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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5737_Библиотеки_им_академика_М_И_Перельмана
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79Protocol Generation
Drying of Granules and Loss on Drying
Check the process step drying of granules in a Lytzen Dryer/Aeromatic Flow bed
dryer at 55°C for rst 3 hours, scraping the semi-dried material and further drying for
3 hours at 55°C, further drying to obtain the target LOD, for the validation batches.
LOD Checking
Check the LOD at 80°C (limits 0.7%–1.0%) for the validation batches.
Check the process step grinding of dried granules and passing through a 1.0 mm
sieve in Frewitt Granulator at medium speed and collecting of granules in polyethyl-
ene bag for the validation batches.
Lubrication
Check the process step of Primojel, Kollidon CL, and Magnesium Stearate sifting
through 500-micron SS sieve and nally mixing for 5minutes manually for the vali-
dation batches
Batch No Date 1st Drying 2nd Drying Additional
Drying
Batch No Date LOD
Temperature
LOD Limits Results
Batch No Date Sieve Size Observation
Batch
No
Date Loading of Material
in Granulator
Observation
1st Mixing
Time
1 minute
2nd Mixing
Time
1 minute
3rd Mixing
Time
1 minute
Additional
Water QTY
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80 Basics of Pharmaceutical Manufacturing and Quality Operations
Checked the nal yield calculation of Granules for the validation batches.
Compression of Tablets
Check the process step of compression using the Rotary compression machine for
validation batches.
The numbers given in the specications are imaginary based on any given
tablet and are only to provide an idea to the readers.
Uniformity of Weight
Weight variation Batch #
Target weight: xxx mg
Lower Limit weight: xxx mg
Upper Limit weight: xxx mg
Batch No Date Theoretical Batch
weight
Actual Batch
weight
% Yield
Test Specication Results
Batch No’s
Weight of tablet
xxx mg ± 3.0%
Thickness
2.4 ± 3.0 mm
Hardness NLT 7–13 kp
Disintegration time NMT 10minutes
Batch No Date Sieve Size Observation
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81Protocol Generation
CRITICAL PROCESS PARAMETERS (PACKAGING)
bListerinG
During blistering in-process checks will be carried out for empty pocket, empty blis-
ter strip, improper sealing, leak test (10 blister), and defective tablets randomly on 32
blisters for the validation batches and results will be recorded in batch documents.
Batch No Date Empty
Pocket
Empty
Blister
Improper
Sealing
Leak Test Defective
Tablets
Time
Weight
1
2
3
4
5
6
7
8
9
10
Max
Min
Average
Range
S.D.
RSD
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82 Basics of Pharmaceutical Manufacturing and Quality Operations
FINAL PACKING RECORD (INSPECTION)
criticaL, Major, and Minor defects (soP 123)
SUMMARY OF RESULTS
resuLts data tabLe
Add rows in the table below as per the number of samples which would depend on
the size of a blender or container, the samples are collected from.
Attribute AQL Acceptance
Criteria
Sample Size
Cumulative
(Code)
Total Rejected
Samples
Batches Numbers
Critical Defects (AQL 0)
Wrong commodity 0.0%
Wrong Batch No 0.0%
Wrong Expiry 0.0%
Wrong Manufacturing 0.0%
Wrong Special stamping 0.0%
Incorrect No of unites in C. Carton 0.0%
Foreign Material 0.0%
Empty unites 0.0%
Major Defects (AQL 1.0%)
Missing component 1.0%
Illegible B.No 1.0%
Illegible Mfg. Date 1.0%
Illegible Exp. Date 1.0%
Other
Minor Defects (AQL 2.5%)
Loose or torn labels/Carton/Box 2.5%
Double labels 2.5%
Printing Smeared Partly 2.5%
Crooked label 2.5%
Excessive Shrinkage label 2.5%
others
TO TA L
Pass/Fail
Conducted by Date:
Reviewed by Date:
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83Protocol Generation
9.2 resuLts data tabLe
Tablet API–Assay
Specication:
a
1.0mg/tablet (Limit:90.0%–105.0% of L.A)
Batch Nº Assay‑1.0mg/tablet % Assay Value
Maximum
Minimum
Range
Average
S.D
RSD
Acceptance Criteria All individual values within 90.0%–105.0% of theoretical value of
active ingredient and RSD for samples should be Less than 6%.
Comments:
Pass/Fail
Reference:
Conducted by Date
Reviewed by QC Manager Date
a
The strength is imaginary and only to provide an idea to the readers.
Related Substances
Specication:
a. Tablet API Related Compound B: NMT 2.5%
b. Any other individual impurity: NMT 0.5%
c. Total impurities excluding Tablet API Related Compound B: NMT 1.0%
d. Over all Total impurities: NMT 3.5%
Batch Nº a) b) c) d)
Maximum
Minimum
Range
(Continued)
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84 Basics of Pharmaceutical Manufacturing and Quality Operations
RESULT DATA TABLE (MICROBIAL ANALYSIS)
Specication: Microbial Limits
1 TAMC: NMT 100 cfu/gm
2 Fungi: NMT 10 cfu/gm
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
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:
Pass/Fail
Reference:
Conducted by Date
Reviewed by
QC Manager
Date
Acceptance Criteria All individual value for validation Batches
samples should be within specication.
Comments:
Pass/Fail
Reference:
Conducted by Date
Reviewed by QA Manager Date
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85Protocol Generation
FINAL BATCH YIELD
Check the nal batch yield for the following validation batches.
RISK ANALYSIS
OBSERVATION
Observation should be recorded during the validation process of the mentioned
product
Batch
No
Batch
Size
Target wt. of Tablets
Limit: xxx mg
Theoretical Number
of Tablets per Batch
Actual Number of
Tablets per Batch
Yield
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
Blistering/Box Packing 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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86 Basics of Pharmaceutical Manufacturing and Quality Operations
FINAL REPORT
Validation department will complete and review the nal Validation report, declar-
ing the successful completion of validation of product name. This nal report will
be reviewed and approved by the heads or manager of Validation and Production and
the director of Quality Assurance as a minimum.
This section deals with the conclusion of the validation results and the discussion.
This section also contains the recommendations of the validation committee.
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7. 2
Sampling and Testing Plan
In the process validation, sampling and testing plans must be developed to consider
the specic attributes being measured and the risks associated with accepting a
defective lot.
A sample is a portion of a material collected according to a dened sampling
procedure. The size of a sample should be sufcient to allow all anticipated test pro-
cedures to be carried out including all repetitions and retention samples.
The Validation Protocol must have predetermined sampling plans and methods.
The sampling procedures documented in the protocol should provide sample loca-
tions, sample size, and sample frequency and should also include the tests or assess-
ments required. Samples must be representative of the population and the sampling
plan should be designed in a way so that any segregation during blending and mixing,
transport or handling could be determined. Besides, the sampling plan may also be
able to assess any variability or other factors that might impact production consis-
tency. The need to show the homogeneity of intermediates should be considered on a
case-by-case basis depending on how the intermediate is used in subsequent process-
ing. In general, studying the homogeneity of an intermediate is of less importance
than that of a nal product, especially if the intermediate will be further processed
in the next or nal step of the process. However, in case the intermediate is critical to
the quality of the nal product prepared from it, ensuring that the blend homogeneity
of the intermediate must be considered in the sampling plan.
SAMPLING LOCATIONS
Equipment structure, shape, and dimensions should be taken into consideration
when establishing sampling locations. Blend uniformity samples should be collected
directly from the blender immediately prior to discharge. It is generally considered
that a blend uniformity sampling from tumble blending should be carried out from,
at least ten locations in the blender. These locations should be chosen to represent
potential areas of poor blending. At minimum samples should be selected from at
least two depths along the axis of the blender.
Similarly, for ribbon blending, a minimum of 20locations in the blender should
be sampled and chosen to adequately address probable dead spots especially in the
corners and discharge areas. Samples may also be taken from discharge stream or
storage containers like drums and bins in case it is not possible to collect samples
from the blender. At least three replicate samples will be taken from each location
with one samples tested per location.
Blend uniformity acceptance criteria: RSD
= 5.0% and all individuals are within
the mean ± 10% (absolute).
87
DOI: 10.1201/9781003366393-9
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88 Basics of Pharmaceutical Manufacturing and Quality Operations
FINISHED PRODUCT SAMPLING
The nished product sampling quantity and sample numbers for each validation
study should be based on risk. For example, a new formulation may carry signi-
cantly higher risks to the patient. In such a case, the following rules should be con-
sidered at minimum for lling/packaging sampling:
• Beginning of Filling: Logically the rst ten samples should be collected and
tested as “Beginning samples”.
•
Middle: During the entire lling process, samples should be collected at a
frequency established in the protocol as per the process run and then ten
samples collected from the entire pool to create the “Middle samples”.
• End: Like the rst ten packages, the last ten packages just before the end of
lling should be collected as the “End samples”.
In addition, if there are critical incidences during the packaging run which may affect
the product, then sampling at start-up immediately following such an event should
also be considered. The rationale behind collection and/or testing of these samples
should be outlined in the protocol.
saMPLinG after a chanGe in raW MateriaL source
A change in the supplier or manufacturer of a raw material is critical and must be
assessed for the impact on product’s quality. Based on the assessment, decision is
made if the change (made to an active or excipient in a formulation) requires reval-
idation. The sampling requirement for the revalidation will be based on risk and
documented in the Raw Material Evaluation Report.
For the products where routine blend testing is not performed, there must be an impact
assessment made on blend uniformity and the requirements of the blend specication.
It may be a good idea to conduct additional monitoring and testing during or post
validation batches of those products. This should also be documented in the valida-
tion protocol.
PROCESS AND EQUIPMENT CHANGE
A similar strategy, as mentioned above, needs to be carried out in case of a change in
the process and/or equipment. Each process or equipment change should be addressed
individually and the validation requirements must be documented in the protocol.
Sampling and testing should be based on risk. For those products where routine
blend testing is not performed, an assessment of the impact on blend uniformity and
the requirements of the blend specication should be performed. Additional monitor-
ing and testing during or post validation batches may be required.
Specication testing of the extremes of the spread will allow full characterization
of the content uniformity. Batch release testing will be performed as per specica-
tion test requirements and must be included in the validation report. A validation
batch using QC reductive testing must meetall QC reductive test requirements for
the validation samples and specication requirements for the release of sale samples.
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