Elsanhouty Pharma Notes, Cairo, Egypt.

Standard Operating Procedure

Title: process validation

1. PURPOSE
1.1. The purpose of this procedure is to provide a high degree of assurance of meeting all the predefined
attributes and the process is capable of consistently delivering a quality product.
1.2. To lay down a procedure for minimum requirement for validation or revalidation of manufacturing
process applicable to marketed drug products in order to provide documented evidence that each
specific process will consistently yield a product meeting all quality and design specifications.

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2. SCOPE
2.1. This process validation protocol is applicable to carry out process validation of Name of the Product
for first three consecutive commercial batches in view of the requirements of Name of market at
formulation Plant of Pharmaceutical Company.
2.2. Process validation may be prospective, retrospective (Obsoleted) or concurrent and is based
on assumption that equipment has been completed prior to commencing process validation for
any product.

3. RESBONSIBLITIES

3.1. Validation-Quality Assurance department

3.1.1. To prepare validation protocol.

3.1.2. To ensure the activities to be followed as per the approved protocol.

3.1.3. To withdraw the sample as per sampling plan mentioned in validation protocol..

3.1.4. To prepare the validation report

3.1.5. Collection of process validation sample.

3.1.6. To approve the protocol.

3.1.7. To review and approve the validation report.

3.1.8. To organize the training and impart the training before validation.

3.2. Quality Control department

3.2.1. To analyze the samples.

3.2.2. To review the protocol

3.2.3. To check the result of the analysis.

3.2.4. Responsible for interpreting the results obtained and maintaining the raw data.

3.2.5. Provide the data for the process validation report to Quality Assurance Dept.

3.3. Production department

3.3.1. To review validation protocol & report and organize the activity.

3.3.2. Execute the manufacturing of the batches along with Research & Development.

3.4. Engineering department

3.4.1. To review the protocol and provide the required services.

3.4.2. Responsible for preventive maintenance and calibration of equipment and

instruments respectively.

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3.5. R&D department

3.5.1. Responsible for change of formula / process / specification based on validation

results, if required.

4. PROCESS VALIDATION STAGES

4.1. Stage 1 – Process Design:

 The commercial manufacturing process is defined during this stage based on knowledge
gained through development and scale-up activities.

 The goal of this stage is to design a process suitable for routine commercial manufacturing
that can consistently deliver a product that meets the majority of its quality attributes of
activities related to stage -1 shall be performed.

4.2. Stage 2 – Process Qualification: During this stage, the process design is evaluated to
determine if the process is capable of reproducible commercial manufacturing.
4.2.1. This stage shall be done in two parts:

 Design of the facility and Qualification of the equipment and utilities:

 Qualification of utilities and equipment shall be covered under individual plans or as part of
an overall project plan.

 The details of the same shall be mention in the Protocol.

 Qualification activities must be completed prior to the start-up of the Process Performance
Qualification (PPQ) stage.

 The suitability of equipment and utilities must be documented in accordance with the
process requirements in all the anticipated operating ranges.

 Process Performance Qualification:

 During stage 2 and onward, cGMP compliance must be followed.

 Successful completion of stage 2 is necessary before commercial distribution.

 Need of training shall be assessed prior to the start-up of process performance qualification
batches.

 During this stage, the process design is evaluated to determine if the process is capable of
consistently manufacturing the product meeting predetermined acceptance criteria.

 Process for new as well as existing products shall be qualified.

 Process qualification shall run according to approved protocol detailing sampling, timing,
location, procedures along with analytical tests and acceptance criteria.

 Three batches of commercial batch size shall be taken for qualification in accordance to the
Process Qualification protocol and batch manufacturing record.
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4.3. Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine
production that the process remains in a state of control.

4.3.1. During this stage, continuous monitoring of process parameters and quality attributes at
the level established during the process validation stage shall be done.

4.3.2. This stage is applicable for Existing Products, Site Transfer Products, and New Products.

5. DEFINITIONS

5.1. Process validation: The collection and evaluation of data, from the process design stage
through commercial production, which establishes scientific evidence that a process is capable
of consistently delivering quality products.

5.2. State of control: A condition in which the set of controls consistently provides assurance of
continued process performance and product quality.

5.3. Performance indicators: Measurable values used to quantify quality objectives to reflect the
performance of an organization, process or system, also known as performance metrics in
some regions.

5.4. Process design: Defining the commercial manufacturing process based on knowledge gained
through development and scale-up activities.

5.5. Concurrent release: Releasing for distribution a lot of finished product, manufactured following
a qualification protocol, that meets the lot release criteria established in the protocol, but before
the entire study protocol has been executed.

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5.6. Capability of a process: Ability of a process to produce a product that will fulfill the
requirements of that product. The concept of process capability can also be defined in statistical
terms.

5.7. Continued process verification: Assuring that during routine production the process remains
in a state of control.

5.8. Process qualification: Confirming that the manufacturing process as designed is capable of
reproducible commercial manufacturing.

5.9. At-line: Measurement where the sample is removed, isolated from, and analyzed in close
proximity to the process stream.

5.10. In-line: Measurement where the sample is not removed from the process stream: can be
invasive or non-invasive.

5.11. Online: Measurement where the sample is diverted from the manufacturing process, and may
be returned to the process stream.

5.12. Life-cycle: All phases in the life of a product from the initial development through marketing
until the product’s discontinuation.

5.13. Critical process parameter (CPP): A process parameter whose variability has an impact on a
critical quality attribute and therefore should be monitored and/or controlled to ensure the
process produces the desired quality.

5.14. Critical quality attributes (CQA): A physical, chemical, biological or microbiological property or
characteristic of materials or products that should be within an appropriate limit, range or
distribution to ensure the desired product quality.

5.15. Quality target product profile (QTPP): A prospectively documented summary of the quality
characteristics of a finished pharmaceutical product (FPP) that ideally will be achieved to ensure
the desired quality, taking into account safety and efficacy of the FPP.

The QTPP forms the basis of design for the development of the product and typically would
include:

A. Intended use in a clinical setting, route of administration, dosage form, delivery

systems.
B. Dosage strength(s).
C. Container-closure system.
D. Therapeutic moiety release or delivery and attributes affecting pharmacokinetic
characteristics (e.g. dissolution) appropriate to the FPP dosage form being developed;

E. FPP quality criteria (e.g. sterility, purity, stability and drug release) appropriate for the
intended marketed product.

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6. PROCESS VALIDATION PREREQUESTS

6.1. Qualify the Manufacturing Equipment and utilities to meet cGMP requirements.

6.2. Qualification of Utilities to be used in manufacture of the product (example – purified water,
compressed air, HVAC system etc.) .

6.3. Calibrate the Instruments used in processing (example – weighing balance. vernier calipers,
hardness tester etc.).

6.4. Validate the Analytical methods for in process testing and finished product analysis.

6.5. Train appropriately the personnel involved in manufacturing and testing of process
validation batches.

7. PROCEDURE
 Draw up a detailed flow chart of the process to be validated with each major and minor stage
being differentiated (incorporate sub-stages, if required in the event of any major stage).

 Define the critical factors/operations, which assure the reliability of the process.

 Prepare a written validation protocol for each critical operation/stages for any related
minor operation/stage.

 Run the test as per the written protocols and under conditions conforming to the actual
production condition.

 Verify the performance of the critical factors by evaluation of data for conformance to
specifications.

 Interpret the results and in case the process performs as per the predetermined specification.
Consider the process validated.

 For non-confirming validation data, critically scrutinize the data collected, recommend the
corrective actions and revalidate the process.

 File the completed validated document of the process along with the test results of analysis and
interpretation confirming its satisfactory performance in a master file for validation of the process
along with such other data like stability studies for the process or product.

 if there is no change in lot size at Granulation stage and only number of lots increased, perform
the process validation of only blending operation and decide the extent of validation study of
other stages based on the risk/impact assessment.

 if a product is manufactured as 10 mg, 20 mg and 40 mg by a common blend, Then the process

validation can include validation up to blend stage with three batches of common blend and
validation of subsequent unit processes like compression, coating etc. with three batches each
strength, In such cases number of batches of different strength may reduce (Bracketing) with

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 appropriate justification and necessary approval from Customer / Regulatory agency.

 Collect the samples as per sampling plan defined in the process validation protocol & tested in
QC and process validation team shall obtain the results to compiled for evaluation by the
process validation team.

 The variations in the critical process parameters in lot to lot/batch to batch shall justify with
scientific logic and shall capture in batch manufacturing record as well as process validation.

 At compression stage Challenge study performs like hopper study, speed study.

 Variability within a validation batch shall assess by QA by comparing the results of samples
drawn from various locations / different intervals using the Relative Standard Deviation criteria
pre-defined in the protocol.

 Release the process validation batches for distribution after Successful completion of process
validation activity and review, approval and signing off the process validation interim report with
supporting raw data and ensure no impact on product quality prior to release of each PV batch

 Revalidation of process may occurred due to the following cases:

a. In case of any change in facility.

b. In case of any change in manufacturing equipment.

c. Change in batch size.

d. Every five years (based on trending stabilization status)if no change in process,

equipment’s, raw materials and composition

e. Based on associated risk and impact analysis the extent of process validation
shall decide which may include the entire process that is impacted.

f. Changes in the master formula, methods, starting material manufacturer,

starting material manufacturing process, excipient manufacturer, and excipient
manufacturing process.

g. Changes associated with equipment calibrations and the preventive maintenance carried out,
which may impact the process.

h. Changes to standard operating procedures.

i. Changes in the manufacturing process (e.g. mixing times, drying temperatures).

j. Production area and support system changes (e.g.re arrangement of areas or a new water-
treatment method)

k. Unexpected changes (e.g. those observed during self-inspection or during routine analysis of
process trend data).

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 For introduction of a New product in the facility:

 Initiate a permanent change control by the user department and approved as per SOP for
Change Control Process.

 After assessment of all the possible impacts. Initiate the manufacturing of PV batch along with
simultaneously the risk assessment report

 Take initial three consecutive batches of new product for PV.

 Identify all the critical process parameters in the protocol for the particular product.

 Example on critical process parameter :

Sr.
Process step Process Parameter to be validated
No.
Sieve Size
1. Sifting & Milling Screen size
Milling speed
Impeller/chopper Speed
2. Dry Mixing
Mixing Time
Binder addition time
Impeller/chopper Speed

3. Wet Granulation Granulation end time

Granulation Time

Ampere load.
Inlet Temperature/RH

Outlet Temperature/RH

4. Drying Air flow

LOD

Total Drying Time

Screen Size

5. Dry Milling & Sifting Milling speed

Sieve Size
Lubrication Load
6. Lubrication RPM of Blend
Mixing Time

7. Compression Compaction main,pre Force

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 Feeder speed

Compression speed

Turret RPM

Inlet Temperature

Outlet Temperature

8. Coating Air flow

Spray rate

Pan RPM
9.
Temperature of Sealing roller

Packing Temperature of Forming roller

Machine Speed

 Example for sapling plan

Sr.
Stage Test parameter Number of Location Sample Quantity
No.
T1, T2, M1, M2, B1 1-3 gm each sample &
& B2. LOD perform on
1 Drying LOD
(One Composite composite sample
sample) (3.0 gm)
Bulk density
Tapped density Top, Middle &
Hausner ratio Bottom
2 Lubrication ………. gm
compressibility index (One Composite
Sieve Analysis Sample)
Blend uniformity
Weight variation
Full Hopper, Half
Compression Hardness No. of stations+5
Hopper & Low Hopper.
A)Hopper study Assay Tablets/sample
(LHS/RHS)
Thickness
Thickness
…..Tablets/sample
3 Diameter (No. of stations+5 Tablets
Disintegration
(High speed, Optimum for Wt. Variation,
B) Speed study Uniformity of dosage
speed & Low speed Hardness & Thickness
form (LHS/RHS) …Tablets for friability
Dissolution 06 Tablets
Friability
for Disintegration)
(One Composite
4 Coating Complete Analysis ….. tablets
Sample)

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8. PROCESS VALIDATION PARAMETERS CLASSIFICATION

9. DEVIATION

9.1. If any deviation or incident observed in the process qualification batches shall be discussed
and resolved as per SOP and shall be recorded in the process qualification report.

10. CHANGE CONTROL

10.1. If any change observed in the process qualification batches shall be allowed only through
Change control Management procedure and shall be recorded in the process qualification
report.

10.2. Change control not required for indicative parameter.

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