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VALIDATION PROTOCOL PROCESS VALIDATION FOR CEFAKID GRANULES

PROTOCOL APPROVAL

6 Equipments/ Materials Required for the validation 5

1 Objective:

The objective of this proces validation protocol is to establish documentedevidence that the processing for CEFAKID GRANULES will consistency produce

a product, which meets its predetermined specification and quality attributes

2 Scope Process Description:

The prospective process validation will be performed with qualified equipment inthe Betalactam non-sterile workshop with three consecutive batches of theproduct CEFAKID GRANULES

This process validation (PV) protocol is written in order to document that the

process used in the manufacturing of the product name CEFAKID GRANULES of

batch size: 150.00 kg # 50,000 sachets complies with process parameters

requirement of the Batch Manufacturing Record (BMR) and finished productspecifications

3 Abbreviations:

 HPLC - High Performance Liquid Chromatography

 SPC - Specifications and Testing Procedure

Recording of observation, collection of data and filling ofBMR

Engineering &

Maintenance

To ensure that all the required utilities are working as perthe respective SOPs

To ensure that the related instruments and equipments are

in calibrated and validated status

To ensure that the environmental conditions of all the areasmet the requirements

QC Testing shall be done as per the sampling plan andrespective specifications

QA

Prepare process validation protocolSampling as per the sampling plan (IPC)Preparation and review of the Validation report, documentsand its compliance to meet the acceptance criteria of theprotocol

 Ensure that all concerned people involved are trained on all current SOPs/SPCs and concerned practices in GMP areas during manufacturing process

as well as sampling for testing

 Ensure that appropriate PPEs (i.e safety gloves, mask, cap, goggles etc.)shall be used

 Checking the electric safety and calibration of instruments

6 Equipment/ Materials Required for the Validation:

IQR-L-KH-1OQR-L-KH-1PQR-L-KH-1

IQR-L-XH-1OQR-L-XH-1PQR-L-XH-1

IPC equipments

7 Validation Study Plan:

7.1 Product information

Product Name CEFAKID granules

API/ Strength Cephalexin 250 mg

Dosage Form Granule

Product Code 50.C45

Batch Size 150.00 kg # 50,000 sachets

Shelf Life 36 months

Category Antibiotic in Cephalosporin group

Label Claim Each sachet contains: Cephalexin monohydrate equivalent tocephalexin anhydrous of 250 mg

7.2 Time schedule (approx.)

7.3 Validation team:

Spain In-houseIn-house SPC-RM-046-01

Corresp to Cephalexin

VN4D01.KCP Sugar milled through0.8 mm sieve Vietnam (KCP) EP 6.0 SPC-RM-009-01 1950.00 65.00 97.50 = (2 x 48.75)

Total of filled ( Not including solvent) 3 000.00 100 150.00

8 Procedure:

8.1 The selected validation approach is prospective validation

 First three consecutive batches of CEFAKID GRANULES aremanufactured as per the authorized BMR no 50.C45/M01/03 (formanufacturing process), the authorized BPR no 50.C45/P01/03 (forpackaging process) and it is performed validation as per specifications inprotocol

 QA staff will do the sampling as per given sampling plan Thesamplings will be identified i.e batch number, stage, the number of sample,locations and sampling as per the sampling plan (refer section 11)

 The samples will be analyzed by IPC/ QC as per approved testingmethod and approved specification

 Packaging will only be done when capsules comply with all the tests byQC

 After satisfactory analytical results, BMR and BPR will be approved byQA

 Test results and data generated during the process validation studieswill be complied and reviewed at each stage of manufacturing and definedprocess parameters

8.2 The trials will include upper and lower processing conditions that will be encountered

normally in the routine production

8.3 These trials may include worst case conditions but not necessarily simulate the

failure range of the product processing conditions

8.4 A summary report will be prepared on the effect of different variables and final

conclusion will be drawn on the effect of different variables on the processing ofthe product

8.5 Manufacturing process and sampling for validation is performed as per the follow

chart

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8.6 Manufacturing process description

Flow of manufacturing process

Dispensed raw materials and intermediate product are transferred torespective process areas as per material movement plan as per SOP 120003

 Weighing and Checking

The weight of the materials received from dispensing area will be checked byIPC, production person against the dispensing labels as per SOP 120003

 Sifting (all dispensed materials)

Sift Aspartam and sugar, manitol 60 through 24 mesh sieve and contain it in

PE bags

Sift Cephalexin monohydrate through 14 mesh sieve and contain it in PE bagsCheck the integrity of sieve before and after use: clean and integrity

 Formulation of paste solution

Pour 10.20 kg 96% ethanol into tank of the stirring mixer Add PVP K29-32slowly when stirring

Stir until the viscous solution become transparent Stir and put slowlyQuinoline yellow lake mixture, stir until the viscous mixture become yellow.Stirring time: 10 - 20 minutes

 High speed mixing

Add sifted-materials in turn to machine: refined sugar, Mannitol 60,Cephalexin monohydrate, Aspartam Mix time: 2 + 1 minutes at speed of 1

400 rpm

After pour slowly paste solution in bowl of high speed mixer Mix time: 2 + 1minutes at speed of 1 400 rpm

 Wet granulating machine

Transfer granules to wet granulating machine Check the integrity of sieve2mm after use: integrity

 Tray dryer

Put stainless steel trays with granules into drying chamber

Remove ethanol: To install supply fan and exhaust fan at speed of 1400 rpm.Drying time : 15 minutes

The 1st drying: To install supply fan and exhaust fan at speed of 1400 rpm.Drying time : 15 minutes drying temperature: 32 – 42oC

The 2st drying: To install supply fan and exhaust fan at speed of 1400 rpm.Drying time : 50-60 minutes drying temperature: 50-60oC

Cooling: To install supply fan and exhaust fan at speed of 1400 rpm Coolingtime: 10 minites

Add in the order: dried granules of lot 1, Apple powder flavour, dried granules

of lot 2 into bowl of the Cubic mixer Mixing speed: 25 rpm Mixing time: 4phút/ minutes

 Sachet packing

Using vertical sachet packing machine, adjust parameters of machine to meetstipulated specifications

Before start up of the sachet packing operation, verify and record thetemperature (18 – 25oC) and relative humidity (NMT 55%)

8.7 Critical process step

 Critical process control variables at each critical manufacturing step andmeasured parameters are as follows:

NA

2 Dispensing ofraw material

Weighingoperations arepersormed usingcalibrated

balances as percurrent SOP

Process does not havevariable effects on theproduct quality whendefined operatingprocedure is followed

This is performedaccording to SOP andBMR

NA

3 Sifting of rawmaterials

Check for anylumps/ foreignmatter after siftingVisually check forthe intactness ofsieve before andafter use

removal of foreignmaterials if any from theactive or excipients

Sieve integritybefore and aftersifting

4 High speed mixing Time and RPM

To demonstrate theblend uniformity withbinder solusion Appearance

5 Final mixing Mixing time andmixing speed

To demonstrate theblend uniformity on

lubrication

Mixing timeMixing speedAppearanceMoisture/ Watercontent

Distributiongranule sizeBulk/ Tape densityBlend uniformity

6 Sachetpacking

Speed, Verticalbar temperature,horizontal bartemperature,Glue-pressedtemperature

To demonstrate thecharacterization of themachine parameters

Speed, Verticalbar temperature,horizontal bartemperature,Glue-pressedtemperatureAppearanceAverage mass of

20 empty sachetsAverage mass of

sachetAverage mass of

1 filled sachetAverage massLength

Leak testIdentificationUniformity ofmass

Uniformity ofcontent

Water contentDissolutionAssay

9 Sampling Plan:

The sampling plan is defined for a batch as per table below:

9.1 Stage of Final mixing (Granules)

 In-process control:

S No Test Item Time Q’ty / sample Number of samples Sampling points procedure Testing

1 Appearance

After completion offinal mixing each sample60 gram for 05 As per the figure 1 SOP 020018

2 Moisture content (LOD)

3 Bulk/ Tape density

Figure 1: Sampling points

 For QC testing:

samples Sampling points Testing procedure

1 Distribution granule size At 4 minutes of finalmixing process sample, in triplicate50 gram for each 05 As per the figure 1 STP-010028

2 Appearance

At 4 minutes of finalmixing process

10 gram for eachsample in triplicate 10 As per the figure 2 SPC-IP-062-01

5 Blend uniformity

Figure 2: Sampling points

9.2 Stage of sachet packing

 Done by IPC:

3 Sachet length Starting, middle, end of batchprocess stage, start of working

day, or unschedule (if any)

10 filledsachets

sachets

1 Characters Start, middle and end of the stage 40 filled

sachets foreach stage, intriplicate

SPC-BP-013-01 Three consecutive validation

6 Uniformity of content

7 Assay

10 Acceptance Criteria:

Each validation batch must meet the specifications of CEFAKID GRANULES

S.

No. Mfg Process Steps Test Item Acceptance Criteria

1 Final mixing (Granules)

Appearance Identical light – yellow granules, no dark spotsand strange coloured traceMoisture content (LOD) 0.7% - 1.4%

Bulk/ Tape density For information testing Distribution granule size For information testing

Identification

In the assay, the chromatogram obtained with test solution shows a peak with the same retention time as the principal peak in the chromatogram obtained with reference solution.

Blend uniformity

 8.3% (w/w)  10.0%; RSD ≤ 5.0%

Uniformity of mass  7.5% compared with average mass ofgranules.

 Expanded testing on three batches of CEFAKID GRANULES shoulddemonstrate reproducible results for the process to be consideredvalidated

 Acceptable results on each of the three consecutive batches are needed tosatisfy the validation requirements

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 If possible, control charts for quantitative validation tests will be analysed fortrends and to show satisfactory process control

 Batches may be dropped from the validation study only if events not related tothe process (e.g mechanical failure) cause a change in the process Suchoccurrences must be fully documented

11.Re-Validation:

11.1 Process validation will be revalidated, if there is:

 Changes location or site

 Changes in formula, manufacturing process, source/ specifications of rawmaterials/ packing materials, product specification or process controlparameters

 Changes in sampling plans

 Changes in equipments, including their location/ critical parts, specificationsand/ or process control parameters in utilities, directly affecting productquality

 Changes in approach to validation/ qualification of analytical method, processvalidation

11.2 If change in batch size, additional protocol/ addendum shall be prepared,

approved and executed through change control/ deviation procedure

12.References:

 BMR (50.C45/M01/03) and BPR (50.C45/P01/03) of CEFAKID GRANULES

 SOP 010002 – Change control

 SOP 010011 - Quality Risk Management (QRM)

 SOP 020009 - Instruction for test the disintegration

 SOP 020016 - Instruction for usage of leak-test apparatus

 SOP 020018 - In-process control on manufacturing of betalactam non-sterileproducts

 SOP 120003 - Dispensing of raw materials and packing materials of nonsterile betalactam

 SPC-IP-062-02 – Finished granules of CEFAKID GRANULES (processvalidation)

 SPC-BP-013-01 – Bulk product of CEFAKID granules

 STP-01014 – Determination of water with Karl Fischer reagent

 STP-01028-Particle-size distribution estimation by analytical sieving

 STP-01003- Test for uniformity of content of single-dose preparations

 STP-01019 – Thin – layer chromatography

 STP-01001 – Test for uniformity of mass of single-dose preparations

 Validation Master Plan

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