3-2. Assessing Production Documents:
executed and master records
Satish Mallya
January , 2011
Documentation
 Good production documentation:
– Ensures uniformity, consistency and a common understanding of
expectations;
– Outlines the procedures for handling raw materials, manufacturing and
control;
– Facilitates decision making on release/quarantine/rejection of a batch;
– Ensures accountability, traceability, and documentation trail that will permit
investigation in the event of product recall;
– Permits retrospective validation and periodic quality review throughout
product lifecycle.
2|
Satish Mallya January
January 20-22,
19-22, 2010
2011
Manufacturing Formula
 Formally authorised Manufacturing Formula and Processing
Instructions should exist for each product and batch size to be
manufactured.
 The Manufacturing Formula should include:
– the name of the product, with a product reference code relating to its
specification;
– a description of the pharmaceutical form, strength of the product and batch
size;
– a list of all starting materials to be used, with the amount of each, described
using the designated name and a reference which is unique to that material;
mention should be made of any substance that may disappear in the course
of processing;
– a statement of the expected final yield with the acceptable limits, and of
relevant intermediate yields, where applicable.
Source: PIC/S Guide to GMP for Medicinal Products – September 2009
3|
January20-22,
19-22,2010
2011
Satish Mallya January
January
19-22,
2011
Processing Instructions
 The Processing Instructions should include:
– a statement of the processing location and the principal equipment to be
used;
– the methods, or reference to the methods, to be used for preparing the
critical equipment (e.g. cleaning, assembling, calibrating, sterilising);
– detailed stepwise processing instructions (e.g. checks on materials, pretreatments, sequence for adding materials, mixing times, temperatures);
– the instructions for any in-process controls with their limits;
– where necessary, the requirements for bulk storage of the products;
including the container, labelling and special storage conditions where
applicable;
– any special precautions to be observed.
Source: PIC/S Guide to GMP for Medicinal Products – September 2009 »
4|
January 20-22,
19-22, 2010
2011
Satish Mallya January
Packaging Instructions
 There should be formally authorised Packaging Instructions for
each product, pack size and type.
 These should normally include, or have a reference to, the
following:
– name of the product;
– description of its pharmaceutical form, and strength where
applicable;
– the pack size expressed in terms of the number, weight or
volume of the product in the final container;
– a complete list of all the packaging materials required for a
standard batch size, including quantities, sizes and types, with
the code or reference number relating to the specifications of
each packaging material;
5|
January20-22,
19-22,2010
2011
Satish Mallya January
Packaging Instructions
– where appropriate, an example or reproduction of the relevant
printed packaging materials, and specimens indicating where to
apply batch number references, and shelf-life of the product;
– special precautions to be observed, including a careful
examination of the area and equipment in order to ascertain the
line clearance before operations begin;
– a description of the packaging operation, including any
significant subsidiary operations, and equipment to be used;
– details of in-process controls with instructions for sampling and
acceptance limits.
Source: PIC/S Guide to GMP for Medicinal Products – September 2009 »
6|
Satish Mallya January
January20-22,
19-22,2010
2011
Batch Processing Records
 Before any processing begins, there should be recorded checks
that the equipment and work station are clear of previous products,
documents or materials not required for the planned process, and
that equipment is clean and suitable for use.
 During processing, the following information should be recorded at
the time each action is taken and, after completion, the record
should be dated and signed in agreement by the person
responsible for the processing operations:
– the name of the product;
– dates and times of commencement, of significant intermediate stages and of
completion of production;
– name of the person responsible for each stage of production;
– initials of the operator of different significant steps of production and, where
appropriate, of the person who checked each of these operations
7|
Satish Mallya January
January20-22,
19-22,2010
2011
Batch Processing Records
– the batch number and/or analytical control number as well as
the quantities of each starting material actually weighed
(including the batch number and amount of any recovered or
reprocessed material added);
– any relevant processing operation or event and major
equipment used;
– a record of the in-process controls and the initials of the
person(s) carrying them out, and the results obtained;
– the amount of product yield obtained at different and pertinent
stages of manufacture;
– notes on special problems including details, with signed
authorisation for any deviation from the Manufacturing Formula
and Processing Instructions
Source: PIC/S Guide to GMP for Medicinal Products – September 2009
8|
Satish Mallya January
January20-22,
19-22,2010
2011
Batch Packaging Records
 A Batch Packaging Record should be kept for each batch or part
batch processed. It should be based on the relevant parts of the
Packaging Instructions and the method of preparation of such
records should be designed to avoid transcription errors.
 The record should carry:
– the batch number and the quantity of bulk product to be
packed, as well as the batch number and the planned quantity
of finished product that will be obtained.
– Before any packaging operation begins, there should be
recorded checks that the equipment and work station are clear
of previous products, documents or materials not required for
the planned packaging operations, and that equipment is clean
and suitable for use.
Source: PIC/S Guide to GMP for Medicinal Products – September 2009 »
9|
Satish Mallya January
January20-22,
19-22,2010
2011
Batch Packaging Records
 The following information should be entered at the time each action is taken and,
after completion, the record should be dated and signed in agreement bythe
person(s) responsible for the packaging operations:
– the name of the product;
–
–
–
–
–
–
–
–
the date(s) and times of the packaging operations;
the name of the responsible person carrying out the packaging operation;
the initials of the operators of the different significant steps;
records of checks for identity and conformity with the Packaging Instructions
including the results of in-process controls;
details of the packaging operations carried out, including references to equipment
and the packaging lines used;
whenever possible, samples of printed packaging materials used, including
specimens of the batch coding, expiry dating and any additional overprinting;
notes on any special problems or unusual events including details with signed
authorisation for any deviation from the Manufacturing Formula and Processing
Instructions;
the quantities and reference number or identification of all printed packaging
materials and bulk product issued, used, destroyed or returned to stock and the
quantities of obtained product, in order to provide for an adequate reconciliation
Source: PIC/S Guide to GMP for Medicinal Products – September 2009 »
10 |
Satish Mallya January
January20-22,
19-22,2010
2011
General Rules
 Master records should be in English, if not a translated version
should be available. It may not be necessary to obtain a translated
version of the executed record if applicant provides an undertaking
that the master is identical to the executed except in the matter of
populated fields and provides a translation of any observations,
comments, reports of deviations or hand written remarks;
 Verify that:
– all pages of master and executed records have been submitted - each page
will generally state the total number of pages (e.g. 1 of 40);
– manufacturing sequence is in harmony with the flow chart and the narrative
description;
– in-process controls are not less stringent than FPP release specs;
– equipment are identified by type and capacity and a unique ID number is
assigned to each equipment;
11 |
Satish Mallya January
January20-22,
19-22,2010
2011
General Rules
 The master record should be compared with the executed record
for biolot in order to ensure that the proposed manufacturing
process is representative of that used to manufacture the biolot;
 It is desirable that each operation be governed by an individual
SOP;
 It is desirable that a list of referenced SOPs be included at the end
of the batch records.
 It is possible that SOPs might make reference to other relevant
SOPs;
12 |
Satish Mallya January
January20-22,
19-22,2010
2011
SOPs
 Serve to reduce the bulk of the batch record;
 Should be written in a language appropriate to the content and to
facilitate understanding by the end user (e.g. operator);
 My not necessarily be specific to a product;
 Are generally intended to describe in detail, a single event,
equipment, operation, process or procedure.
13 |
Satish Mallya January
January20-22,
19-22,2010
2011
SOPs
 Environmental monitoring
 Assembly, calibration, operation, cleaning, sterilization of instruments and
equipment
 Receipt, sampling, labelling, quarantine and dispensing of raw materials and
packaging materials
 System for assigning batch (lot) numbers for intermediate, bulk or FPP
 Manufacturing processes and in-process checks and controls
 Transportation of in-process, intermediate PP or FPP
 Validation procedures
 Criteria and procedures for release/rejection/quarantine of materials and FPP
 Criteria for reprocessing batches
14 |
Satish Mallya January
January20-22,
19-22,2010
2011
Environmental Monitoring Record
 SOP No.:
 Temperature: 15-25ºC; humidity: 30-50% RH, pressure differential: 1-2 mmH2O
Date
Time
Operation
Dispensing
Sifting
Milling
Room
No.
Temp
°C
%RH
Diff. press
(mm H2O)
23
42
2.0
48
1.8
signature
2.0
Verify temperature, humidity and differential pressure are within acceptable limits, date
and time are in chronological order .
15 |
Satish Mallya January
January20-22,
19-22,2010
2011
Line Clearance Record
Previous product
Batch no. of previous product
Alert: Previous product requires segregated facility – note to
inspection
16 |
Satish Mallya January
January20-22,
19-22,2010
2011
Cleaning Records for Processing Areas
 May run into several pages
 SOP Nos.:
Steps
verification
All containers from previous batch removed
√
Filters from return duct cleaned
√
Floor cleaned
√
All previous labels removed
√
xxxxxxx
√
yyyyyy
17 |
Satish Mallya January
January20-22,
19-22,2010
2011
Batch Records
Company
Batch Manufacturing Record
Page No. : 1 of 40
Product Name:
Product Code:
Effective date:
Batch No.:
Batch size (kg):
Batch size (units):
Manufacturing date:
Expiry date:
Shelf life:
Prepared by:
Verified by:
Approved by:
logo
Verify that all pages are submitted & batch record available for each
batch size
18 |
Satish Mallya January
January20-22,
19-22,2010
2011
Batch Records
formulation
 Material Dispensing SOP No.:
Balance ID Nos.:
 Each tablet contains:
Sr.
No.
Ingredient
Material
code
1
API
AP-18
2
Exp 1
√
3
Exp 2
√
4
Exp 3
√
5
Exp 4
√
6
Exp 6
√
19 |
Satish Mallya January
January20-22,
19-22,2010
2011
AR No.
Qty per unit
(mg)
%
Qty per batch
(Kg)
√
Batch Records
formulation
 Calculation of quantity of API per batch:
 Theoretical quantity of API [100% assay (anhydrous) and nil water] = 30 Kg
Lot 1:
Total available quantity (as is basis) (A) = 23.50 Kg
Actual assay (B) = 99.4% ; Water content (C) = 0.34%
Qty of API equivalent to 100% assay and nil water (D)
= A x B/100 x (100-C)/100
= 23.50 x 99.4/100 x (100 – 0.34)/100 = 23.28 Kg
Balance quantity of API required (100% assay and nil water)(E)
= 30 – 23.28 Kg
= 6.72 Kg
20 |
Satish Mallya January
January20-22,
19-22,2010
2011
Batch Records
formulation
Lot 2
Quantity of API required (100% assay and nil water) = 6.72 Kg
Actual assay (B) = 99.1%
Water content (C) = 0.50%
Equivalent quantity of API required from container 2 (E)
= D x 100/B x 100/(100-C)
= 6.72 x 100/99.1 x 100/100-0.50 Kg
= 6.815 Kg
21 |
Satish Mallya January
January20-22,
19-22,2010
2011
Batch Records
formulation
Theoretical quantity of API [100% assay (anhydrous) and nil water] = 30 Kg
Sr.
No
.
AR No.
Total available
quantity (as is basis)
(Kg)
Actual
Assay
(%)
Water
content
(% w/w)
(A)
(B)
(C)
Equivalent
quantity on
100% assay
and nil water
basis (Kg)
Equivalent
quantity on
as is basis
(D)
(E)
(Kg)
1
AP-18
23.50
99.4
0.34
23.28
2
AP-22
60.00
99.1
0.50
6.72
6.815
∑E 30.00
∑E 30.315
22 |
Satish Mallya January
January20-22,
19-22,2010
2011
23.50
Batch Records
formulation
 The total quantity of API + filler will be the same for every batch of the FPP;
 Quantity of filler required will vary with the assay and water content of the API
lot(s);
 If several lots of the API are used in the preparation of a single batch of the FPP,
the total equivalent quantity of API on as is basis (∑E) determines the quantity of
filler to be added in the batch;
Calculation of filler =
23 |
Satish Mallya January
January20-22,
19-22,2010
2011
{Theoretical quantity of API required + theoretical
quantity of filler} – Total quantity of API (∑E)
Raw Material Dispensing Record
RM
Code
24 |
Ingredient
Qty
Kg
AR
No
API
√
Exp 1
Net Wt.
Weighed
by
Checked
by
Date
√
√
√
√
√
√
√
√
√
√
√
Exp 2
√
√
√
√
√
√
Exp 3
√
√
√
√
√
√
Exp 4
√
√
√
√
√
√
Exp 5
√
√
√
√
√
√
Satish Mallya January
January20-22,
19-22,2010
2011
Gross
Wt.
Tare
Wt.
Manufacturing Instructions
list of equipment
25 |
Sr. No.
Name
Capacity
1
Vibratory Sifter
2
ID
SOP No.
20"/30"
√
√
Rapid Mixer
Granulator
500L
√
√
3
Fluid Bed Dryer
150Kg
√
√
4
Conta Blender
500L
√
√
5
Multi Mill
various
√
√
6
Peristaltic pump
N/A
√
√
7
Compression m/c
37 stations
√
√
8
Dedusting m/c
N/A
√
√
9
Metal Detector
N/A
√
√
10
Auto Coater
60"
√
√
Satish Mallya January
January20-22,
19-22,2010
2011
Make
Model
Manufacturing Instructions
sifting
Step
Instructions
1.1
API
…… Kg
Exp 1
…… Kg
Time
start
Time
end
Performed
by
Verified
by
Date
√
√
√
√
√
√
√
√
√
√
Pass through # 40 screen of
Vibratory sifter and collect
material in tared double PE
lined container
1.2
Exp 2
…… Kg
Exp 3
…… Kg
Pass through # 20 screen of
Vibratory sifter and collect
material in tared double PE
lined container
26 |
Satish Mallya January
January20-22,
19-22,2010
2011
Mesh sizes
27 |
Mesh size
Micron
Mms
10
2000
2.000
20
841
0.841
30
595
0.595
40
400
0.400
50
297
0.297
60
250
0.250
70
210
0.210
80
177
0.177
100
149
0.149
120
125
0.125
140
105
0.105
Satish Mallya January
January20-22,
19-22,2010
2011
Manufacturing Instructions
mixing & granulation
 Mixing SOP No.:
Granulation SOP No.:
Ste
p
Instructions
2.1
Load material from 1.1 & 1.2 in RMG
Exp 4
……….Kg
Time
start
Time
end
Performe
d by
Verified
by
Date
√
√
√
√
√
√
√
√
√
√
and mix for 5 minutes with following settings:
Impeller speed-fast; Chopper speed-fast
2.2
Spray purified water into contents of RMG
Impeller speed – fast; Chopper speed - fast
Peristaltic pump atomization press: 0.5-2.5 b
Spray until all purified water is sprayed
Ammeter reading 18-22 amps
28 |
Satish Mallya January
January20-22,
19-22,2010
2011
Manufacturing Instructions
wet milling and drying
 Wet Milling SOP No.:
 Drying SOP No.:
Step
Instructions
3.1
Pass wet mass through 1mm
screen of Multi Mill
LOD: 1.0-2.5% (moisture balance at 105ºC)
Time
start
Time
end
Performed
by
Verified
by
Date
√
√
√
√
√
FBD in let temp 60ºC
√
√
√
√
√
Damper 80% open for 15 min
√
√
√
√
√
Speed – fast; Knives - forward
collect in FBD
3.2
Damper 50% open after 15
minutes ; LOD ……..%
29 |
Satish Mallya January
January20-22,
19-22,2010
2011
Manufacturing Instructions
size reduction & blending
 Size reduction SOP No.:
Step
Instructions
4.1
Fit 0. 8 mm screen to Multi
Mill and pass material from
3.2
Speed – Medium
Blending SOP No.:
Time
start
Time
end
Performed
by
Verified
by
Date
√
√
√
√
√
√
√
√
√
√
Knives - forward
4.2
30 |
Load dried granules from 4.1
into Conta Blender and blend
for 20 mins at 12+1 rpm
Satish Mallya January
January20-22,
19-22,2010
2011
Manufacturing Instructions
lubrication
 Lubrication SOP No.:
Step
Instructions
5.1
Fit 60 mesh screen to vibratory sifter
and pass
Exp 5
……….Kg
Time
start
Time
end
Perform
ed by
Verifie
d by
Date
√
√
√
√
√
√
√
√
√
√
and collect in tared double PE lined
container
5.2
31 |
Add contents from 5.1 to 4.2 and blend
for 3 mins and collect in tared double PE
lined container
Satish Mallya January
January20-22,
19-22,2010
2011
Yield Reconciliation
lubricated granules
A
theoretical batch weight
Kg
B
actual weight
Kg
C
samples
Kg
D
rejection
Kg
Reconciliation Yield = B+C+D/A x 100 =…. .%
Reconciliation Yield Limit: 97-101%
Actual yield =
actual wt. of granules (B)/ theoretical batch size x 100 = ….%,
Yield limit = 95-101%
32 |
Satish Mallya January
January20-22,
19-22,2010
2011
Manufacturing Instructions
compression
 Balance no.:
Vernier Caliper no.:
 Hardness tester no.:
Friability tester no.:
 Disintegration tester no.:
33 |
Tooling
No. of units
Upper punch: …mm x …mm oval shaped
concave embossed…….
37
Lower punch: …mm x …mm oval shaped
concave embossed…….
37
Dies: …mm x ….mm oval shaped
1
Satish Mallya January
January20-22,
19-22,2010
2011
Checked by
Verified by
Manufacturing Instructions
compression
34 |
Parameter
Limit
Machine speed
20 rpm (15-25 rpm)
Wt. of 20 tabs
12.00g +2 (11.76-12.24g)
Theoretical weight/tab
600mg
Hardness
25Kg (20-30 Kg)
Thickness (av. of 10 tabs)
4.10mm +0.15mm (3.95 – 4.25mm)
Length
10mm + 0.1 mm (9.9 – 10.1 mm)
Width
5 mm + 0.1mm (4.9 – 5.1 mm)
Disintegration time
NMT 15 mins
Wt. variation
+ 3% of Av. Wt.
Friability (10 tabs)
NMT 1.0% w/w
Satish Mallya January
January20-22,
19-22,2010
2011
Observation
In-process Checks
Parameter
Frequency
Wt. of 20 tabs
Every hour by production and every two hours by
QA
Hardness, thickness, length, width
Every hour by production, every two hours by QA
Wt. variation
Every half hour by production and every hour by
QA
DT
Every half hour by production, every hour by QA
35 |
Satish Mallya January
January20-22,
19-22,2010
2011
Yield Reconciliation
compressed tablets
 Yield = ∑NW/ theor. wt.
Container
no.
Gross wt.
Kg
x
100 = …… %
Tare weight
Kg
Net weight
Kg
1
√
2
√
3
√
∑NW √
36 |
Satish Mallya January
January20-22,
19-22,2010
2011
Weighed by/
date
Checked by/
date
Yield Reconciliation
compressed tablets
A
Lubricated granules
……Kg, approx. ……..tablets
B
Tablets compressed
……Kg, approx. ……..tablets
C
In-process samples
……Kg, approx. ……..tablets
D
Bulk Samples
……Kg, approx. ……..tablets
E
Rejection
……Kg, approx. ……..tablets
Reconciliation Yield = B+C+D+E / A x 100 = ……..%, Limit : 97-101%
Actual yield = actual tablets compressed (B)/ theoretical batch size x 100 = ….%,
Yield limit = 92-101%
37 |
Satish Mallya January
January20-22,
19-22,2010
2011
Manufacturing Instructions
coating
Step
Instructions
6.1
Introduce compressed tablets into
Auto Coater and spray coating
solution
Time
start
Time
end
Performed
by
Verified
by
Date
√
√
√
√
√
Inlet air temp …….ºC (30-60ºC)
Pan speed……..rpm (2-8 rpm)
Solution rate …..ml/min (20-60
ml/min)
Distance of gun from tablet
bed……cm (20-40cm)
38 |
Satish Mallya January
January20-22,
19-22,2010
2011
Yield Reconciliation
coated tablets
A
Tablets Compressed
……Kg, approx. ……..tablets
B
Tablets Coated
……Kg, approx. ……..tablets
C
In-process samples
……Kg, approx. ……..tablets
D
Bulk Samples
……Kg, approx. ……..tablets
E
Rejection
……Kg, approx. ……..tablets
Reconciliation Yield = B+C+D+E / A x 100 = ……..%, Limit : 97-101%
Actual yield =
actual tablets coated (B) / theoretical batch size x 100 =.. ….%
Yield limit = 90-101%
39 |
Satish Mallya January
January20-22,
19-22,2010
2011
Sterile Products
 Focus
–
–
–
–
–
40 |
Environmental conditions
In-process tests
SOPs
Type and make of sterilizing filter
Type and make of rubber stopper
Satish Mallya January
January20-22,
19-22,2010
2011
Environmental Conditions
sterile products
 Grade A:
Zone for high risk operations, e.g. filling zone.
Normally such conditions are provided by a laminar air flow work station.
 Grade B:
For aseptic preparation and filling, this is the background environment for
the grade A zone.
 Grade C and D: Clean areas for carrying out less critical stages in the manufacture of
sterile products
 Positive pressure should be maintained relative to surrounding areas of a lower grade
under all operational conditions. Adjacent rooms of different grades should have a
pressure differential of 10-15 pascals (recommended values)
 1 Pa (N/m2) = 0.10207 Millimeter of water (15.56º C)
1 Pa (N/m2) = 0.10197 Millimeter of water (4º C)
41 |
Satish Mallya January
January20-22,
19-22,2010
2011
Environmental Conditions
sterile products
Grade
Maximum permitted number of particles/m3 equal to or greater than
the tabulated size
In operation
At rest
0.5µm
5.0µm
0.5µm
5.0µm
A
3,520
20
3,520
20
B
3,520
29
352,000
2,900
C
352,000
2,900
3,520,000
29,000
D
3,520,000
29,000
not defined
not defined
42 |
Satish Mallya January
January20-22,
19-22,2010
2011
Environmental Conditions
sterile products
 Recommended limits for microbial contamination
Grade
43 |
Air sample
cfu/m3
Settle plates
(diam. 90
mm), cfu/4
hours
Contact plates
(diam. 55
mm), cfu/plate
Glove print
5 fingers
cfu/glove
A
<1
<1
<1
<1
B
10
5
5
5
C
100
50
25
-
D
200
100
50
-
Satish Mallya January
January20-22,
19-22,2010
2011
Manufacturing Instructions
list of equipment
44 |
Sr.
No.
Name
Capacity
1
SS Manufacturing Tank
1000 L
2
ID
SOP No.
√
√
Tunnel Sterilizer
√
√
3
Dry Heat Sterilizer
√
√
4
Autoclave
√
√
5
Ampoule/vial filling/
sealing machine
√
√
6
Leak tester
√
√
Satish Mallya January
January20-22,
19-22,2010
2011
Make
Model
Manufacturing Instructions
sterile products
Step
Instructions
Time
start
Time
end
Performed
by
Verified
by
Date
1.1
Take 45 Lts WFI in SS tank
√
√
√
√
√
1.2
Purge nitrogen for …mins
√
√
√
√
√
1.3
Dissolve preservative and stir for … mins
√
√
√
√
√
1.4
Dissolve antioxidant and stir for ….mins
√
√
√
√
√
1.4
Dissolve API and stir for …mins
√
√
√
√
√
1.5
Check pH ……(4.0-6.5)
√
√
√
√
√
1.6
Make volume to 50L and stir for 15 mins
√
√
√
√
√
1.7
Filter bulk through 0.22µ filter
√
√
√
√
√
√
√
√
√
√
SOP No….
1.8
Fill in 2 mL ampoules,
SOP No….
45 |
Satish Mallya January
January20-22,
19-22,2010
2011
In-process Checks
sterile products
Test
Acceptance Criteria
Bioburden (prior to aseptic filtration)
NMT 10Cfu/100ml
pH
5-6
Assay
97-103%
Fill volume
3.8– 4.2 mL
Filter integrity ( pre and post filtration)
NLT 35 psi
46 |
Satish Mallya January
January20-22,
19-22,2010
2011
Critical SOPs
sterile products
SOP
Critical Elements
Cleaning and sterilization of manufacturing
vessels
temperature and dwell time
Washing and sterilization/depyrogenation of
packaging materials
temperature and dwell time
Sterilization of filtration assembly and
components
temperature and dwell time
Aseptic filtration
procedures, filter size
Filter integrity test
limits
Leak test
procedure
Media Fill
no. of units, media, interventions
Terminal sterilization
F0, temperature and dwell time
47 |
Satish Mallya January
January20-22,
19-22,2010
2011
Thanks