3-1.

Assessing Batch Records

Satish Mallya
Quality Workshop, Copenhagen May 18-21,2014

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2010
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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

Vibratory Sifter

20"/30"

Rapid Mixer Granulator

500L

Fluid Bed Dryer

150Kg

Conta Blender

500L

Multi Mill

various

Peristaltic pump

N/A

Compression m/c

37 stations

Dedusting m/c

N/A

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)

API

AP-18

AR-2014-1

25.0

25.0

25.0#

Exp 1(filler)

RM-12

RM- 2014-2

60.0

60.0

60.0@

Exp 2

RM-18

RM2014-3

2.00

2.0

2.0

Exp 3

RM-07

RM2014-4

12.0

12.0

12.0

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)

15.50

99.0

0.34

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 extragranular 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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2010
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May
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