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109Process Validation Report Writing
Samples collected at the frequent interval will be tested for dissolution assay
and results will be tabulated in the table above for all three validation batches. Any
anomaly will be discussed and rationalized in the report if required.
Time 9.00 10.00 11.00 12.00 13.00 14.00
Assay
1
2
3
4
5
6
7
8
9
10
Max
Min
Average
Range
S.D
RSD
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110 Basics of Pharmaceutical Manufacturing and Quality Operations
9.2 resuLts data tabLe
Sulfonamide is one of the related substances that could be found in the products
and is given here as an example only.
Related Substances
Specication:
a. API: NMT 0.4% d. Any unspecied individual: NMT 0.1%
b. API Urethane: NMT 0.1% e. Total excluding Sulfonamide: NMT 0.2%
c. API-3-Isomer: NMT 0.2%
Batch No. a. b. c. d. e.
002
003
004
Maximum
Minimum
Range
Acceptance Criteria All individual value for validation Batch samples should be within
specication.
Comments: All result meet Finished product specication and acceptance criteria.
Pass/Fail Pass
Compiled by Date
Reviewed by
QA Manager
Date
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111Process Validation Report Writing
9.3 resuLt data tabLe (MicrobiaL anaLysis)
Specication: Microbial Limits
1. TAMC: NMT 100 cfu/g
2. Fungi: NMT 10 cfu/g
Pathogen: Absence of Pseudomonas aeruginosa
Absence of Staphylococcus aureus
Batch No.
Results
TAMC Fungi
Absence
of E. coli
Absence of
Pseudomonas
aeruginosa
Absence of
Staphylococcus
aureus
001
< 10 cfu/g < 10 cfu/g
Absent Absent Absent
002
< 10 cfu/g < 10 cfu/g
Absent Absent Absent
003
< 10 cfu/g < 10 cfu/g
Absent Absent Absent
Acceptance
Criteria
Total aerobic microbial count should be LT 100 cfu/g, Fungi LT 10 cfu/g
Pathogen: Absence of E. coli, Pseudomonas aeruginosa, and Staphylococcus
aureus
Comments: All Results Conforms Finished product specication.
Pass/Fail PASS
Compiled by Date
Reviewed by
QA Manager
Date
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112 Basics of Pharmaceutical Manufacturing and Quality Operations
10 FINAL BATCH YIELD
Final batch yield was checked and calculated on the basis of BPR for the following
two batches and found to be unsatisfactory the investigation report and other details
available in the batch documents.
Batch
No.
Batch
Size
Target wt of
Tablets
Limit:.140 mg
SOP 123
Theoretical
Number of
Tablets per
batch
Actual
Number
of Tablets
per batch Yield
001 140.0 mg 100,000 97,000 97.0%
002 140.0
mg 100,000 97,500 97.5%
003 140.0 mg 100,000 95,700 95.70%
All the numbers given in the table above for target weights or number of
tablets are not specic to any product but are presented as an example for the
readers
11 RISK ANALYSIS
12
COMPLIANCE TO FINISHED PRODUCT SPECIFICATION
Final laboratory test results were in compliance to nished product specication,
reported in the following table for the validation batches. Detailed reports attached
with the batch documents.
Critical Process Steps Possible Risk
Critical/Not
Critical
Kind and Content
of Control
During Manufacturing
Blending time Unevenness Critical Visual display
Blending speed Unevenness Critical Visual display
Compression Defectives (Chipping,
Capping Sticking, etc.)
Critical Visual
Manufacturing yield Less productivity Not critical Batch documents
Determination of assay Inferior or higher content
of drug substance
Critical Assay
During Blistering and Packing
Tube lling Less count
May cause complaint
Critical In-process checks
every 1 hour
Critical, Major, Minor
defects
May cause complaint Critical In-process checks
every 1
hour
Printing of batch no.
mfg. and expiry date
May cause complaint Critical In-process checks
every 1 hour
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115Process Validation Report Writing
13 OBSERVATION
The manufacturing and packaging processes were reviewed during the processes
running and were found within the parameters for the validation batches.
The physical parameters such as appearance, color, and consistency, and results
obtained from the QC samples for these validation batches also found within speci-
ed limits.
The results obtained for the assay of active pharmaceutical ingredient of these
batches also show that a quality product was produced.
14 CONCLUSION
The prospective validation study was performed on three consecutive batches of
xyz 1 mg Tablets which were successfully manufactured in ABC Pharmaceutical
industries.
Summarizing the results obtained during the validation for xyz 1
mg Tablets, it
was concluded that:
All three validation batches for xyz 1 mg Tablets meet critical quality attributes
predetermined in acceptance criteria as specied in the nished product specication.
According to the analytical results all of the criteria have been met and the pro-
cess for xyz 1 mg Tablets is considered validated.
15 REVALIDATION
The production process of xyz 1 mg Tablets shall be revalidated if any critical change
which can affect the quality of nal product is made. The change could be but not
limited to:
• Active ingredient supplier
• Mixing time
• Introducing a new equipment
• Primary packaging material
QUESTIONS AND ANSWERS
1. What is a process validation report?
Answer: The process validation report is a document which demonstrates
evidence that a manufacturing process is capable of consistently delivering
quality products. It provides proper documentation of process validation
protocols. Process validation reports are generally completed before the
routine commercial production for a new product.
2. What is the best time to publish the process validation report?
Answer: Process validation reports are generally completed before the rou-
tine commercial production for a new product.
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116 Basics of Pharmaceutical Manufacturing and Quality Operations
3. What are the contents of a validation report in general?
Answer: The validation report generally contains an executive summary
listing the most prominent results of the validation. A short introduction
stating who produced it, when, and for what purpose. The process valida-
tion report also includes the details of the materials used with the batch
numbers, the equipment with the ID numbers, and the personnel who car-
ried out the processes with their training records ensuring that the process
controls were performed by experienced operators. The raw data are further
discussed in the report.
4. Is there a need to report anomalies that happened during the validation
study, in the validation report?
Answer: If there has been any anomaly during the validation study, it is
important to address it in the report with the details of investigations carried
out as well as the outcome of the investigation and corrective and preventa-
tive actions taken.
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8
Cleaning Validation
Cleaning validation is a procedure used to assure that cleaning processes for manu-
facturing equipment remove chemical and microbial residues of the active, inactive,
or detergent ingredients of the product manufactured from the equipment and pre-
vents product contamination.
Health regulatory bodies and inspectors expect pharmaceutical industries to have
cleaning validation master plan to describe in detail the approach that the company
will be utilizing in cleaning the manufacturing equipment between the batches of the
same products and between different products. A written standard operating proce-
dure (SOP) detailing the cleaning processes used for various pieces of equipment is
also signicant.
There are two basic principles in all cleaning processes:
1. pH
2. Physical removal
The best approach is physical removal that helps in removing the microbial con-
tamination. Physical removal also lessens the numbers of pathogens from all surfaces
as well as removes the food sources from the equipment surface that aide in their
growth.
CLEANING VALIDATION MASTER PLAN
The Validation Master Plan is a document that includes systems, equipment, meth-
ods, facilities, etc., which are in the scope of the plan and the current validation
status for the systems within the project scope. The master plan explains compliance
requirements for validation, including how the validated state will be maintained.
The plan also includes a matrix according to which the cleaning procedures will be
validated. Once a new product or a new manufacturing equipment is introduced, the
matrix is updated to include the new product/process if required.
cLeaninG ProGraM norMs
The cleaning procedures used in a facility can uncover important factors regard-
ing process control, process reproducibility, sample collection procedures, and ways
of monitoring the efcacy of cleaning procedures to rst characterize the types of
cleaning that are used in the facility. Cleaning methods used in the facility can tell
us about the factors related to process reproducibility, process control, how to chal-
lenge the process, how to collect samples, and the best ways of monitoring cleaning
efcacy during cleaning.
117DOI: 10.1201/9781003366393-11
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118 Basics of Pharmaceutical Manufacturing and Quality Operations
CLEANING METHODS
autoMated and ManuaL cLeaninG
There are two types of cleaning methods. Automated and manual. Manual clean-
ing is a normal practice in the pharmaceutical industry, yet the use of automated
cleaning usually provides reproducible results. The automated system is validated
by challenging the procedure and the cleaning cycle is proved to be rugged which
provides reproducible results. Sometimes the design and construction of equipment
make manual cleaning a necessity. Ruggedness of the method can also be given
emphasis in manual cleaning; however, reproducibility depends on strict adherence
to the cleaning procedures.
cLean in PLace and cLean out of PLace
The Clean in Place (CIP) system involves the cleaning of large pieces of equipment at
its permanent location in a conguration very similar to that utilized for production.
The process is quite similar to automated cleaning, where the control system also
becomes part of cleaning validation. On the other hand, smaller equipment may be
transported to a designated wash area where cleaning is performed. This practice is
known as clean out of place (COP).
However, using automated wash systems for COP reduces the differences between
CIP and COP to a signicant extent, mainly due to the reproducibility of the results.
EQUIPMENT
dedicated and non‑dedicated eQuiPMent
In pharmaceutical industries, dedicated equipment is used for the production of only
a single product. This practice markedly reduces the chances of cross-contamination.
Where the same equipment is used for the production of a range of products, the
prevention of cross-contamination between products becomes the main challenge in
the cleaning validation efforts.
The cleaning of dedicated and non-dedicated equipment also gives rise to con-
cerns. CIP systems are often used for more than one tank in a facility. Special care
needs to be taken in designing CIP systems. By using appropriate valving and back-
ow prevention, cross-contamination can be prevented. Similarly, any circulation
within the CIP system should be constructed carefully and monitored closely during
routine cleaning.
Minor and Major eQuiPMent
Major equipment represents those that play a central role in production processes.
Typically, the cleaning of major equipment will be the subject of specic SOPs, and it
is important to differentiate those pieces of equipment that are central to the produc-
tion process from those that play a secondary role (utensils). Material of construction
should be of signicant importance when establishing a cleaning validation program.
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