1. 3-2. Assessing Production Documents: executed and master records
Satish Mallya
January , 2011

2. 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.
January 19-22, 2011

3. 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
January 19-22, 2011
January 19-22, 2011

4. 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 19-22, 2011

5. 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;
January 19-22, 2011

6. 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
January 19-22, 2011

7. 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
January 19-22, 2011

8. 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
January 19-22, 2011

9. 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
January 19-22, 2011

10. 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
January 19-22, 2011

11. 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;
January 19-22, 2011

12. 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;
January 19-22, 2011

13. 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.
January 19-22, 2011

14. 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
January 19-22, 2011

15. Environmental Monitoring Record
SOP No.:
Temperature: 15-25ºC; humidity: 30-50% RH, pressure differential: 1-2 mmH2O
Date
Time
Operation
Room No.
Temp °C
%RH
Diff. press (mm H2O)
signature
Dispensing 23 42
2.0
Sifting 48
1.8
Milling
Verify temperature, humidity and differential pressure are within acceptable limits, date and time are in chronological order .
January 19-22, 2011

16. Line Clearance Record
Previous product
Batch no. of previous product
Alert: Previous product requires segregated facility – note to inspection
January 19-22, 2011

17. 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
January 19-22, 2011

18. Batch Records
Company
logo
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:
Verify that all pages are submitted & batch record available for each batch size
January 19-22, 2011

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

20. 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) = 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
= x 99.4/100 x (100 – 0.34)/100 = Kg
Balance quantity of API required (100% assay and nil water)(E) = 30 – Kg
= 6.72 Kg
January 19-22, 2011

21. 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/ Kg
= Kg
January 19-22, 2011

22. 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)
(A)
Actual Assay (%)
(B)
Water content
(% w/w)
(C)
Equivalent quantity on 100% assay and nil water basis (Kg)
(D)
Equivalent quantity on as is basis
(Kg)
(E) 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
January 19-22, 2011

23. 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)
January 19-22, 2011

24. Raw Material Dispensing Record
RM Code
Ingredient
Qty Kg
AR No
Gross Wt.
Tare Wt.
Net Wt.
Weighed by
Checked by
Date
API √
Exp 1
Exp 2
Exp 3
Exp 4
Exp 5
January 19-22, 2011

25. Manufacturing Instructions list of equipment
Sr. No.
Name
Capacity
Make
Model ID
SOP No. 1
Vibratory Sifter
20"/30" √ 2
Rapid Mixer Granulator
500L 3
Fluid Bed Dryer
150Kg 4
Conta Blender 5
Multi Mill
various 6
Peristaltic pump
N/A 7
Compression m/c
37 stations 8
Dedusting m/c 9
Metal Detector 10
Auto Coater
60"
January 19-22, 2011

26. Manufacturing Instructions sifting
Step
Instructions
Time start
Time end
Performed by
Verified by
Date
1.1
API …… Kg
Exp …… Kg
Pass through # 40 screen of Vibratory sifter and collect material in tared double PE lined container √
1.2
Exp …… Kg
Exp …… Kg
Pass through # 20 screen of Vibratory sifter and collect material in tared double PE lined container
January 19-22, 2011

27. 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
January 19-22, 2011

28. Manufacturing Instructions mixing & granulation
Mixing SOP No.: Granulation SOP No.:
Ste p
Instructions
Time start
Time end
Performe d by
Verified by
Date
2.1
Load material from 1.1 & 1.2 in RMG
Exp ……….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: b
Spray until all purified water is sprayed Ammeter reading amps
January 19-22, 2011

29. Manufacturing Instructions wet milling and drying
Wet Milling SOP No.:
Drying SOP No.: LOD: % (moisture balance at 105ºC)
Step
Instructions
Time start
Time end
Performed by
Verified by
Date
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 ……..%
January 19-22, 2011

30. Manufacturing Instructions size reduction & blending
Size reduction SOP No.: Blending SOP No.:
Step
Instructions
Time start
Time end
Performed by
Verified by
Date
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
January 19-22, 2011

31. Manufacturing Instructions lubrication
Lubrication SOP No.:
Step
Instructions
Time start
Time end
Perform ed by
Verifie d by
Date
5.1
Fit 60 mesh screen to vibratory sifter and pass
Exp ……….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
January 19-22, 2011

32. Yield Reconciliation lubricated granules
Reconciliation Yield = B+C+D/A x 100 =…. .%
Reconciliation Yield Limit: %
Actual yield = actual wt. of granules (B)/ theoretical batch size x 100 = ….%,
Yield limit = % A
theoretical batch weight Kg B
actual weight C
samples D
rejection
January 19-22, 2011

33. Manufacturing Instructions 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 concave embossed……. 37
Lower punch: …mm x …mm oval shaped concave embossed…….
Dies: …mm x ….mm oval shaped 1
January 19-22, 2011

34. Manufacturing Instructions compression
Parameter
Limit
Observation
Machine speed
20 rpm (15-25 rpm)
Wt. of 20 tabs
12.00g +2 ( g)
Theoretical weight/tab
600mg
Hardness
25Kg (20-30 Kg)
Thickness (av. of 10 tabs)
4.10mm +0.15mm (3.95 – 4.25mm)
Length
10mm 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
January 19-22, 2011

35. 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
January 19-22, 2011

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

37. Yield Reconciliation compressed tablets
Reconciliation Yield = B+C+D+E / A x = ……..%, Limit : %
Actual yield = actual tablets compressed (B)/ theoretical batch size x 100 = ….%,
Yield limit = % A
Lubricated granules
……Kg, approx. ……..tablets B
Tablets compressed C
In-process samples D
Bulk Samples E
Rejection
January 19-22, 2011

38. Manufacturing Instructions coating
Step
Instructions
Time start
Time end
Performed by
Verified by
Date
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 ( ml/min)
Distance of gun from tablet bed……cm (20-40cm) √
January 19-22, 2011

39. Yield Reconciliation coated tablets
Tablets Compressed
……Kg, approx. ……..tablets B
Tablets Coated C
In-process samples D
Bulk Samples E
Rejection
Reconciliation Yield = B+C+D+E / A x = ……..%, Limit : %
Actual yield = actual tablets coated (B) / theoretical batch size x 100 =.. ….%
Yield limit = %
January 19-22, 2011

40. Sterile Products Focus Environmental conditions In-process tests SOPs
Type and make of sterilizing filter
Type and make of rubber stopper
January 19-22, 2011

41. 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 pascals (recommended values)
1 Pa (N/m2) = Millimeter of water (15.56º C) 1 Pa (N/m2) = Millimeter of water (4º C)
January 19-22, 2011

42. Environmental Conditions 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 A
3,520 20 B 29
352,000
2,900 C
3,520,000
29,000 D
not defined
January 19-22, 2011

43. Environmental Conditions sterile products
Recommended limits for microbial contamination
Grade
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 B 10 5 C
100 50 25 - D
200
January 19-22, 2011

44. Manufacturing Instructions list of equipment
Sr. No.
Name
Capacity
Make
Model ID
SOP 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
January 19-22, 2011

45. 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
Dissolve API and stir for …mins
1.5
Check pH ……( )
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,
January 19-22, 2011

46. 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
January 19-22, 2011

47. Critical SOPs sterile products
Critical Elements
Cleaning and sterilization of manufacturing vessels
temperature and dwell time
Washing and sterilization/depyrogenation of packaging materials
Sterilization of filtration assembly and 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
January 19-22, 2011

48. Thanks