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Process Validation Protocol For Gliclazide Modified Release Tablets

 Label claim :

Each uncoated modified release  tablet contains

Gliclazide Ph. Eur …………60 mg                               

 Master Formula No. : 

 Product Code :

 Batch Size  :                     

 Shelf Life  :

 Protocol No. :

 Effective Date :

PROTOCOL CONTENTS 

Sr.No. Section Title Pages No.
NA Protocol Contents
NA Protocol Approval Sheet
1.0 Objective
2.0 Scope
3.0 Responsibility
4.0 Validation Team Members
5.0 Abbreviations
6.0 Pre-requisite for Validation
7.0 Manufacturing Procedure
8.0 Critical Process Steps and Process Parameters for Validation with Justification
9.0 Process steps – Sampling and Analysis Plan with Acceptance Criteria
10.0 Hold Time study
11.0 Revalidation
12.0 OOSs and Investigations
13.0 Validation Report
14.0 Reference Documents
15.0 List of Annexures / formats Attached

 

PROTOCOL APPROVAL SHEET

This is a specific protocol for Process Validation of uncoated modified release tablet of Gliclazide Modified Release 60 Tablets which is manufactured at solid oral manufacturing facility in Pharmaceutical company

This protocol has been approved by the following: 

Prepared by:

Functional Area Name Designation Signature Date

 

Quality Assurance

                 

Checked by:

Functional Area Name Designation Signature Date

 

Process Development
Quality Assurance

 

      Approved by:

Functional Area Name Designation Signature Date

 

R&D
Production
Quality Control
Regulatory Affairs
Quality Assurance
  • Objective

To provide documented evidence with high degree of assurance that the manufacturing process is capable of producing the finished product consistently of required quality, meeting its predetermined specifications and quality attributes.

  • Scope

This concurrent process validation protocol is applicable to carry out the process validation for Gliclazide Modified Release 60 Tablets on three consecutive batches at formulation Plant of pharmaceutical company.

  • Responsibility

Quality Assurance                                :    Preparation, review and approval of process validation protocol.

R&D                                                     :    R&D to approve the process validation protocol

Production                                            :    Production to approve the process validation protocol.

Quality Control                                    :    QC to approve the process validation protocol.

Process Development                           :    To review the process validation protocol.

IPQA                                                    :    Sampling of samples as per the sampling plans discussed in
this process validation protocol.

Engineering                                          :    To provide support with respect to utilities and equipment

Regulatory Affairs                               :    Regulatory Affairs to approve the process validation protocol

      4.0  Validation Team Members

        Validation team is comprises of the Trained  representatives from following departments:

  • Production
  • R&D
  • Process Development
  • Quality Control
  • In-process Quality Assurance
  • Quality Assurance
  • Engineering
  • Abbreviations

R&D : Research and Development

QC  : Quality Control

IPQA: In-process Quality Assurance

RSD : Relative Standard Deviation

NMT : Not More Than

NLT  : Not Less Than

STP  : Standard Test Procedure

LOD  : Loss on Drying

GTP  : General Test Procedure

ID No.: Identification Number

Spec. No.: Specification No.

RH% : Relative Humidity

SOP  : Standard Operating Procedure

IQ : Installation Qualification

OQ : Operational Qualification

PQ : Performance Qualification

IH  : In-house

IPC’s : In Process Containers

Representative Sample :A sample collection from one location / place; representing the characteristics of the whole batch / lot.

Composite Sample :A desired amount of sample shall be taken after collection of samples from different location in one sample bag.

  • Pre-requisites for Validation
    • Process Equipments

All equipments to be used for the manufacturing process are qualified as per IQ/OQ/PQ acceptance criteria. The following equipments are to be used for manufacturing of Gliclazide Modified Release 60 Tablets

S.No. Equipment Name Process Step&  Area Make Equipment

 ID No.

Capacity

 

Qualification

status(report no.)

    1. Vibro Sifter Sifting
    2. Conta Blender Mixing
    3. Roll – Compactor Slugging
    4. Comminuting-Mill Milling
    5. Compression M/C Tablet Compression
    6. Blister Packing Machine Packing

 

  • Equipments / Instruments used for In-process checks

The following calibrated equipments / Instruments are used for in-process checks.

S. No. Equipment /Instrument Name Equipment ID. No. Calibration status

(kit-used for calibration)

1.        Analytical weighing Balance    
2.        Friability Test Apparatus
3.        Hardness Tester
4.        Vernier Caliper

 

Following specifications and Standard Test Procedures are referred for carrying out testing of validation samples.

               *SPECIFICATIONS No.                                                  *STP No.

In-process:

Finished Product -Release:

*Testing of samples is done as per current version of STP’s and GTP’s

  • Approved Raw Materials

The raw material used for manufacturing process are from approved vendors and all the Raw Materials are  tested before manufacturing process  to ensure that material are of the acceptable quality prior to their use in the manufacturing .

Approved Raw Materials List 

Ingredient Pharmacopoeial Status  Item Code Standard Quantity

 Per batch In kg

Pharmaceutical

role

Gliclazide * Active
Calcium Hydrogen Phosphate

Dihydrate

Filler
Cellactose 80 Filler
Hypromellose Rate controlling excipients
Hypromellose Rate controlling excipients
Silica, Colloidal Anhydrous Glidant
Povidone (K-30) Binder
Magnesium Stearate Lubricant
Talc Lubricant
Magnesium Stearate Lubricant
Talc Lubricant

*Given quantity of Gliclazide is BASED ON ASSAY (ODB) = 100.00  %  W/W

L.O.D =     0.00   %  W/W

  • Manufacturing Procedure :
    • Manufacturing procedure in brief comprise of following steps:
      • SIFTING : Sift Gliclazide, Calcium Hydrogen Phosphate Dihydrate, Hypromellose, Silica, Colloidal Anhydrous, Povidone (K-30)  Magnesium Stearate, Talc through Vibro Sifter fitted with sieve of mesh size 80, and retention through Vibro Sifter fitted with sieve of mesh size 60 collect the sifted material in IPCs.
      • SIFTING : Sift Cellactose 80 through Vibro Sifter fitted with sieve of mesh size 30 collect the sifted material in IPCs.
      • DRY MIXING : Perform dry mixing  of  materials of Previous step  in Blender’s bin. ( mix for 20 minutes at 5 rpm)
      • SLUGGING : Slug the mass of step in Roll-Compactor, adjust and record Feed screw rate and speed of rollers and weigh the slugs.
      • DESLUGGING : Mill the Slug mass  by comminuting mill fitted with 5.0 mm Screen at knife forward orientation and at slow speed .
      • SIFTING :Sift the milled mass through Vibro Sifter fitted with sieve of mesh size 20 and pass the retention through comminuting mill fitted with 2.0 mm Screen at knife forward orientation and at slow speed , repeat the above process till all the material  passed through sieve of mesh size 20 .
      • SIFTING :
  1. a) Sift the material through Vibro Sifter fitted with sieve of mesh size  40,collect and weigh the retention.
  2. b) If the retention of sifting  is less than 45 % then collect  & weigh (using  calibrated balance )separately the fines.

If the fines percentage is more than 55 % then repeat process  steps slugging,milling and sifting for  fines until fines % is less than  55 % ,if it is less 55 % then directly proceed for next  step

  • LUBRICATION OF GRANULES : a) Transfer the Milled material  to a Blender’s bin.
  1. b) Sift Magnesium Stearate, Talc through Vibro Sifter fitted with sieve of mesh size 60 & transfer to  Blender’s bin of milled material.  Blend for 10 minutes at 5 rpm.
  • WEIGHING :Weighing of lubricated granules is done  by using a calibrated balance and calculate the actual  .
  • SAMPLING : Inform to IPQA Department through In-process Analytical Request to collect the sample of blended granules , IPQA personnel  send the sample to Quality Control Department for testing as per In-process Specification.
  • COMPRESSION : After getting approval from IPQA Department, compress the lubricated blend , into tablets of required specification using 37 station compression machine fitted with oval dies and standard concave punches (14.00 ± 0.05 mm x  00 ±  0.05 mm),plain on both sides.

                                                  COMPRESSION PARAMETERS

  • Description : White to off-white, oval , biconvex uncoated tablets, plain on both sides.

Average Weight: 422.0 to 438.0 mg

Thickness: 5.00 ± 0.20 mm

Length : 14.15 ± 0.05 mm

Width : 7.05 ± 0.05 mm

Hardness : 70 – 100 N

Friability : NMT 1.0 %w/w

Weight variation : Individual mass of 20 tablets should not deviate by more than 5.0 % of the average weight.

  • IPQA CHECKS : Carry out in-process control /check as per SOP..
  • SAMPLING : Inform to IPQA Department through In-process Analytical Request to collect the sample of tablets for analysis as per approved in process specification No.   
  • WEIGHING : Collect the Compressed tablets in HDPE containers lined with double poly ethylene bags & weigh and calculate the  final yield of Compressed Tablet.                      
  • PACKAGING : After getting approval from IPQA Department, pack the approved tablets as per  approved BPR.
  • Critical Process Steps and Process Parameters for Validation with Justification :

Process Step Process Parameters Justification
DISPENSING % RH & Dispensing aids Influence the stability and manufacturing of product
SIFTING Sieve size , sifting time and integrity of sieve. To  evaluate the sifting time

during sifting process

DRY-MIXING Dry-mixing time,and Blending RPM After completion of sifting, the process of dry mixing is evaluated for Homogeneity of drugs through sampling of the mixed blend after 20 minutes at 5 rpm. Blending is done using Conta Blender.  This process step is evaluated for adequate blending time assessment  through the determination of blend uniformity analysis of samples collected from different locations. .Refer  Annexure-02 for sampling plan and analytical data compilation and acceptance criteria.It can influence both the content uniformity & assay of  product.
SLUGGING Feed screw rate, Speed of rollers. For detail refer Annexure-01. To record and evaluate the variability of critical process variables for process step of slugging to achieve granules size of desired properties.
DESLUGGING/ MILLING Feed rate of slugs. Milling speed, Blade orientation and Screen size. For detail refer Annexure-01. Effective deslugging is achieved by adjusting the feed rate to 10.0 kg/ 40-60 minutes.
SIFTING Sieve size , sifting time and integrity of sieve for detail refer annexure -01 To record and evaluate the variability of critical process variables during sifting.
LUBRICATION/ BLENDING Blender speed (rpm) and Blending time etc. For detail refer annexure-01 After addition of sifted Magnesium Stearate,Talc to the granules; blending is  done using Conta Blender. This process step is evaluated for adequate blending of the lubricant by sampling of the blended granules from different locations from the blender bin after 10 minutes of blending. The assessment is taken through the determination of blend uniformity analysis in samples collected from different locations. The blend to be monitored for Bulk Density & Tapped Density on the composite sample collected after 5  minutes to determine the flow properties of the blended granules. Sampling is done by using suitable sampling thief. Refer Annexure-03 for sampling plan and analytical data compilation and acceptance criteria.
COMPRESSION  Machine Speed, Description, Average Weight, Uniformity of Weight, Thickness, Length, Width, Hardness, Friability etc. For detail refer Annexure-01. Tablets are Compressed using 37 Station Double Rotary Compression Machine. This process is evaluated through sampling the compressed tablets from both sides (left & right) produced at different intervals (Start, Middle and towards the end of compression). Samples are checked for the determination of Description, Average Weight, Uniformity of Weight, Thickness, Length, Width, Hardness & Friability against the established specifications at IPQA Laboratory

Compressed tablets are subjected for the determination of Uniformity of dosage units (by content uniformity for total Gliclazide Ph.Eur & Drug release .

One composite sample is subjected for complete analysis as per the established

specifications. Refer Annexure-04 for sampling and analysis plan compilation with acceptance criteria

 

Process Steps – Sampling and Analysis Plan with Acceptance Criteria

Sampling is  done as per mentioned in Sampling plan. The process parameters are  challenged in the three validation batches.

 

Process Step Sampling and Analysis Plan  with Acceptance Criteria
Dry Mixing Refer Annexure-02
Lubrication Refer Annexure-03
Compression Refer annexure-04

 

 Hold time Studies

Process Step Hold Time Studies Sampling and Analysis Plan with Justification
 

 

BLENDING /

LUBRICATION

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

TABLET COMPRESSION

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

About 300 gms material from blended mass is kept under simulating conditions. The material is subjected to analysis for Assay of Gliclazide Ph.Eur. Related substances   and LOD at 0 day, after 7th day & after 15th day. These samples are tested for Bulk Density, Tapped Density, Compressibility Index and Hausner Ratio to rule out the de-blending of the materials. Hold time Study shall be carried out in one batch only.

Samples are also  subjected separately for microbiological testing at 0 day, 7th day and 15th day.

 

Storage Environment (Bulk Storage Area)

Temperature : NMT 25ºC

Relative Humidity: NMT 45%

Closed S.S. Container / IPC lined with double polyethylene bags of appropriate size.

Test Method

 

Description, Assay of Gliclazide, LOD: Refer STP.

Related substances:  Refer STP.

Microbial Limit Test :

Refer GTP  for microbiological testing as per Ph.Eur.

Bulk Density, Tapped Density, Compressibility Index and Hausner Ratio

Acceptance Criteria 

Description: White to off white, flowing granules. sampled after 7th day and 15th day are comparable with that of 0 hr (initial).

Assay: Each 430 mg of granules contain not less than 97.5% and not more than 102.5% (58.5 mg to 61.5 mg) of the label claim of Gliclazide Ph.Eur., C15H21N3O3S (60 mg).

Related substances:

Single highest impurity :                                Not more than 0.75%

(specified RRT about 0.30)

Single highest unknown impurity :                 Not more than 0.3%

Total  impurities :                                           Not more than 1.0%

Loss on drying: Between 1.0% to 3.2% w/w, determined at 105C for 7 minutes.

Bulk Density, Tapped Density,  Compressibility Index and Hausner Ratio: Results of the samples sampled after 7th day & 15th day should be comparable with that of 0 day (initial)

Microbial Limits:

Total aerobic microbial count: NMT  500 cfu/g.

Total combined molds and yeasts count: NMT 50 cfu/g.

Escherichia coli: should be absent

Salmonella species: should be absent

Pseudomonas aeruginosa: should be absent

Staphylococcus aureus: should be absent

 

After completion of compression about 200.0 gms of compressed tablets are kept under simulating conditions for carrying hold Time studies. The sampling is done at 0 day, after 7th day & after 15th day. The sample is evaluated for the tests like Description, Assay and Related substances. Hold Time studies shall be carried out in one batch only.

Samples shall be subjected separately for microbiological testing at 0 day, after 7th day & after 15th day.

Storage Environment(Bulk storage Area)

Temperature : NMT 25ºC

Relative Humidity: NMT 45%

Closed HDPE lined with double polyethylene bags container of appropriate size.

Description, Assay: Refer STP.

Related substances: Refer STP.

Drug Release: Refer STP..

Microbial Limits:

Refer GTP for microbiological testing as per Ph.Eur.

Acceptance Criteria (0 day, 7th day and 15th day)

Description: White to off white oval, biconvex uncoated tablets, plain on both sides.

Assay: Each uncoated tablet contains not less than 95.0% and not more than 105.0% (57.0 mg to 63.0 mg) of the label claim of Gliclazide Ph.Eur., C15H21N3O3S (60 mg)

Drug Release : 

Complies with the test .Percentage of the labeled amount of Gliclazide is dissolved with in the range stated at each of following points.

2 Hrs.  :   NLT 14% and NMT  32 % of the label claim.

4 Hrs.  :   NLT 32% and NMT  55 % of the label claim.

12Hrs.  :   NLT 85% of the label claim.

Related substances:

Single highest impurity :                                Not more than 0.75%

(specified RRT about 0.30)

Single highest unknown impurity :                 Not more than 0.3%

Total  impurities :                                           Not more than 1.0%

Microbial Limits:

Total aerobic microbial count: NMT 500 cfu/g.

Total combined molds and yeasts count: NMT 50 cfu/g.

Escherichia coli: should be absent

Salmonella Species: should be absent

Pseudomonas aeruginosa: should be absent

Staphylococcus aureus: should be absent

Revalidation

If required, revalidation is  considered and carried out when any of the following conditions occur or prevail:

–   Change in critical formulation component i.e. raw material

  • Change in manufacturer or vendor of Active Pharmaceutical Ingredient
  • Change in critical specifications of the product
  • Change in manufacturing process which may affect the quality of the products.
  • Change in the facility and /or plant (location or site)
  • Change in batch size, if more than ten times of the present batch size

Note:  In case of the requirements for revalidation, because of above mentioned reasons, the validation of the critical steps shall be undertaken through addendum attached to this  protocol .

 

 

Annexure -I

Critical Process Variables   

Batch Number :………

Stage Equipment

Name

Process Variables Observation

 

Sifting ( Gliclazide, Calcium Hydrogen Phosphate Dihydrate, Hypromellose ,Colloidal Anhydrous, Povidone K-30,Magnesium stearate , Talc)  Vibrosifter

 

 

 

Sieve size  

 

Integrity of sieves Before
After
Sifting time
Sifting )  Cellactose 80 Vibrosifter

 

Sieve size
Integrity of sieves Before
After
Sifting time
Dry mixing Conta blender

 

 

Blender rpm  

 

Mixing time  

 

Capacity of Blender Bin
Slugging Roll- compactor Feed screw rate.
Speed of rollers
Deslugging  Comminuting –

mill

Feed rate of slugs
Screen size
Screen integrity Before
After
Milling speed
Sifting of Post Granulation Ingredients Vibro sifter Sieve Size
Integrity of Sieve Before
After
Sifting time
Stage Equipment

Name

Process Variables Observation

 

Lubrication

 

Conta Blender Blender rpm
Blending time
Capacity of Blender Bin
Compression 37 station Double rotary compression machine Machine Speed
Feed frame (open/ forced)
Compression force
Packaging (Blistering) Blister Packing Machine

CH 240

Sealing plate temperature

 

Intial
End
Strip size
Leak test Intial
Middle
End

Prepared by____________                                                        Authorized By ____________

(Sign & Date)                                                                            (Sign & Date)

Annexure -II

SAMPLING PLAN, ANALYTICAL DATA COMPILATION & ACCEPTANCE CRITERIA

STAGE:  DRY MIXING

 (Sampling Plan)                         

Batch Number: …………………..                                       Equipment Name: Conta Blender

Sampling Time & speed  = after 14,15 & 16 minutes mixing at 6 rpm.

 Sampling Quantity = About 425.2 mg  to 1275.6 mg for each location sample and about 5 gm for composite sample

Shape of the blender bin with sampling location from 01 to 11
Sampling is done in triplicate from each sampling location using suitable sampling Device
Shape of the blender bin with sampling location from 01 to 11
Sampling is done in triplicate from each sampling location using suitable sampling Device
Record the following:

Sampling Location Sampled by

(Sign & Date)

Sampling Date & Time

 

14 min 15 min 16 min
1        
2
3
4
5
6
7
8
9
10
11
Composite sample

 

STAGE:  BLENDING

Analysis Plan & Analytical Data Compilation:

Determination of Blend uniformity analysis of samples as per STP for location samples and determination of assay, L.O.D on the composite sample.

Batch Number: …………………..  

                                               

Claim per unit Mass:  Each 425.2 mg of blended mass contains:

Gliclazide 60 mg Ph. Eur. .

Record the analytical findings in following manner:

 

Sampling Location Results % variation (±) from mean value A.R. Number

 

1    
2    
3    
4    
5    
6    
7    
8    
9    
10    
11    
 

Mean Value

  Acceptance Criteria

·    All individual values should be within ± 10% of the mean value.

·    % RSD for all individual results should be NMT 5.0

% RSD  

Analysis Plan for composite sample: Determination of assay

 

Test Results

 

A.R.No.
L.O.D    

 

  Assay    
Acceptance Criteria

L.O.D: Between 1.0 % w/w and 3.2 % w/w, Determined at 105 ºC for 7 minutes.

Assay: Each 425.2 mg of blend contains NLT 97.5% and NMT 102.5 % (58.5 mg to 61.5 mg)     of the label claim of Gliclazide Ph. Eur., C15H21N3O3S (60 mg)

 

Annexure -III

SAMPLING PLAN AND ANALYTICAL DATA COMPILATION WITH ACCEPTANCE CRITERIA

                                                             STAGE:  LUBRICATION

Sampling Plan:

Batch Number: …………………..                                       Equipment Name: Conta Blender

Equipment ID No.: ……………….                                                                           

Sampling Quantity = 430 mg to 1290 mg from each location in triplicate and about 10 gm for composite sample.

Shape of the blender bin with sampling location from 01 to 11
Sampling shall be done in triplicate from each sampling location using suitable sampling thief

Sampling Time = after 8 mins. of blending with  Magnesium stearate ,Talc.

Blending Time and Speed specified: 10 mins at 5 rpm

Blending Time actual: ……………. Minutes                                  Speed Actual: ……………. RPM

Record the following:

Sampling Location Sampled by

(Sign and Date)

1  
2
3
4
5
6
7
8
9

 

10  
11
Composite sample

  Note: Samples shall be sent to QC through the Analytical Request/ Report as per SOP

                                                            STAGE:  LUBRICATION

 Analysis Plan:

Determination of blend uniformity analysis for Gliclazide  Ph.Eur

Batch Number: …………………..                                                  

Claim per unit :  Each 430 mg of granules contain not less than 97.5% and not more than 102.5% (58.5 mg to

61.5 mg) of the label claim of Gliclazide  Ph.Eur C15H21N3O3S (60 mg)    

Record the analytical findings in following manner:

Sampling Location Results % variation (±) from mean value A.R. Number

 

1    
2    
3    
4    
5    
6    
7    
8    
9    
10    
11    
Mean value  

      

Acceptance Criteria

·    All individual values should be within ±10% of the mean value.

·    % RSD should be NMT 5.0%.

% RSD

 

Analysis Plan for composite sample:

Determination of assay, bulk density, tapped density, angle of repose, Compressibility Index and Hausner Ratio.

 

TESTS Results

 

A.R.No.
Assay  

 

 

 

 

Bulk Density  

 

Tapped Density  

 

Angle of Repose  

 

Compressibility Index

 

 
Hausner Ratio

 

 

Comments on the Process:

 

Annexure-IV

SAMPLING PLAN AND ANALYTICAL DATA COMPILATION WITH ACCEPTANCE CRITERIA

SAMPLING PLAN

STAGE: COMPRESSION  

Batch Number:……………..                                                                                   

Equipment Name:   37 Station Double Rotary Compression Machine

Equipment ID No.:………….                                                                                                                    

60 tablets are collected from machine at START, MID and towards the END of the compression and  given to QC for determination of Uniformity of dosage units (by content uniformity), Drug release  as per STP No.  Also the 100 tablets as COMPOSITE SAMPLE (collected at start, mid and end & then pooled) is subjected to analysis as per STP at QC.

Note: Samples to be collected for determination of In-process at IPQA laboratory as per SOP and recording shall be done accordingly.

  Date/Time (Hrs) of start of Compression after Machine setting  : 

  Date/Time (Hrs) of completion of Compression                            : 

Sampling Interval No. of tablets sampled for QC Testing(Intial , Middle End & Composite Sample Sampled by

(Name and Sign/Initials)

Sampling Date
R.H.S L.H.S
START (Time :……..)        
MID (Time :……..)        
END(Time :……..)                           

                       

Batch Number:……………..

Analysis Plan:

In-Process Controls: Description, Average weight, Uniformity of Weight, Friability, Length, Width Thickness & Hardness.

Testing at QC: As per STP on the samples of Start, mid and towards the end of compression and also on composite sample collected after completion of compression. 

DESCRIPTION: 

Sampling Intervals Description  Checked By

(Sign and Date)

Acceptance

Criteria

 

START

(Time:…

 

 

 

  White to off white oval, biconvex uncoated tablets,  plain on both sides .
MID

(Time:…

   
END

(Time:……….)

   

 

THICKNESS, LENGTH & WIDTH:                                                        

Sample size=10 tablets

Vernier Caliper ID No.:……………………

Equipment calibration date:……………….           Equipment calibration due date:………………….

Sampling Interval Thickness (mm) Length (mm) Width (mm) Checked by

(Sign and Date)

START

(Time:……….)

       
     
     
     
     
     
     
     
     
     
Average       Acceptance Criteria:

 

Thickness = 5.00 ± 0.2 mm

Length = 14.15 ± 0.05 mm

Width  = 7.05 ± 0.05 mm

Minimum      
Maximum      

 THICKNESS, LENGTH & WIDTH : 

Sampling Interval Thickness (mm) Length (mm) Width (mm) Checked by

(Sign and Date)

MID

(Time:……….)

       
     
     
     
     
     
     
     
     
     
Average        

 

Acceptance Criteria:

 

Thickness = 5.00 ± 0.2 mm

Length = 14.15 ± 0.05 mm

Width  = 7.05 ± 0.05 mm

Minimum      
Maximum      

  THICKNESS, LENGTH & WIDTH : 

Sampling Interval Thickness (mm) Length (mm) Width (mm) Checked by

(Sign and Date)

END

(Time:……….)

       
   
     
     
     
     
     
     
     
     
Average       Acceptance Criteria:

 

Thickness = 5.00 ± 0.2 mm

Length = 14.15 ± 0.05 mm

Width  = 7.05 ± 0.05 mm

Minimum      
Maximum      

 

AVERAGE WEIGHT AND WEIGHT VARIATION:

Sample size=20 tablets

Analytical Weighing Balance ID No.:………………

Equipment calibration date:…………..                              Equipment calibration due date:………………

Sampling Interval Average Weight Checked by

(Sign and Date)

START

   (Time :……….)

  1.                       2.                      
  3.                       4.                    
  5.                       6.                    
  7.                       8.                    
  9.                     10.                  
11.                   12.                  
13.                   14.                  
15.                   16.                  
17.                   18.                  
19.                   20.                  
Average Weight (mg)   Acceptance Criteria

Average Weight :

422.0 mg to 438.0 mg

Weight Variation :
ndividual weight of 20Tablets
should not deviate more than
± 5 % of the average weight

Maximum weight   (mg)  
Minimum weight (mg)  
Variation + %  
Variation–– %  

  

AVERAGE WEIGHT AND WEIGHT VARIATION:

Sample size=20 tablets

Analytical Weighing Balance ID No.:………………

Equipment calibration date:…………..                              Equipment calibration due date:………………

Sampling Interval Average Weight Checked by

(Sign and Date)

MID

   (Time :……….)

  1.                       2.                      
  3.                       4.                    
  5.                       6.                    
  7.                       8.                    
  9.                     10.                  
11.                   12.                  
13.                   14.                  
15.                   16.                  
17.                   18.                  
19.                   20.                  
Average Weight (mg)   Acceptance Criteria

Average Weight :

422.0 mg to 438.0 mg

 

Weight Variation :
Individual weight of 20Tablets
should not deviate more than
± 5 % of the average weight

Maximum weight (mg)     
Minimum weight (mg)  
Variation + %  
Variation–– %  

 

AVERAGE WEIGHT AND WEIGHT VARIATION:

Sample size=20 tablets

Analytical Weighing Balance ID No.:………………

Equipment calibration date:…………..                              Equipment calibration due date:………………

Sampling Interval Average Weight Checked by

(Sign and Date)

   END

(Time :……….)

  1.                       2.                      
  3.                       4.                    
  5.                       6.                    
  7.                       8.                    
  9.                     10.                  
11.                   12.                  
13.                   14.                  
15.                   16.                  
17.                   18.                  
19.                   20.                  
Average Weight (mg)   Acceptance Criteria

Average Weight :

422.0 mg to 438.0 mg

 

Weight Variation :
Individual weight of 20Tablets
should not deviate more than
± 5 % of the average weight

Maximum weight (mg)     
Minimum weight (mg)  
Variation + %  
Variation–– %  

 

FRIABILITY

Sample size= 10 tablets

Friability Test Apparatus ID. No.:……………….

Equipment calibration date:………………………            Equipment calibration due date:………………

Sampling Interval Friability Obtained Checked by

(Sign and Date)

START (Time:…….)    
MID (Time:…….)    
END (Time:……..)    
Acceptance Criteria

Not more than 1%w/w

 

HARDNESS:

Sample size=10 tablets

Tablet Hardness Test Apparatus ID No.:…………..

Equipment calibration date:………………………..          Equipment calibration due date:…………

Sampling Interval Hardness Obtained (N) Checked by

(Sign and Date)

START 

(Time:……….)

   
 
 
 
 
 
 
 
 
 
Average hardness   Acceptance Criteria:                                    

 

60-100 N

 

 

Minimum hardness  
Maximum hardness  

 

HARDNESS: 

Sampling Interval Hardness Obtained (N) Checked by

(Sign and Date)

MID

(Time:……….)

   
 
 
 
 
 
 
 
 
 
Average hardness   Acceptance Criteria:                                     

 

60-100 N

 

Minimum hardness  
Maximum hardness  

 

HARDNESS

 

Sampling Interval Hardness Obtained (N) Checked by

(Sign and Date)

END

(Time:……….)

   
 
 
 
 
 
 
 
 
 
Average hardness   Acceptance Criteria:                                     

 

70-100 N

 

Minimum hardness  
Maximum hardness  

 

Analysis Plan for uniformity of dosage units by content uniformity: (Tested as per STP)

Results from QC at START of compression

S. No. LEFT HAND SIDE RIGHT HAND SIDE
Assay (%) Assay (%)
1    
2    
3    
4    
5    
6    
7    
8    
9    
10    
Mean Value  
% RSD  
L1 Value  
Acceptance Criteria

  • Mean value shall be 95 – 105% of the target potency value.
  • None of the individual assay value  shall deviate by ± 10 % of average assay value.
  • % RSD should be NMT 5.0%.
  • The acceptance value of the 10 dosage units is less than or equal to L1 (L1=15)

 

DRUG RELEASE :

Sample Tablet-1 Tablet-2 Tablet-3 Tablet-4 Tablet-5 Tablet-6 A. R. No.
% DISSOLUTION IN 2 Hrs % DISSOLUTION IN 4 Hrs. % DISSOLUTION IN 12 Hrs  
LHS  

 

     
RHS  

 

     
Acceptance Criteria:  2 Hrs.  :   NLT 14% and NMT  32 % of the label claim.

4 Hrs.  :   NLT  32 % and NMT  55 % of the label claim

12 Hrs.  :   NLT  85 % of the label claim.

Results from QC at MID of compression

S. No. LEFT HAND SIDE RIGHT HAND SIDE
Assay (%) Assay (%)
1    
2    
3    
4    
5    
6    
7    
8    
9    
10    
Mean Value  
% RSD  
L1 Value  
Acceptance Criteria

  • Mean value shall be 95 – 105% of the target potency value.
  • None of the individual assay value shall deviate by ± 10 % of average assay value.
  • % RSD should be NMT 5.0%.
  • The acceptance value of the 10 dosage units is less than or equal to L1 (L1=15)

 

DRUG RELEASE :

Sample Tablet-1 Tablet-2 Tablet-3 Tablet-4 Tablet-5 Tablet-6 A. R. No.
% DISSOLUTION IN 2 Hrs % DISSOLUTION IN 4 Hrs. % DISSOLUTION IN 12 Hrs  
LHS  

 

 

 

 

 

 
RHS  

 

 

 

 

 

 
Acceptance Criteria:  2 Hrs.  :   NLT 14% and NMT  32 % of the label claim.

4 Hrs.  :   NLT  32 % and NMT  55 % of the label claim

12 Hrs.  :   NLT  85 % of the label claim.

 

Results from QC at END of compression 

S. No. LEFT HAND SIDE RIGHT HAND SIDE
Assay (%) Assay (%)
1    
2    
3    
4    
5    
6    
7    
8    
9    
10    
Mean Value  
%RSD  
L1 Value  
Acceptance Criteria

  • Mean value shall be 95 – 105% of the target potency value.
  • None of the individual assay value  shall deviate by ± 10 % of average assay value.
  • % RSD should be NMT 5.0%.
  • The acceptance value of the 10 dosage units is less than or equal to L1 (L1=15)

DRUG RELEASE :

Sample Tablet-1 Tablet-2 Tablet-3 Tablet-4 Tablet-5 Tablet-6 A. R. No.
% DISSOLUTION IN 2 Hrs % DISSOLUTION IN 4 Hrs. % DISSOLUTION IN 12 Hrs  
LHS  

 

 

 

 

 

 
RHS  

 

 

 

 

 

 
Acceptance Criteria:  2 Hrs.  :   NLT 14% and NMT  32 % of the label claim.

4 Hrs.  :   NLT  32 % and NMT  55 % of the label claim

12 Hrs.  :   NLT  85 % of the label claim.

 

QC ON COMPOSITE SAMPLE

Analysis Plan on Composite Sample (Sample to be tested as per STP):

Tests Acceptance Criteria Results A.R. Number
Description White to off white oval, biconvex uncoated tablets, plain on both sides .  

 

 

 

 

 

 

Identification

 

 

    By HPLC

 

The retention time of  Gliclazide  peak in the chromatogram of the test solution corresponds to that standard solution, as obtained in the assay
Drug Release Complies with the test .Percentage of the labeled amount of Gliclazide is dissolved with in the range stated at each of following points.

2 Hrs.  :   NLT 14% and NMT  32 % of the label claim.

4 Hrs.  :   NLT 32% and NMT  55 % of the label claim.

12Hrs.  :   NLT 85% of the label claim.

Average mass Between 422.0 and 438.0 mg
Uniformity Of Dosage Units (By content uniformity  The acceptance value of the 10 dosage units is less than or equal to L1 (L1=15)  

 

 

Related substances:

 

 

 

Single highest impurity

(Specified RRT about 0.30):

Not more than 0.75%

Single highest unknown impurity :

Not more than 0.3%

Total  impurities :

Not more than 1.0%

 Assay Each uncoated tablet contains not less than 95.0% and not more than 105.0% (57.0 mg to 63.0 mg) of the label claim of Gliclazide Ph.Eur., C15H21N3O3S (60 mg)

Comments on the Process:

Annexure -VI

SAMPLING PLAN AND ANALYTICAL DATA COMPILATION WITH ACCEPTANCE CRITERIA 

HOLD TIME STUDIES FOR BLENDED MASS AFTER BLENDING/LUBRICATION 

Batch Number           :

Material Storage Area: Bulk Storage Area

Sampling Plan 

Sample Quantity: 300.0  gms

Sampling Intervals

(days)

Environmental Conditions at the time of sampling

(Temp.: NMT 25ºC

RH: NMT 45%)

Sampled by

(Name and Sign)

Sampling Date & Time
0      
7th      
15th      

 ANALYSIS PLAN :

               

                 TESTS

SAMPLING INTERVAL (days)
0 7th 15th
Description

(   White to off white, flowing granules )

     
Assay

Each 430 mg of granules contain not less than 97.5% and not more than 102.5% (58.5 mg to 61.5 mg) of the label claim of Gliclazide Ph.Eur., C15H21N3O3S (60 mg).

   
LOD

Between 1.0% to 3.2% w/w, determined at 1050C for 7 minutes

     
               Related substances:

Single highest impurity

(specified RRT about 0.30) :

Not more than 0.75%

Single highest unknown impurity :

Not more than 0.3%

Total  impurities :

Not more than 1.0%

     
Bulk Density      
Tapped Density      
Compressibility Index      
Hausner Ratio      
Microbiological  Evaluation*      
A.R. Number      

*Acceptance limits :    

Total  aerobic microbial count: NMT 500 cfu/ g

Total combined molds and yeasts count: NMT50 cfu / g.

Escherichia coli: should be absent

Salmonella Species: should be absent

Pseudomonas aeruginosa: should be absent

Staphylococcus aureus: should be absent

 

HOLD TIME STUDIES AFTER COMPRESSION 

Batch Number :                                                                                                                                                     Material Storage Area : Bulk Storage Area

Sampling Plan:  200 gms

Sampling Intervals

(days)

Environmental Conditions at the time of sampling

(Temp.: NMT 25ºC

RH: NMT 45%)

Sampled by

(Name and Sign)

Sampling Date & Time
0      
7th      
15th      

Analysis Plan

               

                 TESTS

SAMPLING INTERVAL (days)
0 7th 15th
Description

White to off white oval, biconvex uncoated tablets plain on both sides .

 

 

 

 
Assay

Each uncoated tablet contains not less than 95.0% and not more than 105.0% (57.0 mg to 63.0 mg) of the label claim of Gliclazide Ph.Eur., C15H21N3O3S (60 mg)

     
Uniformity of dosage units :

 ( By Content Uniformity )

The acceptance value of the 10 dosage units is less than or equal to L1 (L1=15)

     
Drug Release :

Complies with the test .Percentage of the labeled amount of Gliclazide is dissolved with in the range stated at each of following points.

2 Hrs.  :   NLT 14% and NMT  32 % of the label claim.

4 Hrs.  :   NLT 32% and NMT  55 % of the label claim.

12Hrs.  :   NLT 85% of the label claim.

     
Related substances:

Single highest impurity

(specified RRT about 0.30) :

Not more than 0.75%

Single highest unknown impurity :

Not more than 0.3%

Total  impurities :

Not more than 1.0%

     
 Microbiological  Evaluation*      
A.R. Number      

*Acceptance limits :

Total  aerobic microbial count: NMT 500 cfu/ g

Total combined molds and yeasts count: NMT50 cfu / g.

Escherichia coli: should be absent

Salmonella Species: should be absent

Pseudomonas aeruginosa: should be absent

Staphylococcus aureus: should be absent

 

 

 

 

 

 

 

 

 

 

 

About Pharmaceutical Guidanace

Mr. Shiv Kumar is the Author and founder of pharmaceutical guidance, he is a pharmaceutical Professional from India having more than 14 years of rich experience in pharmaceutical field. During his career, he work in quality assurance department with multinational company’s i.e Zydus Cadila Ltd, Unichem Laboratories Ltd, Indoco remedies Ltd, Panacea Biotec Ltd, Nectar life Science Ltd. During his experience, he face may regulatory Audit i.e. USFDA, MHRA, ANVISA, MCC, TGA, EU –GMP, WHO –Geneva, ISO 9001-2008 and many ROW Regularities Audit i.e.Uganda,Kenya, Tanzania, Zimbabwe. He is currently leading a regulatory pharmaceutical company as a head Quality. You can join him by Email, Facebook, Google+, Twitter and YouTube

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