3-2 AssessingProductionDocuments

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

January20-22,
January 19-22,2010
19-22, 2011
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, pre-
treatments, 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 »

January 20-22,
19-22, 2010
2011
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;

January20-22,
19-22,2010
2011
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.

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

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

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.

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
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;

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;

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.

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

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 Room Temp %RH Diff. press signature

No. °C (mm H2O)
Dispensing 23 42 2.0
Sifting 48 1.8
Milling 2.0
Verify temperature, humidity and differential pressure are within acceptable limits, date
and time are in chronological order .

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

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

January20-22,
19-22,2010
2011
Batch Records
Company Batch Manufacturing Record Page No. : 1 of 40
logo
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:
Verify that all pages are submitted & batch record available for each
batch size

January20-22,
19-22,2010
2011
Batch Records
formulation
 Material Dispensing SOP No.: Balance ID Nos.:
 Each tablet contains:
Sr. Ingredient Material AR No. Qty per unit % Qty per batch
No. code (mg) (Kg)
1 API AP-18 √
2 Exp 1 √
3 Exp 2 √
4 Exp 3 √
5 Exp 4 √
6 Exp 6 √

January20-22,
19-22,2010
2011
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

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

January20-22,
19-22,2010
2011
Batch Records
formulation
Theoretical quantity of API [100% assay (anhydrous) and nil water] = 30 Kg
Sr. AR No. Total available Actual Water Equivalent Equivalent

No quantity (as is basis) Assay content quantity on quantity on
. (Kg) (%) 100% assay as is basis
(% w/w) and nil water
(A) (B) basis (Kg) (Kg)
(C)
(D) (E)
1 AP-18 23.50 99.4 0.34 23.28 23.50
2 AP-22 60.00 99.1 0.50 6.72 6.815
∑E 30.00 ∑E 30.315

January20-22,
19-22,2010
2011
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 = {Theoretical quantity of API required + theoretical

quantity of filler} – Total quantity of API (∑E)

January20-22,
19-22,2010
2011
Raw Material Dispensing Record
RM Ingredient Qty AR Gross Tare Net Wt. Weighed Checked Date

Code Kg No Wt. Wt. by by
API √ √ √ √ √ √
Exp 1 √ √ √ √ √ √
Exp 2 √ √ √ √ √ √
Exp 3 √ √ √ √ √ √
Exp 4 √ √ √ √ √ √
Exp 5 √ √ √ √ √ √

January20-22,
19-22,2010
2011
Manufacturing Instructions
list of equipment
Sr. No. Name Capacity Make Model ID SOP No.
1 Vibratory Sifter 20"/30" √ √

2 Rapid Mixer 500L √ √
Granulator
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" √ √

January20-22,
19-22,2010
2011
sifting
Step Instructions Time Time Performed Verified Date
start end by by
1.1 API …… Kg √ √ √ √ √
Exp 1 …… Kg
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

January20-22,
19-22,2010
2011
Mesh sizes
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

January20-22,
19-22,2010
2011
mixing & granulation
 Mixing SOP No.: Granulation SOP No.:
Ste Instructions Time Time Performe Verified Date

p start end d by by
2.1 Load material from 1.1 & 1.2 in RMG
Exp 4 ……….Kg √ √ √ √ √
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

January20-22,
19-22,2010
2011
wet milling and drying
 Wet Milling SOP No.:
 Drying SOP No.: LOD: 1.0-2.5% (moisture balance at 105ºC)

start end by by
3.1 Pass wet mass through 1mm
screen of Multi Mill
√ √ √ √ √
Speed – fast; Knives - forward
collect in FBD
3.2 FBD in let temp 60ºC √ √ √ √ √
Damper 80% open for 15 min √ √ √ √ √
Damper 50% open after 15

minutes ; LOD ……..%

January20-22,
19-22,2010
2011
size reduction & blending
 Size reduction SOP No.: Blending SOP No.:

start end by by
4.1 Fit 0. 8 mm screen to Multi

Mill and pass material from
3.2
Speed – Medium √ √ √ √ √
Knives - forward
4.2 Load dried granules from 4.1
into Conta Blender and blend
for 20 mins at 12+1 rpm √ √ √ √ √

January20-22,
19-22,2010
2011
lubrication
 Lubrication SOP No.:
Step Instructions Time Time Perform Verifie Date

start end ed by d by
5.1 Fit 60 mesh screen to vibratory sifter

and pass
Exp 5 ……….Kg
√ √ √ √ √
and collect in tared double PE lined
container
5.2 Add contents from 5.1 to 4.2 and blend
for 3 mins and collect in tared double PE
lined container √ √ √ √ √

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%

January20-22,
19-22,2010
2011
compression
 Balance no.: Vernier Caliper no.:
 Hardness tester no.: Friability tester no.:
 Disintegration tester no.:
Tooling No. of units Checked by Verified by
Upper punch: …mm x …mm oval shaped 37

concave embossed…….
Lower punch: …mm x …mm oval shaped 37

concave embossed…….
Dies: …mm x ….mm oval shaped 1

January20-22,
19-22,2010
2011
compression
Parameter Limit Observation
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

January20-22,
19-22,2010
2011
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

January20-22,
19-22,2010
2011
compressed tablets
 Yield = ∑NW/ theor. wt. x 100 = …… %
Container Gross wt. Tare weight Net weight Weighed by/ Checked by/
no. Kg Kg Kg date date
1 √
2 √
3 √
∑NW √

January20-22,
19-22,2010
2011
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 = ….%,

January20-22,
19-22,2010
2011
coating
start end by by
6.1 Introduce compressed tablets into

Auto Coater and spray coating
solution
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)

January20-22,
19-22,2010
2011
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 =.. ….%

January20-22,
19-22,2010
2011
Sterile Products
 Focus
– Environmental conditions
– In-process tests
– SOPs
– Type and make of sterilizing filter
– Type and make of rubber stopper

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)

January20-22,
19-22,2010
2011
sterile products
Grade Maximum permitted number of particles/m3 equal to or greater than
the tabulated size
At rest In operation
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

January20-22,
19-22,2010
2011
sterile products
 Recommended limits for microbial contamination
Grade Air sample Settle plates Contact plates Glove print

cfu/m3 (diam. 90 (diam. 55
mm), cfu/4 mm), cfu/plate 5 fingers
hours
cfu/glove
A <1 <1 <1 <1
B 10 5 5 5
C 100 50 25 -
D 200 100 50 -

January20-22,
19-22,2010
2011
list of equipment
Sr. Name Capacity Make Model ID SOP No.

No.
1 SS Manufacturing Tank 1000 L √ √
2 Tunnel Sterilizer √ √
3 Dry Heat Sterilizer √ √
4 Autoclave √ √
5 Ampoule/vial filling/ √ √
sealing machine
6 Leak tester √ √

January20-22,
19-22,2010
2011
sterile products
start end by by
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….

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

January20-22,
19-22,2010
2011
Critical SOPs
sterile products
SOP Critical Elements
Cleaning and sterilization of manufacturing temperature and dwell time
vessels
Washing and sterilization/depyrogenation of temperature and dwell time
packaging materials
Sterilization of filtration assembly and temperature and dwell time
components
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

January20-22,
19-22,2010
2011
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3-2.

Assessing Production Documents:

 Good production documentation:

– Ensures uniformity, consistency and a common understanding of

– Outlines the procedures for handling raw materials, manufacturing and

– Facilitates decision making on release/quarantine/rejection of a batch;

– Ensures accountability, traceability, and documentation trail that will permit

– Permits retrospective validation and periodic quality review throughout

2| Satish Mallya January

Source: PIC/S Guide to GMP for Medicinal Products – September 2009

3| Satish Mallya January

 The Processing Instructions should include:

Source: PIC/S Guide to GMP for Medicinal Products – September 2009 »

4| Satish Mallya January

 There should be formally authorised Packaging Instructions for

5| Satish Mallya January

– where appropriate, an example or reproduction of the relevant

6| Satish Mallya January

 Before any processing begins, there should be recorded checks

7| Satish Mallya January

– the batch number and/or analytical control number as well as

Source: PIC/S Guide to GMP for Medicinal Products – September 2009

8| Satish Mallya January

 A Batch Packaging Record should be kept for each batch or part

9| Satish Mallya January

10 | Satish Mallya January

 Master records should be in English, if not a translated version

11 | Satish Mallya January

 The master record should be compared with the executed record

12 | Satish Mallya January

 Serve to reduce the bulk of the batch record;

 Should be written in a language appropriate to the content and to

 My not necessarily be specific to a product;

 Are generally intended to describe in detail, a single event,

13 | Satish Mallya January

14 | Satish Mallya January

 Temperature: 15-25ºC; humidity: 30-50% RH, pressure differential: 1-2 mmH2O

Date Time Operation Room Temp %RH Diff. press signature

15 | Satish Mallya January

Batch no. of previous product

Alert: Previous product requires segregated facility – note to

16 | Satish Mallya January

 May run into several pages

Filters from return duct cleaned √

All previous labels removed √

17 | Satish Mallya January

Company Batch Manufacturing Record Page No. : 1 of 40

18 | Satish Mallya January

 Each tablet contains:

19 | Satish Mallya January

 Theoretical quantity of API [100% assay (anhydrous) and nil water] = 30 Kg

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)

= 23.50 x 99.4/100 x (100 – 0.34)/100 = 23.28 Kg

20 | Satish Mallya January

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)

= 6.72 x 100/99.1 x 100/100-0.50 Kg

21 | Satish Mallya January

Sr. AR No. Total available Actual Water Equivalent Equivalent