SOP on In-process Sampling and Analysis of Oral Drug Products

0
11997

1.0 Objective:

1.1 To lay down the procedure for in-process sampling and analysis of oral drug products during manufacturing.

2.0 Scope:

2.1 This procedure is applicable for in-process sampling, analysis and reporting to be carried out during manufacturing of drug products at formulation Plant.

3.0 Responsibility:

3.1 Quality Assurance department.

4.0 Accountability:

4.1 Head-QA shall be accountable for compliance of SOP.

5.0 Procedure:

5.1 In-process specifications and test procedures along with the acceptance criteria shall be prepared for each product.

5.2 The in-process analysis shall be carried out at different stages such as dry mixing, drying, blending, lubrication, compression / filling (capsules and powder filling), coating and packaging operations as per the requirements.

5.3 In process sampling and analysis is basically divided into two sections:

5.3.1 In process, semi-finish and finish sample intimation slip generate by production / pilot plant.

5.3.2 In process analysis carried out by quality assurance during routine production activity.

5.4 In process analysis request cum report raised by production/ pilot plant:

5.4.1 Production/ Pilot plant shall intimate to quality assurance for sampling at various stages during production for QC analysis as per SOP on Sampling of semi-finished product respective Annexure.

5.4.2 Before proceeding for the sampling activity, QA person shall ensure the preparatory   set up for sampling of semi-finished product, finished product and rinse water / swab test samples to be carried out as per respective SOPs.

5.4.3 For process validation QA person shall carry out the sampling as per the process validation protocol or as mentioned in the BMR and for routine manufacturing. QA person shall carry out the sampling as per respective SOPs.

5.4.4 After sampling for QC analysis, the details of the samples withdrawn shall be entered in the in-process logbook as per Annexure-I and respective batch manufacturing / packing record.

5.4.5 The samples shall be then forwarded to the QC department along with the Sampling Intimation Slip in duplicate for testing of the analytical parameters as per the established specifications.

5.4.6 All Sampling Intimation Slip shall have QC reference number which is allotted by QC at the time of receipt of the sample and the request as per SOP for Allotment of Analytical Reference Number.

5.4.7 The physical parameters of In-process samples (e.g. DT, moisture analysis, weight variation etc.) shall be checked by QA personnel and the analytical parameters (e.g. Assay, Content uniformity, Microbial analysis, Water content, LOD, bulk density, tapped density, Dissolution etc.) shall be checked in QC as per the specifications and standards.

5.4.8 After completion of analysis, results shall be recorded in the sampling intimation slip by QC.

5.4.9 After completion of the Finish product analysis report shall be sent to QA for final review and approval. The QA person shall check the results for compliance then hand over the report to the production department.

5.5 In process tests carried out during routine work:

5.5.1 In addition to the analysis of the tests requested by the Production/ Pilot plant, QA shall carry out the routine sampling and testing of the batches manufactured.

5.5.2 Sampling and testing shall include in process tests during granulation, tablet compression, coating, capsule filling, powder filling, packing operations etc.

5.5.3 All the tests conducted during the above mentioned processes shall be recorded in the respective formats as mentioned under Point number 6.0 ‘List of Annexure / Formats’. Critical parameters during in process check are LOD, weight variation, filled weight, hardness, thickness, DT, weight gain, leak test, batch overprinting detail.

5.5.4 The in-process tests including the frequency of testing are mentioned in the table 1:

S.No. Test

parameters

Sample

quantity

Procedure Frequency Reporting
1.

 

 

Appearance

/Description

for tablets

1 tablet from each station of compression machine Check for defects like surface finish, lamination, mottling, chipping and swelling powder on the tablets embossing (if any), picking, capping and sticking. The appearance of the tablets should comply with that mentioned in the individual specification. Initial, every 2 hours and at the end of the batch. Annexure-II
2. Appearance /

Description for

capsules

20 capsules Take about 20 capsules at random check for defects like dented capsules, telescopic capsules, empty capsules, capsules with notch, printing quality, crust / lump formation in the blend, improper colour distribution of the blend, powder leaking from the locking end and powder on capsules. The appearance of the capsules should comply with that mentioned  in the individual Specification Initial, every 2 hours and at the end of the batch Annexure-III
3. Appearance /

Description for

dry syrup

1 bottle Examine for lump formation, caking, quality of suspension odour. The appearance should comply with that mentioned in the individual specification. Initial, every 2 hours and at the end of the batch Annexure-IV
4. Appearance /

Description for

blend

Visual inspection of sample collected for QC analysis Examine for colour, lumps formation. The appearance should comply with that mentioned in the individual specification. Final blending or as per specification Annexure-I
5. Disintegration

time testing for tablets

6 tablets

Operate the disintegration tester as per SOP number QA-SG-006. Place 1 dosage unit in each of the six tube of the basket and, if prescribed add a disk. Operate the apparatus, using water or the specified medium as the immersion fluid, maintain temperature at 37+2ºC or given in specification. At the end of the time limit specified, lift the basket from the fluid, and observed the tablets. All of the tablets have disintegrated completely. If 1or 2 tablets fail to disintegrate completely, repeat the test on 12 additional tablets. The requirement is met if not less than 16 of the total of 18 tablets are disintegrated. The displayed disintegration time shall be reported in terms of minutes by converting the seconds in to minutes

For Example: Suppose the display shows the time of 4:32 this indicates the disintegration time is 4 minutes and 32 seconds while reporting 32 seconds shall be converted to minutes by dividing 32 by 60. So the reported time shall be 4.53 minutes.

Initial, every 2

hours and at

the end of the

batch

Annexure-II
6. Disintegration

time testing for capsules

6 capsules Introduce 1 capsule in to each tube and operate the disintegration tester as per respective SOP. Insert disk over each capsule. Operate the apparatus, using water or the specified medium as the immersion fluid, maintain at 37+2ºC. At the end of the time limit specified Capsules pass the test if all of them disintegrate completely. Result reporting is same as for tablets. Initial, every 2

hours and at

the end of the

batch

Annexure-III
7. Friability  test Tablets with a unit mass equal to or less than 650 mg, take a sample of

Whole Tablets

Corresponding to 6.5 g. For

Tablets with a

Unit mass of

More Than

650 mg,

take a sample

of 10 Whole

Tablets.

The tablets should be

Carefully de-dusted prior to testing. Accurately weigh the tablets sample, and place the tablets in the drum. Rotate the drum 100 times, and remove the tablets. Remove any loose dust from the tablets and accurately weigh.

Operate friability test apparatus as per respective SOP.

Initial,  every 2

hours and at

the end of the

Batch.

Annexure
8. Hardness

Testing

6 tablets Hardness test shall be performed with the help of tablet hardness tester as per respective SOP. Initial, every 2 hours and at the end of the batch. Annexure-II
9. Thickness testing for compressed/ coated tablets 6 tablets Thickness shall be determined using vernier caliper/ digital tablet hardness tester as per respective SOP Initial, every 2 hours and at the end of compression/ At the end of each coating lot Annexure-II
10. Weight variation (For uncoated tablets) 1 tablet from each station of compression machine Weigh individually all tablets, calculate the average weight. Using analytical balance as per respective. Initial, every 2 hours and at the end of the batch Annexure-II
11. Weight gain of coated tablets 100 tablets Take weight of 100 pre warmed tablets and Weigh the 100 coated tablets. Calculate the weight gain. At the end of each coating lot Annexure-II
12. Weight variation    (For capsules) 20 capsules

a) Weigh 20 intact capsules individually and determine the average weight.

b) Remove the contents of each capsule with the aid of small brush or plug of cotton. Weigh the emptied shells individually and calculate for each capsule the net weight of its content by subtracting the weight of the shell from respective gross weight, determine the average net content from the sum of the individual net weights.

Initial,  every 2

hours and at

the end of the

Batch.

Annexure-III
13. Lock length of the capsules 6 capsules Lock length of the capsules shall be determined using vernier caliper as per respective SOP. Initial, every 2 hours and at the end of the batch Annexure-III
14. Loss on drying (Powders / Granules) Approximately 2 g or as per specification Determine the loss on drying with the help of IR moisture analyzer as per SOP on Operation of Moisture Analyzer End of drying or as per the specification In BMR if applicable
15. Fill weight of dry syrups No. of bottles filled while single rotation of dosing wheel Take  Bottles directly from the dry syrup filling machine and check the fill weight of powder Initial, every 2 hours and at the end of the batch Annexure-IV
16. Leak Test Strips from 1 rotation of CSR /blisters from sealing plate sealed per stroke/2 bottles (in case of induction sealing)/ Bottles equal to no. of sealing head. Leak test shall be performed as per respective SOP. Initially and every 2 hours. Annexure-IV,

Annexure-V

17. Non Fill Detection One tablet/ capsule from each position of sensor track Remove one tablet/ capsule each from the pockets from each position of the sensor track. Check the blisters whether they are rejected Initial and After every 2 hrs. Annexure-VI
18. Overprinting details Random sampling Visually check the blister, strips, carton, label for batch details, wrinkles, proper pasting, appearance, etc. Initial and every two hour Annexure-V

Annexure-VI

Annexure-VII

19. Bottle / Jar Cleanliness Two bottles/Jar Visually check the bottles/Jar for their cleanliness Initial and every 2 hrs. Annexure-VI

Annexure-VII

20. Tablet Count Random sampling Visually check the counts of the tablets as per the pack size mentioned in the BPR. Initial and every 2 hrs. Annexure-V
21. Desiccant insertion Two Jars Visually check the number of the desiccants and insertion of as mentioned in the BPR. Initial and every 2 hrs. Annexure-VI
22. Induction sealing Two bottles/jars Visually check for the induction sealing and ensure that it is okay. Initial and every 2 hrs. Annexure-VI

Annexure-VII

23. Labeling Random sampling Visually check the labeling for any defects like Wrinkles/ crumpled/ slanted/ stained or any other abnormal observations. Initial and every 2 hrs. Annexure-VI

Annexure-VII

24. Leaflet Placement Two bottles/jars Visually check whether the leaflet is placed correctly on the bottle cap/ inside the cartons.(as applicable) Initial and every 2 hrs. Annexure-V

Annexure-VI

Annexure-VII

25. Measuring Cup Placement Two bottles Visually check whether the Measuring Cup is placed correctly on the bottle. Initial and every 2 hrs.  

Annexure-VII

 

26. Tests to be conducted during blister and strip packing Random sampling Visually check for any punctures, empty pocket, overprinting details, sealing quality, knurling quality, forming quality, sealing and forming plate and roller temperature. Initial and every 2 hrs. Annexure-V

 

27. Carton packing Random sampling Visually check for the correct coding, Product details, and weight of the Carton. Initial and every 2 hrs  

Annexure-V

Annexure-VII

 

 

28. Tests to be conducted during shipper packing Random sampling Visually check for the correct coding, number of unit packed, proper BOPP taping, shipper number and weight of the shipper. Initial, every 2 hrs and at the end of the batch. Annexure-V

Annexure-VI

Annexure-VII

   
29. Wad sensor for Induction caps 1 bottle and cap Remove aluminum wad of cap mark it and pass Bottle and cap through wad sensor. Check the bottle whether it is rejected. Initial Annexure-IV
30. Metal detector challenge test Ferrous non ferrous and S.S. blocks. Pass ferrous non ferrous and S.S. blocks through metal detector. Check the blocks whether it is rejected. initial Annexure-II
31. Uniformity of Dispersion Two tablets Place two tablets in 100ml of water and stir gently until completely dispersed. A smooth dispersion is obtained which passes through a sieve screen with a nominal mesh aperture of 710µm (sieve no.22). Initial and every 2 hrs Annexure-II

Note: If the processing time for the batch is less than 2 hours, then the in process checks shall be carried out during initial, middle and end of operation.

flow-chart-for-in-process-sampling-and-analysis

in-process-and-qc-analysis-during-routine-production

capsules

dry-syrup

Table-2

Following are the in-process tests and actions to be taken in case of any discrepancy observed.

Stage In-process Test Action to be taken
Drying/ Blending/ Lubrication LOD QA to investigate.

Isolate the container and label it “Under Hold”

Withdraw more samples and check.

If the results are not satisfactory, perform trials in consultation with Pilot plant.

If the trials meet the specification, continue further processing.

The investigation shall be extended to the steps already completed.

Follow the SOP for Deviation Handling.

Compression Appearance, Weight variation, Hardness, Thickness, DT, Friability, Uniformity of Dispersion. Stop the operation

Isolate the container and label it “Under Hold”

Investigation by quality assurance by withdrawing samples from various positions from the container.

Trials on the existing / next container i.e. in-process testing for all physical parameters.

If the samples meet the requirement, continue the processing.

The remaining tablets during trial and under hold container will be kept as “Non-recoverable”

The investigation shall be extended to the already compressed tablets and if required random sampling shall be carried out from these containers.

Follow the SOP for Deviation Handling.

Coating Appearance, % Weight gain, Thickness Stop the operation

Isolate the lot or batch and label it “Under Hold”

Investigation by quality assurance by withdrawing samples from various positions from the container.

Trials on the existing / next lot or batch i.e. in-process testing for all physical parameters.

If the samples meet the requirement, continue the processing.

The investigation shall be extended to the steps already completed.

The remaining tablets during trial and under hold container will be kept as “Non-recoverable”. Follow the SOP for Deviation Handling.

Capsule Filling Lock Length of filled capsule; fill content, average weight, weight variation, moisture content, DT. Stop the machine

Inform production officer and IPQA officer.

Investigate.

Corrective actions e.g. machine settings to rectify the problem.

If required take trials on fresh containers.

After setting, perform complete in-process analysis for physical parameters.

Reject the trial and in-process test samples.

The investigation shall be extended to the steps already completed.

Continue the processing.

Follow the SOP for Deviation Handling.

Packing

Leak Test Stop machine.

Inform production.

QA shall investigate.

Corrective actions to rectify the problem.

Recheck for leak test from the already packed strips/ blisters at random.

If found satisfactory, packing to be continued.

If not, then analyze the strips/ blisters for the pack quality and reject.

Perform the leak test and if find OK then start the operation.

The investigation shall be extended to the steps already completed and if required the random sampling from already packed shippers shall be carried out for leak test.

Non Fill Detection  

Inform to the production officer and IPQC officer.

Quarantine the strips/ blisters packed between previous intervals.

Check the quarantined strips/blisters.

If the results are not satisfactory, rectify the NFD system and recheck all the strips/blisters packed between previous intervals.

Check proper functioning of the NFD system and alert the checkers.

Continue the packing activity.

Packing Overprinting Details Stop the machine.

Inform production officer.

QA shall investigate.

Corrective actions to rectify the problems.

Rejection and destruction of all overprinted material.

Line clearance by IPQA.

Rechecking of overprinting details after rectification by production officer and IPQA officer.

If required, recheck the packed product if any with random sampling for overprinting details.

Continue the packing activity.

If any rework is required then follow the SOP for Deviation Handling.

Bottle inspection, induction sealing, Measuring cup placement labeling, weight of the carton and shipper, shipper number. Stop the machine.

Inform production officer.

QA shall investigate.

Corrective actions to rectify the problems.

Line clearance by IPQA.

Rechecking after rectification by production officer and IPQA officer.

If required, recheck the packed product if any with random sampling.

Continue the packing activity.

If any rework is required then follow the SOP for Deviation Handling.

Dry syrup filling Air jet cleaning, fill weight, wad sensor challenge test, cap/closure placement, sealing/ induction sealing. Stop the operation

Isolate the bottles and label it “Under Hold”

QA shall investigate.

Corrective actions to rectify the problems.

Line clearance by IPQA.

Rechecking after rectification by production officer and IPQA officer.

Continue the packing activity.

 

6.0 List of Annexure / Formats:

6.1 In Process Logbook                                        Annexure-I

6.2 In Process Control: Tablets                             Annexure-II

6.3 In Process Control: Capsules                        Annexure-III

6.4 In Process Control: Dry Syrup Filling             Annexure-IV

6.5 In Process Control: Packing                           Annexure-V

6.6 In process Control: Bulk Packing                   Annexure-VI

6.7 In Process Control: Dry Syrup packing          Annexure-VII

7.0 References (If any):

7.1 SOP on Sampling of finished product.

7.2 SOP on Sampling of semi-finished product.

7.3 SOP on Sampling of rinse and swab sample after equipment cleaning.

7.4 SOP on operation, calibration and cleaning of hardness tester.

7.5 SOP for Allotment of A.R. No.

7.6 SOP for Handling of Deviation.

7.7 SOP on operation of disintegrator tester.

7.8 SOP on operation of friability test apparatus.

7.9 SOP on operation of hardness tester.

7.10 SOP on operation of vernier caliper.

7.11 SOP on operation of moisture analyzer.

7.12 SOP on operation leak test apparatus.

7.13 SOP on operation of analytical balance.

7.14 Indian Pharmacopoeia.

7.15 SOP on in process labeling system and its format.

8.0 Distribution

Master copy –           Quality Assurance

Controlled copies – Production, Quality Control & Quality Assurance

9.0 History

     Date    Revision Number                       Reason for Revision
                       New SOP

 

10.0 Abbreviation and Definition:

IPQA    :           In- Process Quality Assurance

BMR     :           Batch Manufacturing Record

BPR      :           Batch Packing Record.

Q.A.      :           Quality Assurance

SOP      :           Standard Operating Procedure

CSR      :           Counter sealing roller

D.T.       :           Disintegration time testing

LOD      :           Loss on Drying.

BOPP   :           Bi-oxially polypropylene

IR          :           Infra red

ECS      :           Empty capsule sorter

NFD      :           Non-Fill Detection

A.R. No.:           Analytical Reference Number

QC        :           Quality control

Annrxure-I

1

Annrxure-II

2-5

2-3

2-2

2-1

Annrxure-III

3a

3-1

Annrxure-IV
4

4-1

Annrxure-V

5

Annrxure-VI

6

6-1

6-2

6-3

Annrxure-VII

7-1

7

o

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