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

3-2. Assessing Production Documents: executed and master records

3-2. Assessing Production Documents: executed and master records

Satish Mallya

January , 2011

Satish Mallya January 20-22, 20102 |

DocumentationDocumentation

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


Manufacturing FormulaManufacturing 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, 2011January 19-22, 2011


Processing InstructionsProcessing 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


Packaging InstructionsPackaging 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


Packaging InstructionsPackaging 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.


January 19-22, 2011


Batch Processing RecordsBatch 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


Batch Processing RecordsBatch 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


Batch Packaging RecordsBatch 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.


January 19-22, 2011


Batch Packaging RecordsBatch 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


January 19-22, 2011


General RulesGeneral 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


General RulesGeneral 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


SOPsSOPs

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


SOPsSOPs

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


Environmental Monitoring RecordEnvironmental Monitoring Record

SOP No.:

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

DateTimeOperationRoom No.

Temp °C

%RHDiff. press (mm H2O)

signature

Dispensing23422.0

Sifting481.8

Milling2.0

Verify temperature, humidity and differential pressure are within acceptable limits, date and time are in chronological order .

January 19-22, 2011


Line Clearance RecordLine Clearance Record

Previous product

Batch no. of previous product

Alert: Previous product requires segregated facility – note to inspection

January 19-22, 2011


Cleaning Records for Processing AreasCleaning Records for Processing Areas

May run into several pages

SOP Nos.:

Stepsverification

All containers from previous batch removed √

Filters from return duct cleaned √

Floor cleaned √

All previous labels removed√

xxxxxxx√

yyyyyy

January 19-22, 2011


Batch RecordsBatch Records

Company

logo

Batch Manufacturing RecordPage 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


Batch Recordsformulation


Material Dispensing SOP No.: Balance ID Nos.:

Each tablet contains:

Sr. No.

IngredientMaterial code

AR No.Qty per unit (mg)

%Qty per batch (Kg)

1APIAP-18√

2Exp 1√

3Exp 2√

4Exp 3√

5Exp 4√

6Exp 6√

January 19-22, 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

January 19-22, 2011




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

January 19-22, 2011




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)

1AP-1823.5099.40.34 23.28 23.50

2AP-2260.0099.10.50 6.72 6.815

∑E 30.00∑E 30.315

January 19-22, 2011




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


Raw Material Dispensing Record Raw Material Dispensing Record

RM Code

IngredientQty 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


Manufacturing Instructionslist of equipment

Manufacturing Instructionslist of equipment

Sr. No.NameCapacityMakeModelIDSOP No.

1Vibratory Sifter20"/30"√√

2Rapid Mixer Granulator

500L√√

3Fluid Bed Dryer150Kg√√

4Conta Blender500L√√

5Multi Millvarious√√

6Peristaltic pumpN/A√√

7Compression m/c37 stations√√

8Dedusting m/cN/A√√

9Metal DetectorN/A√√

10Auto Coater60"√√

January 19-22, 2011


Manufacturing Instructionssifting

Manufacturing Instructionssifting

StepInstructionsTime start

Time end

Performed by

Verified by

Date

1.1API …… Kg

Exp 1 …… Kg

Pass through # 40 screen of Vibratory sifter and collect material in tared double PE lined container

√√√√√

1.2Exp 2 …… Kg

Exp 3 …… Kg

Pass through # 20 screen of Vibratory sifter and collect material in tared double PE lined container

√√√√√

January 19-22, 2011


Mesh sizesMesh sizes

Mesh sizeMicronMms

1020002.000

208410.841

305950.595

404000.400

502970.297

602500.250

702100.210

801770.177

1001490.149

1201250.125

1401050.105

January 19-22, 2011


Manufacturing Instructions mixing & granulation

Manufacturing Instructions mixing & granulation

Mixing SOP No.: Granulation SOP No.:

Step

InstructionsTime start

Time end

Performed by

Verified by

Date

2.1Load 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

√√√√√

2.2Spray 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

√√√√√

January 19-22, 2011


Manufacturing Instructions wet milling and drying

Manufacturing Instructions wet milling and drying

Wet Milling SOP No.:

Drying SOP No.: LOD: 1.0-2.5% (moisture balance at 105ºC)


Time end

Performed by

Verified by

Date

3.1Pass wet mass through 1mm screen of Multi Mill

Speed – fast; Knives - forward

collect in FBD

√√√√√

3.2FBD in let temp 60ºC

Damper 80% open for 15 min

Damper 50% open after 15 minutes ; LOD ……..%

√

√

√

√

√

√

√

√

√

√

January 19-22, 2011


Manufacturing Instructions size reduction & blending

Manufacturing Instructions size reduction & blending

Size reduction SOP No.: Blending SOP No.:


Time end

Performed by

Verified by

Date

4.1Fit 0. 8 mm screen to Multi Mill and pass material from 3.2

Speed – Medium

Knives - forward

√√√√√

4.2Load dried granules from 4.1 into Conta Blender and blend for 20 mins at 12+1 rpm√√√√√

January 19-22, 2011


Manufacturing Instructions lubrication

Manufacturing Instructions lubrication

Lubrication SOP No.:


Time end

Performed by

Verified by

Date

5.1Fit 60 mesh screen to vibratory sifter and pass

Exp 5 ……….Kg

and collect in tared double PE lined container

√√√√√

5.2Add contents from 5.1 to 4.2 and blend for 3 mins and collect in tared double PE lined container√√√√√

January 19-22, 2011


Yield Reconciliationlubricated granulesYield Reconciliationlubricated granules

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%

Atheoretical batch weight Kg

Bactual weight Kg

Csamples Kg

Drejection Kg

January 19-22, 2011


Manufacturing Instructions compression


Balance no.: Vernier Caliper no.:

Hardness tester no.: Friability tester no.:

Disintegration tester no.:

ToolingNo. of unitsChecked byVerified by

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 shaped1

January 19-22, 2011




ParameterLimitObservation

Machine speed20 rpm (15-25 rpm)

Wt. of 20 tabs12.00g +2 (11.76-12.24g)

Theoretical weight/tab600mg

Hardness25Kg (20-30 Kg)

Thickness (av. of 10 tabs)4.10mm +0.15mm (3.95 – 4.25mm)

Length10mm + 0.1 mm (9.9 – 10.1 mm)

Width5 mm + 0.1mm (4.9 – 5.1 mm)

Disintegration timeNMT 15 mins

Wt. variation+ 3% of Av. Wt.

Friability (10 tabs)NMT 1.0% w/w

January 19-22, 2011


In-process ChecksIn-process Checks

ParameterFrequency

Wt. of 20 tabsEvery hour by production and every two hours by QA

Hardness, thickness, length, widthEvery hour by production, every two hours by QA

Wt. variationEvery half hour by production and every hour by QA

DTEvery half hour by production, every hour by QA

January 19-22, 2011


Yield Reconciliation compressed tabletsYield Reconciliation compressed tablets

Yield = ∑NW/ theor. wt. x 100 = …… %

Container no.

Gross wt. KgTare weight Kg

Net weight Kg

Weighed by/ date

Checked by/ date

1√

2√

3√

∑NW √

January 19-22, 2011


Yield Reconciliation compressed tabletsYield Reconciliation compressed tablets

Reconciliation Yield = B+C+D+E / A x 100 = ……..%, Limit : 97-101%

Actual yield = actual tablets compressed (B)/ theoretical batch size x 100 = ….%,


ALubricated granules……Kg, approx. ……..tablets

BTablets compressed……Kg, approx. ……..tablets

CIn-process samples……Kg, approx. ……..tablets

DBulk Samples……Kg, approx. ……..tablets

ERejection……Kg, approx. ……..tablets

January 19-22, 2011


Manufacturing Instructions coating

Manufacturing Instructions coating


Time end

Performed by

Verified by

Date

6.1Introduce 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)

√√√√√

January 19-22, 2011


Yield Reconciliation coated tablets

Yield Reconciliation coated tablets

Reconciliation Yield = B+C+D+E / A x 100 = ……..%, Limit : 97-101%

Actual yield = actual tablets coated (B) / theoretical batch size x 100 =.. ….%


ATablets Compressed……Kg, approx. ……..tablets

BTablets Coated……Kg, approx. ……..tablets

CIn-process samples……Kg, approx. ……..tablets

DBulk Samples……Kg, approx. ……..tablets

ERejection……Kg, approx. ……..tablets

January 19-22, 2011


Sterile Products 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


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)

January 19-22, 2011




GradeMaximum 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

A3,520203,52020

B3,52029 352,000 2,900

C352,000 2,900 3,520,000 29,000

D3,520,000 29,000 not defined not defined

January 19-22, 2011




Recommended limits for microbial contamination

GradeAir 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

B10555

C1005025-

D20010050-

January 19-22, 2011


Manufacturing Instructions list of equipment

Manufacturing Instructions list of equipment

Sr. No.

NameCapacityMakeModelIDSOP No.

1SS Manufacturing Tank1000 L√√

2Tunnel Sterilizer√√

3Dry Heat Sterilizer√√

4Autoclave√√

5Ampoule/vial filling/ sealing machine

√√

6Leak tester√√

January 19-22, 2011


Manufacturing Instructionssterile products

Manufacturing Instructionssterile products


Time end

Performed by

Verified by

Date

1.1Take 45 Lts WFI in SS tank√√√√√

1.2Purge nitrogen for …mins√√√√√

1.3Dissolve preservative and stir for … mins√√√√√

1.4Dissolve antioxidant and stir for ….mins√√√√√

1.4Dissolve API and stir for …mins√√√√√

1.5Check pH ……(4.0-6.5)√√√√√

1.6Make volume to 50L and stir for 15 mins√√√√√

1.7 Filter bulk through 0.22µ filter

SOP No….

√√√√√

1.8Fill in 2 mL ampoules,

SOP No….

√√√√√

January 19-22, 2011


In-process Checks sterile products

In-process Checks sterile products

TestAcceptance Criteria

Bioburden (prior to aseptic filtration)NMT 10Cfu/100ml

pH5-6

Assay97-103%

Fill volume3.8– 4.2 mL

Filter integrity ( pre and post filtration)NLT 35 psi

January 19-22, 2011


Critical SOPs sterile products

Critical SOPs sterile products

SOPCritical 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 filtrationprocedures, filter size

Filter integrity testlimits

Leak testprocedure

Media Fillno. of units, media, interventions

Terminal sterilizationF0, temperature and dwell time

January 19-22, 2011

Thanks

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

Documents

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