Download 3-1 AssessingBatchRecords

3-1. Assessing Batch Records
Satish Mallya
Quality Workshop, Copenhagen May 18-21,2014
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2010
May
18-21,2014
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Outline
 Focus on immediate release solid dosage forms
 Design and content
 Expectations
 Case Studies
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Documentation
 Relevance:
– 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.
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Documentation
 Requirements:
– Copies of the FPP master production documents should be
provided for each proposed strength, commercial batch size
and manufacturing site.
– Master records should be in English, if not a translated version
should be available.
– Pilot batches should be manufactured by a procedure fully
representative of and simulating that to be applied to a full
production-scale batch.
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Preliminary Verification
 Ascertain that copies of the FPP master production documents are provided for
each proposed strength, commercial batch size and manufacturing site.
 Compare the blank master batch record with the executed batch record for the
biolot to ensure that the proposed manufacturing process for the commercial
product is representative of the process used to manufacture the biolot.
 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). Ensure that
provision is made (e.g on page 1) for the following information and it is accurate:
– Product name, product code, batch number, batch size and date of manufacture
– Multiple signatures and dates recording chain of approval process and
responsibilities
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Preliminary Verification
 Environmental Monitoring : Verify temperature, humidity and
differential pressure are within acceptable limits, date and time are
in chronological order . For photosensitive products ensure
adequate lighting precautions are in place
 Line Clearance Record - Alert: Previous product requires
segregated facility – note to inspection
 Cleaning Record for processing areas: May be several pages (not
high risk for solid oral dosage forms -eyeball)
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Manufacturing Methods
WET GRANULATION
DRY GRANULATION
DIRECT COMPRESSION
Milling/Screening
Milling/Screening
Milling/Screening
Pre-blending
Pre-blending
Blending/lubrication
Addition of binder
Slugging/roller compaction
Compression
Screening of wet mass
Dry screening
Drying of the wet granules
Blending of lubricant
Screening of dry granules
Compression
Blending of lubricant (and
disintegrant)
Compression
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Manufacturing Equipment
Ensure that all critical equipment have been identified at least by type and working
capacity – check if all listed equipment are referenced in the manufacturing process
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Sr. No.
Name
Capacity
Make
Model
ID
1
Vibratory Sifter
20"/30"
√
√
√
2
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"
√
√
√
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Detailed Assessment
 Master formula:
– Ensure batch formulation in line with unit formulation;
– Check for overages of API and excipients;
– Verify if provision is made for recording material codes and
analytical report numbers;
– Ascertain calculation(s) for API content is accurate
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Calculating API content
 When the amount of API is adjusted based on the assay results and/or on
anhydrous basis - single lot of API
– 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
Calculation for API = {Theoretical quantity of API required x 100 x 100}
{% Assay of API x (100-%water content)}
Calculation for filler = {Theoretical quantity of API required + theoretical
quantity of filler} – quantity of API
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Case Study 1
 Batch Size: 1000,000 tablets
Each tablet contains: 25 mg of API
No.
Ingredient RM Code AR No.
Qty per unit (mg)
%
Qty per batch (Kg)
1
API
AP-18
AR-2014-1
25.0
25.0
25.0#
2
Exp 1(filler)
RM-12
RM- 2014-2
60.0
60.0
60.0@
3
Exp 2
RM-18
RM2014-3
2.00
2.0
2.0
4
Exp 3
RM-07
RM2014-4
12.0
12.0
12.0
5
Exp 4
RM-46
RM 2014-5
1.00
1.0
1.0
 # actual quantity = A = [25 x 100 x 100]/ [%assay x (100-% water content)]
 @ actual quantity = (API + filler) – A = 85-A
 Assay = 98%, water content= 0.5%, calculate the quantities of API and Exp 1
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Calculating API content
When the amount of API is adjusted based on the assay results and/or on
anhydrous basis - multiple lots of API
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)
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Case Study 2
 Calculation of quantity of API per batch:
 Theoretical quantity of API [100% assay (anhydrous) and nil water] = 25 Kg
Lot 1:
Total available quantity (as is basis) (A) = 15.50 Kg
Actual assay (B) = 99.0% ; Water content (C) = 0.34%
Qty of API equivalent to 100% assay and nil water (D)
= A x B/100 x (100-C)/100
= …… Kg
Balance quantity of API required (100% assay and nil water)
= 25 – ….. Kg
= …… Kg
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Case Study 2 (continued)
Lot 2
Quantity of API required (100% assay and nil water) (D) = …… Kg
Total available quantity (as is basis) (A) = 30.00 Kg
Actual assay (B) = 99.4%
Water content (C) = 0.50%
Equivalent quantity of API required from lot 2
= D x 100/B x 100/(100-C)
= ……. Kg
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Case Study 2 (contd)
Theoretical quantity of API [100% assay (anhydrous) and nil water] = 25 Kg
Lot No.
Total available
quantity (as is basis)
(Kg)
Assay (%)
Water content
(B)
(% w/w)
Actual
Quantity
used in FPP
(C)
(Kg)
(A)
1
15.50
99.0
0.34
2
30.00
99.4
0.50
∑
Quantity of Filler required (case study 1) = …………………….Kg
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Detailed Assessment
 Process parameters (e.g. mixing time, mixing speed, milling screen
size, processing temperature range, granulation end-point, tablet
machine speed);
 In-process tests (e.g. loss on drying, weight variation, hardness,
disintegration time, weight gain during coating);
 Sampling plan at different stages (number of samples to be tested
and frequency of testing during drying, lubrication, compression);
 Holding times at intermediate stages;
 Yield reconciliation (lubricated granules, core tablets, coated
tablets).
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Case study # 3
 Tablets are manufactured by a wet granulation process. Intra-granular materials
are sifted and mixed in a rapid mixer granulator. The granulating fluid is prepared
separately and added to the blend. The end point of granulation is determined by
the operator by pressing the wet mass in the palm to make a ball and then
breaking it with the thumb - it should break in small lumps. The wet mass is sifted
through a multimill and the granules thus formed are dried in a fluid bed dryer
until the granules attain a LOD value of NMT 3%. The maximum processing time
from dispensing to end of drying should not be more than 30 days. The dried
granules are passed through a sieve, mixed with previously sieved extra-granular
excipients and collected in drums. This blend can be stored for up to 30 days.
Tablets are compressed on a rotary machine. Total compression time is 3 hours.
Weight variation and DT are checked every hour during compression. The limit
for average weight of 20 tablets is set at target weight + 5% and the limit for
individual weight variation is set at target weight + 15%. The time elapsed
between end of compression and beginning of coating should not exceed 90
days
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Thanks
Questions ?
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