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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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99Process Validation Report Writing
7.3 ManufacturinG Process
7. 3 .1 Process Flow, Variables and Responses for Tablet Products
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
7. 3 . 2 Addition and Mixing
Sieving and Dry Mixing
7.3.2.1 Avicel pH 101, Primojel, and Lactose monohydrate passed through a 630 μm
sieve using Russel sifter and transferred to a polyethylene bag for blending. This
process step was checked in the batch document and was found satisfactory for the
following three validation batches
Batch No. Date Sieve Size Observation
001 630 μm Satisfactory
002
630 μm
Satisfactory
003
630 μm
Satisfactory
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100 Basics of Pharmaceutical Manufacturing and Quality Operations
7.3.2.2 API and Lactose monohydrate were mixed manually in polyethylene bag
and passed through 630 μm sieve using sifter and transferred to polyethylene bag for
blending.
This process step was checked in the batch document and was found to be satis-
factory for the following three validation batches.
7.3.2.3 Iron oxide Red and Lactose monohydrate were mixed manually in a poly-
ethylene bag and passed through a 250 μm sieve using Russel sifter and transferred to
Diosna for mixing. This process step was checked in the batch document and was
found to be satisfactory for the following three validation batches
Preparation of Granulating Solution
7.3.2.4 The mixing of iron oxide red in puried water and the addition of Tween
80 were reviewed and recorded from the MFM for the validation batches.
7.3.2.5 The quantity of granulating solution was reviewed and recorded from the
MFM for the two validation batches.
Batch No. Date Sieve Size Observation
001 630 μm Satisfactory
002
630 μm
Satisfactory
003
630 μm
Satisfactory
Batch No. Date Sieve Size Observation
001 250 μm Satisfactory
002
250 μm
Satisfactory
003
250 μm
Satisfactory
Batch No. Date
Dispersion of
Iron Oxide Mixing Time
001 uniform 5minutes
002 uniform 5minutes
003 uniform 5minutes
Batch No. Date
Theoretical QTY of
Granulating Solution
Actual QTY of
Granulating Solution
001 x.00 kg 3.03 kg
002 x.00 kg 3.03 kg
003 x.00 kg 3.03 kg
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101Process Validation Report Writing
7.3.2.6 The manual mixing in polyethylene bag for 3minutes was done for Avicel
pH 101, Primojel, and Lactose monohydrate. This process step was checked in the
batch document and was found to be satisfactory for the following validation batches
Wet Granulation
7.3.2.7 The process of wet granulation was checked in the batch document for the
following step
1. The loading of manually pre-mixed material in the granulator 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. All the
steps were found to be satisfactory for the following validation batches.
Drying of Granules and LOD
7.3.2.8 The Drying of granules in a Dryer was done at 55°C for 10 hours, was checked
in the batch document, and was found to be satisfactory for the following validation
batches.
Batch No. Date
Loading of
Material in
Granulator
1st Mixing
Time 1
Minute
2nd Mixing
Time 1
Minute
3rd Mixing
Time 1
Minute
Additional
Water QTY
001 Satisfactory 1minute 1minute 1minute x.0 kg
002 Satisfactory 1minute 1minute 1minute x.0
kg
003 Satisfactory 1minute 1minute 1minute x.0 kg
Batch No. Date Temperature Drying
001 55°C xx Hours
002
55°C xx Hours
003
55°C xx Hours
Batch No. Date Time Limit 3 Minutes Observation
001 500
μm Satisfactory
002
500 μm
Satisfactory
003
500
μm
Satisfactory
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102 Basics of Pharmaceutical Manufacturing and Quality Operations
LOD Checking
7.3.2.9 The LOD was noted at 80°C (limits 0.7%–1.0%) checked in the batch docu-
ment and was found to be satisfactory for the validation batches.
7.3.2.10 Grinding of Dried granules and passing through a 1.0 mm sieve in a
Granulator at medium speed and collecting of granules in SS drum was checked in
the batch document and was found to be satisfactory for the validation batches.
Numbers given in the tables above for measuring time or any other param‑
eter are not referring to any specic product but are only to provide an idea to
the readers.
Lubrication
7.3.2.11 Primojel, Kollidon CL, and Magnesium Stearate were sifted through a
500 μm SS sieve and added to the ground and sieved granules, and nally mixed for
5minutes manually; this process was reviewed and recorded from the MFM for the
two validation batches.
7.3.2.12 The nal yield calculation of Granules for the three batches re-checked
from batch document, and found satisfactory.
Batch No. Date LOD Temperature LOD Limits Results
001 80°C 0.7%–1.0% 0.90%
002
80°C
0.7%–1.0% 0.80%
003
80°C
0.7%–1.0% 0.90%
Batch No. Date Sieve Size Results
001 1.0 mm Satisfactory
002 1.0
mm Satisfactory
003 1.0 mm Satisfactory
Batch No. Date Sieve Size Observation
001 500 μm Satisfactory
002
500 μm
Satisfactory
003
500 μm
Satisfactory
Batch No. Date
Theoretical Batch
Weight
Actual Batch
Weight % Yield
001 14.0 kg 13.86 kg 99.0%
002 14.0 kg 13.88 kg 99.14%
003 14.0 kg 13.7 kg 97.85%
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103Process Validation Report Writing
Compression of Tablets
7.3.2.13 Tablets were compressed using Rotary compression machine. This
process step was checked in the batch document and the following param-
eters were found satisfactory for the following two validation batches.
In‑Process Testing–Use What Is Applicable
The analysis performed throughout this run is ten tablets at the following time points:
• The rst ten tablets from the start of the compression process
• From a composite* sample of 20 dosages from each bucket throughout the
run
• Critical Time Points–rst ten tablets off the machine, after the event.
Examples of Critical Time Points
• Major break down of tablet machine
• After an extended break in compression (i.e. outside normal operational
stops and starts) and blockages
• The last ten tablets off the machine
The potency of the unit dosage with both the highest and lowest absorbance from the
NIR scans over the entire run was analyzed for potency by the QC Lab to equate the
absorbance to the actual concentration.
In-process weight results and statistical analysis performed to identify the state of
process control are documented in this report in Section 7.3.3.
This report documents the sampling and testing required and performed on the
nished product.
Full product testing on the routine end–of the–run sample of tablets was required
apart from Dissolution, Assay, and Content Uniformity which were required to be
tested on the additional validation samples. The additional validation samples, taken
from seven different time points distributed throughout the validation run, include
start, middle, and end of run. Assay and Content Uniformity testing were required
on 70 tablets (ten tablets from each time point) and [Comparative] Dissolution test-
ing was required on 12 [or six if only dissolution prole] tablets from the end–of
Test Specication Results
Batch Nos 001 002 003
Weight of tablet
140mg ± 3.0%
140
mg 140 mg 140 mg
Thickness
2.4
± 3.0 mm
2.4
mm 2.5 mm 2.5 mm
Hardness NLT 7–13 kp 9 kp 9 kp 10 kp
Disintegration Time NMT 10minute 7minutes 6minutes 0.5minute
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104 Basics of Pharmaceutical Manufacturing and Quality Operations
the–run sample. The Comparative Dissolution prole is required to be performed
on three batches of the current process and compared to each validation batch [if
applicable].
7.3.3 Uniformity of Weight
Weight variation Batch # 001
Target weight: 140 mg
Lower Limit weight: 133 mg
Upper Limit weight: 147 mg
Time 16.00 16.30 17.00 17.30 18.00 18.30 19.00 19.30 14.00
Weight
1 143 140 139 140 139 140 138 136 138
2 138 144 144 142 143 145 143 141 142
3 140 142 142 141 142 136 134 134 147
4 139 138 142 143 142 149 147 145 140
5 141 141 140 140 146 139 137 135 145
6 139 139 144 142 141 142 140 138 139
7 145 143 141 137 144 144 142 140 143
8 139 140 140 138 140 139 137 135 140
9 141 140 138 140 143 142 140 138 138
10 144 145 140 137 143 140 138 136 140
Max 145 145 144 143 146 149 147 145 147
Min 138 138 138 137 139 136 134 134 138
Average 141 141 141 140 142 142 140 138 141
Range 7 7 6 6 7 13 13 11 9
S.D 2.24 2.25 2.00 2.11 2.00 3.69 3.69 3.54 3.01
RSD 1.59% 1.59% 1.42% 1.51% 1.41% 2.60% 2.64% 2.57% 2.13%
All the weights given in the target, lower and upper limits are not for any specic
product but are only an example to present an idea to the readers.
Weight variation Batch # 002
Target weight: 140 mg
Lower Limit weight: 133 mg
Upper Limit weight: 147 mg
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105Process Validation Report Writing
All the weights given in the target, lower and upper limits are not for any specic
product but are only an example to present an idea to the readers.
Weight variation Batch # 003
Target weight: 140 mg
Lower Limit weight: 133 mg
Upper Limit weight: 147 mg
Time 9.00 10.00 11.00 12.00 13.00 14.00
Weight
1 140 140 140 141 143 141
2 143 139 138 143 142 142
3 143 142 139 141 145 142
4 143 138 141 140 142 140
5 142 141 137 144 144 144
6 143 141 140 142 142 141
7 143 143 142 141 141 140
8 142 139 140 142 144 139
9 142 138 143 141 142 144
10 142 139 143 140 140 141
Max 143 143 143 144 145 144
Min 140 138 137 140 140 139
Average 142 140 140 142 143 141
Range 3 5 6 4 5 5
S.D 0.95 1.70 2.00 1.27 1.51 1.65
RSD 0.67% 1.21% 1.43% 0.90% 1.06% 1.16%
Time 9.30 10.00 10.30 11.00 11.30 12.45 13.00 13.30 14.00 14.30
Weight
1 139 138 140 137 139 137 142 140 137 138
2 137 141 143 141 143 135 146 143 141 144
3 140 139 141 143 145 140 139 139 137 141
4 145 142 144 140 142 143 143 137 139 141
5 139 139 141 135 137 137 145 140 143 140
6 135 141 143 142 144 133 140 146 142 143
7 142 138 140 134 136 140 141 143 141 138
8 145 140 142 138 140 143 144 142 146 140
9 140 138 140 142 144 138 142 140 142 142
10 140 144 146 146 148 136 140 138 139 136
Max 145 144 146 146 148 143 146 146 146 144
Min 135 138 140 134 136 133 139 137 137 136
Average 140 140 142 140 142 138 142 141 141 140
Range 10 6 6 12 12 10 7 9 9 8
S.D 3.16 2.00 2.00 3.77 3.77 3.29 2.30 2.70 2.79 2.45
RSD 2.25% 1.43% 1.41% 2.69% 2.66% 2.38% 1.62% 1.92% 1.98% 1.75%
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106 Basics of Pharmaceutical Manufacturing and Quality Operations
All the weights given in the target, lower and upper limits are not for any specic
product but are only an example to present an idea to the readers.
In the actual report, the set of ten tablets can be repeated as per the pre-approved
protocol for each of the validation batches. Depending on the size of the batches and
duration of compression, the set of ten tablets for weight variation could vary from
three to ve or even more if needed and the results can be tabulated as per the tables
shown above.
Similar tables could be used to tabulate the results of assay, dissolution, and con-
tent uniformity tests as described under the section “in-process testing”.
The same approach could be used for liquid dosage forms validation batch reports.
The physical attributes of tablets and capsules could be replaced with pH, specic
gravity, viscosity, etc.
8 CRITICAL PROCESS PARAMETERS
(PACKAGING) (SOP QAS‑0110)
8.1 bListerinG
During blistering in-process checks were carried out for empty pocket, empty blister
strip, improper sealing, leak test (ten blister), and defective tablets were checked ran-
domly on 32 blisters for the batches and results were found to be satisfactory.
Adetailed report is available in batch le.
Numbers of defects given in the table above are only examples to provide an
idea to the readers.
Batch No. Date Empty pocket Empty blister
Improper
sealing Leak test
Defective
tablets
001 0/32 0/32 0/32 0/10 0/32
002 0/32 0/32 0/32 0/10 0/32
003 0/32 0/32 0/32 0/10 0/32
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107Process Validation Report Writing
8.2 finaL PackinG record (insPection)
Critical, Major, and Minor Defects (SOP 123)
Attribute AQL
Acceptance
Criteria
Sample Size
Cumulative
160 (k)
Total Rejected samples
Batches Numbers
001 002 003
Critical Defects (AQL 0)
Wrong commodity 0.0% 0 160–192
Wrong Batch No 0.0% 0 160–192
Wrong Expiry 0.0% 0 160–192
Wrong Manufacturing 0.0% 0 160–192
Wrong Special
stamping
0.0% 0 160–192
Incorrect No of unites
in C. Carton
0.0% 0 160–192
Foreign Material 0.0% 0 160–192
Empty unites 0.0% 0 160–192
Major Defects (AQL 1.0%)
Missing component 1.0% 4 160–192
Illegible Batch No. 1.0% 4 160–192
Illegible Mfg. Date 1.0% 4 160–192
Illegible Exp. Date 1.0% 4 160–192
Other
Minor Defects (AQL 2.5%)
Loose or torn labels /
Carton/Box
2.5% 8 160–192
Double labels 2.5% 8 160–192
Printing Smeared
Partly
2.5% 8 160–192
Crooked label 2.5% 8 160–192 0
0
0
0
0
0
Excessive Shrinkage
label
2.5% 8 160–192 0
0
0
0
0
0
others
TO TA L 0 0 0
Pass/Fail PASS PASS PASS
Compiled and
Reviewed by
Date:
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108 Basics of Pharmaceutical Manufacturing and Quality Operations
9 SUMMARY OF RESULTS
9.1 resuLt data tabLe
Dissolution Test
Target: 90%–110% mg
Lower Limit:
Upper Limit:
API–Assay
Specication: 1.0mg/tablet (Limit:90.0%–105.0% of LA)
Batch No. Assay‑1.0mg/tablet % Assay value
001
002
003
Maximum
Minimum
Range
Average
S.D
RSD
Acceptance Criteria All individual values within 90.0%–105.0% of the theoretical value of
active ingredient and RSD for 2 Batch samples should be less than 6%.
Comments: All result meet Finished product specication and acceptance criteria.
Pass / Fail Pass
Compiled by Date
Reviewed by QA
Manager
Date
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