signatories before the validation activities
start.
A typical validation protocol should be comprised of the following segments;
Purpose/Objective: The aim of the validation study needs to be described under
Purpose/Objective.
For example, the objective of this validation protocol is to provide documented
evidence to demonstrate that the manufacturing process for (Name of Product), when
carried out within dened parameters, will consistently perform its intended func-
tion and meetall pre-determined specications and quality attributes.
Scope: The area or department where the protocol is concerned as well as the
product’s name will be mentioned.
Introduction: In this section a brief description of product is provided. Description
will include the formulation of the product. The formulation can be presented in a list
with the raw material code, description, and total quantity in the batch as follows:
Raw Material Code Description Quantity
Per XXX L Batch
Label Claim
Comments:
Besides the formulation of the product, details of the raw materials and manufac-
turing equipment are also enlisted in the introduction section of the protocol.
Raw Materials:
Raw Material Code Lot # Supplier
73DOI: 10.1201/9781003366393- 8
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74 Basics of Pharmaceutical Manufacturing and Quality Operations
Manufacturing Equipment:
The number of rows in the tables above are only for example. The actual number
of raw materials and equipment will usually be more and can be added accordingly.
PROCESS
Process overvieW
Under Process Review, a brief summary of manufacturing steps in the manufacture
of the product is given with the help of approved compounding instructions. The fol-
lowing important information is provided;
• The delivery of material from dispensing to different equipment as per the
process requirements is given.
• For further information regarding the manufacturing process for the prod-
uct, refer to the master document.
vaLidation strateGy
Three consecutive, successful production trials for each representative process/prod-
uct will be necessary in order to consider the process/product validated.
The batches of XYZ 1 mg Tablets will be manufactured in ABC manufacturing
area. These batches will be used for the above-mentioned type of process validation
study. This work focused on the evaluation of the following steps:
• Review of the manufacturing formula and method, packaging instructions,
raw material and nished product specications and related SOPs.
• Issuance of Raw Material and Equipment used during manufacturing.
• Mixing time and mixer speed at different manufacturing steps.
• Temperature of vessel during mixing.
• The routine in-process control data and the critical parameters according to
the manufacturing formula and method (MFM)
•
Manufacturing and nal batch yield.
• Critical packaging parameters.
• Physicals, Chemical, and microbiological properties of the active ingredi-
ents for the nished product
Equipment Serial
Number
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75Protocol Generation
PROCEDURE AND PLANNED ACTIVITIES
• Dene the procedures to be used in the validation
• Dene planned activities in detail for the validation
docuMentation
Check the following in use documents before the start of process validation.
Raw Material Specications
Provide the raw material specications below in a similar fashion like above.
criticaL Process ParaMeters (ManufacturinG)
Formulation (Active/Inactive Ingredients)
Composition of Product
Documents Name and Title Reference No. Issue Date
• Manufacturing Formula and Method (MFM)
•
Master Packaging Instructions
Finished Product Specication
In-process Specication (Manufacturing)
In-process Specication (Packaging)
Planned Activity Responsibility
Manufacturing of Batches Manufacturing Department
Sampling from Blender/Tank/Bin Validation Specialist
Additional Sampling from line/Press Validation Specialist/QA
Testing of all samples Quality Control Department/Microbiology Department
Issuing nal Validation report Validation Specialist
Circulation of nal report for approvals Validation Specialist
Scale
Weight in
mg/tablet
Item
No.
Material’s Name Code Quantity/Batch
XXX kg
(100,000 tablet)
QC
Status
1 Active Pharma Ingredient
4 Lactose Monohydrate
5 Microcrystalline Cellulose
(Continued)
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76 Basics of Pharmaceutical Manufacturing and Quality Operations
Names of the raw materials in the list above are added as an example of any given
tablet based on the fact that most of the solid dosage forms have generally the same
excipients. However, the table is only to give an idea as to how to create the list of
materials for the protocol.
Issuance of Raw Materials
Re-check the quantities of all active and in-active raw materials for the following
three consecutive batches before the start of manufacturing.
7.2 Equipment Used
Check the following details of major equipment which are to be used during
manufacturing.
SrNo. Equipment Name Manufacturer’s Name IQ/OQ
Completion Date
Model Serial
No
1
2
3
4
Batch No. Issued On Observation
Scale
Weight in
mg/tablet
Item
No.
Material’s Name Code Quantity/Batch
XXX kg
(100,000 tablet)
QC
Status
6 Sodium Starch Glycolate
(Primojel)
7 Crospvidone (Kollidon CL)
8 Polysorbate 80 (Tween 80)
9 Iron Oxide Red
10 Magnesium Stereate
11 Puried water
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77Protocol Generation
Addition and Mixing
Check the dispersion of iron oxide red in puried water and mixing time and addition
of Tween 80, for the validation batches.
Check the quantity of granulating solution after preparation for the validation
batches.
Batch No Date Dispersion of Iron
Oxide
Mixing Time
Batch No Date Theoretical QTY of Granulating
Solution
Actual QTY of Granulating
Solution
Process Flow
Control Variables
Measured Responses
*Released by QC
Addition of Raw Materials
Active and Excipients
*Weighing / Sampling
*Warehouse / QA
Screen Type
Screen Size
*Granules Size
Distribution
Sizing
Sifter
Milling / Sieving
Mixing Mixing Time
*
*
*
*
Mixer Speed
Dry and Wet mixing
Addition of granulating fluid
D
rying
Oven / Fluid Bed
*Drying Time
*Drying Temperature
*LOD
*Moisture Content
Blending
*Blend Uniformity
*Flow Characteristics
*Load Size
*rpm
*Blending Time
Double Cone Blender / Tumbler
Addition of Raw Materials
Binders / Lubricants / Disintegrants
Compressing
High Speed Rotary Machine
*Compression Rate
*Granules Feed Rate
*Fill-O-Matic Speed
Packing
Automatic packing line *Packing line speed
*Weight Variation
*Friability
*Hardness
*Thickness
*Disintegration
*Attribute characteristics
Critical, Major, Minor
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78 Basics of Pharmaceutical Manufacturing and Quality Operations
Sieving and Dry Mixing
Check the process step of Avicel PH 101, Premojel, and Lactose monohydrate were
passed through a 500-micron sieve using the Russell sifter and then transferred to a
polyethylene bag for blending for the validation batches
Check the process step of Glimepiride and Lactose monohydrate were mixed
manually in polyethylene bag and passed through 500-micron sieve using Russell
sifter and transferred to polyethylene bag for blending for the validation batches
Check the process step of Iron oxide red and Lactose monohydrate mixing manu-
ally in polyethylene bag and passing through 500-micron sieve using Russell sifter
and transferring to polyethylene bag for blending for three validation batches.
Check the process step of manual mixing in polyethylene bag for 3minutes for
Avicel PH 101, Premojel, and Lactose monohydrate for the three validation batches.
Wet Granulation
Check the following process step of wet granulation.
1. The loading of the manually pre mixed material in Diosna granulator/FBD
from the polyethylene bag.
2. Mixing at speed 1 for 1minute.
3. Addition of granulating solution through a sample inlet and again mixing
with speed 1 for 1minute. Adding of additional quantity of water for the
validation batches
Batch No Date Sieve Size Observation
Batch No Date Sieve Size Observation
Batch No Date Sieve Size Observation
Batch No Date Time Limit
3 minutes
Observation
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