The document discusses process validation for pharmaceutical manufacturing. It provides details on validation master planning, organizing validation work, process characterization, validation protocols, qualification of facilities and equipment, and validation options like prospective, concurrent and retrospective validation. Specific processes like wet granulation, tableting and coating are also discussed with parameters to consider for validation.

1. VALIDATION
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.
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2. Planning for validation
Validation activities can be organized by preparing
the validation master plan (VMP). It should be brief,
concise and clear. The EEC guide recommends the
following contents in a VMP.
Validation Policy
Organizational structure of validation activities.
Summary of facilities, systems, equipment and
processes to be validated.
Documentation format
Planning and scheduling
Change control
Reference to exiting documents.
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3. Process validation work in a pharmaceutical industry
can be organized in one of the three structures;
The consultant
The task force
The dedicated group
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4. The consultant: The consultant are the group of persons
which are hired by the company for a specific job. They
can immediately review processes and present protocol
for validation.
They can take advantage of experience gained in other
companies to solve the problem in lesser time than the
company’s men.
They are not the permanent employees of the company
and it may be advantageous to the company.
If the validation job is not completed within agreed time
and costs, the company may be left with an incomplete
job.
The consultant should be hired after careful
consideration of time and money.
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5. The Task force:
The task force concept refers to an organization
approach in which persons from various divisions of
the company are selected and assigned validation
work. Usually persons from production, engineering,
quality assurance and validation work. These
persons meet as a committee. The head of this
committee, leader of the task force is the person
responsible for validation work and documentation.
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6. The major advantages of this structure are:
When the job is complete they can return back full
time to their previous assignments.
Some of the members of the task force can be
replaced with others depending upon the work to
be tackled.
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7. The Dedicated group
The dedicated group describes a set of persons
whose principle assignment is validation work. They
work autonomous. The advantage of this structure is
that this group is totally dedicated and responsible
for validation work. As such there is no conflict of
interest.
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8. Process characterization:
To find out critical process parameters, process
characterization and process ranging studies
should be carried out.
Methods used to find out the critical processing
steps and process control variables that affect the
quality and consistency of the product attributes
constitute process characterization.
Studies used to identify the critical process and
their respective control limits affecting the quality
and consistency of the product attributes
constitute process ranging.
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9. The process characterization techniques that may be
used to designate the critical unit operations in the
manufacturing process are:Cause and Effect or fishbone diagram: There may
exist different relationships and interrelationships
among various process variables (causes) and single
response or product attribute (effect). This can be
represented by a fishbone diagram.
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10. After having decided the structure of the team for
validation, it is advisable to make a list of categories
of the products that should be validated in order of
priority.
A list which may be used as guideline is given below.
Large volume Parenterals
Small volume parenterals
Ophthalmics and sterile solids.
Tablets and capsules
Oral liquids and topical.
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11. A fishbone diagram of the processing steps and inprocess variables during Tablet Manufacture is
given below.
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12. Branches of the central line represent the influence
of process steps. Process variables of process steps
have been represented by sub branches.
To find out the effect of the process variable, it is
varied in a measured way within operating ranges. If
there is no effect on final outcome, the input
variable is considered noncritical variable and that
which influence the final outcome are considered
critical.
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13. Rakesh Kumar Sharma
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14. Constraint analysis: Application of constraint
analysis makes evaluation and performance
qualification trials manageable.
In this constrain the number of process variables
and product attributes that require analysis,
similarly application of constrain analysis will also
limit and restrict the operational range of each
process variable and or the specification limits of
each product attribute.
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15. Information comes from the following source for
constraining process variables.
Previous experience with related product and
processes, processing equipment, etc.
In practice, pareto principle or 80-20 rule can be
used. The pareto rule states that about 80% of the
variation in the process output is caused by only
about 20% of all the input process variable.
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16. Validation protocol
After preparing VMP, the next step is to prepare
validation protocol. There are at least the following
contents in a validation protocol.
Purpose and scope of validation
Responsibilities and functioning of persons units
involved in the validation.
Type of validation to be conducted
Number of process validation runs.
Quality of materials used in the process
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17. Description of the process
All major equipment to be used, their IQ and OQ.
Critical process parameters and operating ranges.
Sampling plans
Specifications and test data to be collected.
Acceptance criteria to conclude that validation has
been successful.
Measures to be taken in the event of process
validation failure.
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18. Pre-requisites of Validation
(Facilities, Systems and Equipment)
Qualification is pre-requisite of validation. The
qualification includes the followings.
Design qualification [DQ]: In this qualification,
compliance of design with GMP should be
demonstrated.
The principles of design should such as to achieve
the objectives of GMP with regards to equipment.
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19. Installation qualification [IQ]: Installation
qualification should be carried out on new or
modified facilities, systems and equipment.
The following points should be included in the
installation qualification.
Checking of installation of equipment, piping,
service and instrumentation.
.
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20. Collecting of supplier’s operating working
instructions and maintenance and their calibration
requirement.
Verification of material(s) of construction
Source of spares and maintenance
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21. Operational qualification [OQ]:
OQ should follow IQ.
OQ should include the following
Test(s) developed from the knowledge of the
process(s), system(s) and equipment.
Defining lower and upper operating limits.
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22. Completion of OQ will result in finalization of
Calibration
Operating and cleaning procedure
Operator’s training
Maintance requirements
Formal release of the facilities, systems and
equipment.
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23. Performance Qualification [PQ]: After IQ and OQ
have been completed, the next qualification that
should be completed is PQ.
PQ should include the following
Test using production materials, substitutes or
simulated products.
These can be developed from the knowledge of the
process and facilities, system or equipment.
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24. Tests to include conditions(s) with upper and lower
limits.
It will be useful to discuss briefly process capability
design and testing and process qualification.
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25. VALIDATION OPTIONS
In the WHO text and EEC guide four options have
been recommended namely,
Prospective validation
Concurrent validation
Retrospective validation
Revalidation
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26. The process validation, normally, should be completed
prior to distribution and sale of finished dosage forms.
Such a validation is called prospective validation.
When the process is validated during routine production
of formulation. Such a validation is called concurrent
validation.
When the processes are well established and a number
of batches have been produced, such process may be
validated Retrospectively.
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27. Prospective Process validation
Prospective process validation should be carried
out only when the following operations and
procedures have been completed satisfactorily:It should be ensured that facilities and equipment
meet GMP’s requirements.
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28. The persons who will run the validation batches
should have understanding of the process and its
requirements.
Critical processing steps and process variables
should be identify using pilot laboratory batches.
Detailed technical information on the product and the
manufacturing process should be obtained.
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29. At least one qualification trial using pilot production
batch should be made to show that there were no
significant deviations from the expected performance
of the process.
Usually two or three pilot production batches are
prepared for validation. While preparing these
batches following points may be considered.
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30. Different lots of raw materials should be used.
Batches should be run in succession on different
days.
Batches should be manufactured in the equipment
and other facilities meant for commercial production.
Critical process variables should be set within their
upper and lower control limits during process
operation.
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31. Retrospective Validation
This option of validation is chosen for established
products and where prospective validation cannot be
justified for economic considerations and resource
limitations.
Following method can be used for retrospective
validation
Collect numerical values of in process data and end –
product testing result.
Organize these data in chronological order using
spread sheet formula.
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32. Include data from at least 20-30 batches for analysis
Reduce the number of data to be included in analysis
by eliminating test results from non-critical
processing steps
Subject the data to analysis and evaluation.
Draw conclusions as to the state of control of the
manufacturing process.
Issue a report of the findings
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33. Usually one or more of the following measured
responses are selected for statistical analysis.
For solid dosage forms
Assay result from uniformity test
Tablet hardness value
Tablet thickness value
Tablet/ capsule weight variation
Tablet/ capsule dissolution time
Tablet/ capsule disintegration time
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34. Concurrent validation
In-process monitoring of critical processing steps can
show that manufacturing process is in state of control.
Such a validation is called concurrent validation.
In-process tests that can be monitored in solid dosage
forms are:
Powder-blend uniformity
Moisture content
Granule size distribution
Content uniformity
Weight variation
Disintegration/ dissolution time
Hardness
Selection of in-process test parameters should be made
on the basis of the critical processing variables to be
evaluated.
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35. For semisolids and liquid dosage forms
pH values
viscosity
density
color
unit weight variation
average particle size
potency value
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36. Revalidation:
US FDA guidelines on general principles of Process
revalidation is recommended whenever there are
changes in critical component like packaging,
formulation
change in the facility, equipment, critical part of the
equipment
increase or decrease in batch size
Batch fail to conform product specifications for
example batch fail in uniformity test, dissolution test
etc.
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37. VALIDATION OF WET GRANULATION PROCESS
Wet granulation parameters to be considered
during development and validation are
Binder concentration and addition: The optimal
binder concentration will need to be determined
for the formulation. If the binder is to be sprayed,
the binder solution needs to be diluted enough so
that it can be pumped through the nozzle. It
should also be sufficiently concentrated to form
granules without overwetting the materials.
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38. Amount of binder solution: how much binder or
solvent solution is required to granulate the
materials?. Too much binder or solvent solution will
over wet the materials and prolong the drying time.
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39. Binder solution addition rate: Define the rate at
which the binder solution can be added to the
material.
Mixing time: How long the material should be
mixed to ensure proper formation of granules.
Over mixing the granulation can lead to harder
granules and a lower dissolution rate.
Granulation end point: How is the granulation end
point determined?
Is it controlled by specifying critical processing
parameters?.
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40. Does the wet granulation need to be milled to
break up the lumps and enhance drying of the
granulation?. Wet granules that have a wide
aggregate range can lead to inefficient drying.
Factors to consider are:
Equipment size and capacity: the mill should be
large enough to delump the entire batch within a
reasonable time period to minimize manufacturing
time and prevent the material from drying during
this operation.
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41. screen size: The screen needs to be small enough
to delump the material, but not too small to cause
excessive heating of the mill, resulting in drying of
the granulation.
Mill speed: The speed should be sufficient to
efficiency delump the material without straining the
equipment
Feed rate: the feed rate of the wet granulation is
interrelated to screen size and mill size and speed.
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42. Tablet compression
Compression is a critical step in the production of
tablet dosage forms. The material being
compressed will need to have adequate flow and
compression properties.
Factors to consider during compression are as
follows
Tooling: The shape, size and concavity of the
tooling should be examined.
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43. Compression speed and force: compression speed of
the tablet press is adjusted based on the flow rate of
the granulation, tablet weight required and tablet
hardness required.
The following in-process tests should be carried out
during the compression stage
Appearance, Hardness, tablet weight, friability,
disintegration, weight uniformity.
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44. TABLET COATING
Key area to consider for film coating of tablets
Tablet properties: tablet properties such as
hardness, shape are important to obtain good film
coated tablets.
Equipment type: the type of coater will need to be
selected. Conventional or perforated pan and fluid
bed coaters are potential options.
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45. Coater load: what is the acceptable tablet load range
of the equipment? Having too large a pan load could
cause attrition of the tablets. In case of fluid bed
coater, there may not be sufficient airflow to
fluidized the tablets.
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46. Pan speed: what is optimum pan speed?. This will
be interrelated to other coating parameters, such as
inlet temp, spray rate.
Spray guns: the number and types of guns should
be determined in order to efficiently coat the
tablets. The location and angle of the spray gun(s)
should be positioned to get adequate coverage.
Having the guns positioned too close together can
lead to the tablets to be overwet.
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47. Spray rate: the optimal spray rate should be
determined. Spraying too fast will cause the tablets
to become overwet, resulting in clumping of the
tablets. Spraying too slowly will cause the coating
materials to dry before adhesion to the tablets. This
will result in rough tablet surface.
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48. Inlet/outlet temperature: These parameters are
interrelated and should be set to ensure that the
atomized coating solution reaches the tablet
surface and then is quickly dried.
Coating solution: The concentration and viscosity
of the coating solution will need to be determined.
The solution will need to be sufficiently diluted in
order to spray the material on the tablets.
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49. Coating weight: a minimum and maximum
coating weight should be established for the
tablet.
Sufficient coating material should be applied
to the tablets to provide a uniform
appearance.
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50. Residual solvent level: if the organic solvent used
for tablet coating, the residual solvent level will
need to be determined.
In-process testing includes
Appearance, cracking or peeling of the coating
Color uniformity
Disintegration time
Tablet hardness.
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51. EQUIPMENT EVALUATION
In an ideal situation, the equipment used to
manufacture tablet dosage forms
would be selected based on such factors as
formulation, safety requirements,
handling/production efficiencies, and commercial
demands.
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52. MIXER/GRANULATOR
a. What is the method of mixing (e.g., planetary,
pneumatic)?
b. Is the equipment capable of providing low and/or
high shear to the material?
c. Can the mixing be varied (e.g., changing the rpm
of the impeller)?
d. Does the mixer/granulator have a monitoring
system (e.g., end
point detection) or can it accommodate one?
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53. e. What is the working load range and capacity of the
equipment?
f. How is material charged and discharged from the
unit? Is it manual, semi-automated, or automated?
g. Are there options to introduce the granulating
fluid (e.g., dump, meter, or spray)?
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54. DRYER
a. What is the operating principle of the dryer (e.g.,
direct heating—fluid bed, indirect conduction—tray,
or indirect radiant—microwave)?
b. Will the wet material be static (e.g., tray) or fluid
(e.g., fluid bed)?
c. What is the working load range and capacity of
the equipment?
d. What is the heating range and airflow capabilities
of the equipment?
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55. e. What is the heat distribution of the unit? Are there
any hot and/ or cold spots?
f. Can the unit pull a vacuum? What is the vacuum
range of the unit?
g. Can the equipment handle different types of filter
bags? For example, can a filter bag be dedicated to a
particular product?
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56. TABLET COMPRESSION MACHINE
a. How many compression stations does the
compressor have?
b. What is the operating range (rpm) of the unit?
c. What is the output range of the compressor (e.g.,
tablets per min)?
Will the unit meet the demands (sales forecast) for
the product?
d. What kind of powder feeding capabilities does
the equipment
have (e.g., gravity, power-assisted, or centrifugal)?
Can this capability
be altered or controlled (e.g., open feed frame,
forced below
feeder)?
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57. e. What is the compression force range of the
equipment?
f. Is the equipment capable of monitoring
compression and ejection
force?
g. Does the unit have precompression capabilities?
h. How long can the equipment operate without
routine maintenance?
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58. TABLET COATER
a. What is the coater type (e.g., pan or fluid bed)?
b. Is the pan perforated?
c. Can the coater accommodate different size pans?
d. What is the working capacity range of the coater
(i.e., pan load)?
e. Does the pan coater have a ―variable drive‖
capability? This maybe needed to achieve proper
tablet mixing in the pan so that the coating solution
is applied uniformly to the tablets.
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59. f. Can the angle of the pan’s pitch be varied?
g. What kind of air input (volume and temperature)
and vacuum drag-off is required for optimal
operation of the coater? These utility requirements
may exceed the capacities available in the plant.
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60. h. What type of spray system can be used with the
equipment?
i. What is the shape of the coating pan (e.g., oval,
mushroom, round)? The shape characteristic will
affect the degree of agitation and the direction of
tablet flow in the pan. The spray nozzle configuration
will have to be designed to ensure adequate spray
coverage over the tablet bed.
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61. j. Is it possible to utilize the equipment for sugar
coating as well as
film coating? Certainly, if this were possible, capital
expenditures would be reduced.
k. Is it possible to modify the pan with the
installation of baffles?
Baffles may be needed to ensure good tablet
movement in the pan.
l. Can various solvents (ethanol) be used in the
equipment?
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62. THANKS
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