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In-process control of oral drug product during manufacturing & Packing

  • Objective

To lay down the procedure for in-process control of oral drug products during manufacturing & Packing.

  • Scope

This procedure is applicable for in-process sampling, analysis and reporting to be carried out during manufacturing and packing of drug products at formulation Plant of Torque Pharmaceutical (P) Ltd., Unit-I, Dappar.

  • Responsibility
    • Quality Assurance and production personnel shall responsible to follow the procedure mentioned in this SOP.
  • Accountability
    • Head Production & Head QA shall be accountable for implementation of this SOP.
  • Abbreviations and Definitions
QA : Quality Assurance
SOP : Standard Operating Procedure
QC : Quality Control
LOD : Loss on drying
DT : Disintegration Test
  • Procedure
    • In process tests carried out during routine manufacturing of oral dosage forms by Production &
    • The in-process tests including the procedure and action taken if any discrepancy found shall mentioned under individual headings & annexures.
    • 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.
    • The in-process test shall be carried out at different stages such as:
      • For tablet following stage shall be consider in-process – drying, lubrication, compression, coating, Inspection and packaging operations as per the requirements.
      • For Capsule following stage shall be consider in-process -blending, capsules powder filling, packaging operations as per the requirements.
      • For Liquid following stage shall be consider in-process -Washing, Bottle filling & sealing and packaging operations as per the requirements.
      • For Ointment following stage shall be consider in-process -tube filling & sealing and packaging operations as per the requirements.
    • All the in-process tests conducted during the above mentioned processes shall be recorded in the respective formats (from Annexure III to IX).
    • In-process test parameters shall be consider during routine production i.e. as follows:
      • Tablets
S .No. Stage In-process Test Sample Qty. Test Frequency
1.

 

Drying Description 10 gm. After completion of drying
LOD
2. Compression Description 20 Tablets For Production

Initial, every 1 hours and at the end of the batch.

 

For QA

Initial, every 2 hours and at the end of the batch.

Average weight
Uniformity of weight
DT
Hardness
Thickness
Friability
3. Coating Description 20 Tab. For Production & QA

After completion of coating of composite sample

Average weight
Uniformity of weight
DT
Thickness
Weight Gain 200 Tab. For each lot For Production

After completion of each lot

 

4. Inspection Challenge test from Metal For Production

Initial, every 1 hours and at the end of the batch.

 

For QA

Initial, every 2 hours and at the end of the batch.

Inspection for defects 20 Tab.
5.
Packing

 

 

Sealing & forming temp. For Production

Initial, every 2 hour, after every breakdown and at the end of the batch.

Batch coding details   For Production

Initial, every 1 hours and at the end of the batch.

 

For QA

Initial, every 2 hours and at the end of the batch.

Defective Tablets, cut pockets and overprinting  
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. For Production

Initial, every 2 hours and at the end of the batch.

 

For QA

Initial, every 4 hours and at the end of the batch.

  • Capsules
S .No. Stage In-process Test Sample Qty. Test Frequency
1. Capsule

filling

Description 20 Capsules For Production

Initial, every 1 hours and at the end of the batch.

 

For QA

Initial, every 2 hours and at the end of the batch.

Fill weight
Average weight
Uniformity of weight
DT
Locking length
2. Inspection Optical Defects
3. Packing Sealing & forming temp. For Production

Initial, every 2 hour, after every breakdown and at the end of the batch.

Batch coding details For Production

Initial, every 1 hours and at the end of the batch.

 

For QA

Initial, every 2 hours and at the end of the batch.

Defective Capsules, cut pockets and overprinting
Leak Test

 

 

Strips from 1 rotation of CSR / blisters from sealing plate sealed per stroke sealing. For Production

Initial, every 2 hours and at the end of the batch.

 

For QA

Initial, every 4 hours and at the end of the batch.

 Liquid

S .No. Stage In-process Test Sample Qty. Test Frequency
1. Bottle washing Volume of water per nozzle per station 6 nos. of bottles Initially by production
Visual examination of washed bottles For Production

Initial, every 1 hours and at the end of the batch.

 

For QA

Initial, every 2 hours and at the end of the batch.

1. Bottle

filling & sealing

Description 08 Bottles
Filled volume
Leak Test
2. Inspection Optical Defects
3. Packing Batch coding & overprinting details

 

For Production

Initial, every 1 hours and at the end of the batch.

 

For QA

Initial, every 2 hours and at the end of the batch.

 Ointment

S .No. Stage In-process Test Sample Qty. Test Frequency
1. Tube

filling & sealing

Description 06 tubes For Production

Initial, every 1 hours and at the end of the batch.

 

For QA

Initial, every 2 hours and at the end of the batch.

Net Content
Average fill mass 20 tubes
Individual fill mass
Batch coding on crimping
Lose Capping
Crimping
2. Packing Batch coding & overprinting details

 

For Production

Initial, every 1 hours and at the end of the batch.

 

For QA

Initial, every 2 hours and at the end of the batch.

 

  • Records
    • All the tests conducted during the in-processes shall be recorded in the respective formats as mentioned under Point number 7.0 ‘Forms and records’ (From Annexure III to X).
    • Discrepancies during IPQA with their Recommended Action shall be as per Annexure-I.
    • In-Process Tests Including the procedure of Testing is summarize in Annexure-II
  • Forms and Records
    • Discrepancies during In-process with their Recommended Action: Annexure-I
    • In-Process Tests Including the Frequency of Testing: Annexure-II
    • In Process Control: Tablets : Annexure-III
    • In Process Control: Capsules : Annexure-IV
    • In Process Control: Liquid Filling & Sealing : Annexure-V
    • In Process Control: Liquid Packing : Annexure -VI
    • In Process Control: Capsule packing : Annexure –VII
    • In Process Control: Ointment Filling & Sealing : Annexure –VIII
    • In Process Control: Ointment Packing: Annexure –IX
    • In Process Control: Tablet packing : Annexure –X
  • Distribution
    • Master Copy              –          Documentation Cell (QA)
    • Controlled Copies   –          Quality Assurance and Production

  • History 
   Date Revision Number
Reason for Revision
       – New SOP

Annexure-I

In case of any deviation follow the SOP on Handling of Deviation

Discrepancies during In-process with their Recommended Action 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 Head QA.

If the trials meet the specification, continue further processing.

The investigation shall be extended to the steps already completed.

Compression Appearance, Weight variation, Hardness, Thickness, DT, Friability 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.

Coating Appearance, % Weight gain, Thickness,

DT,

Average Wt.,

Uniformity of weight

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”.

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

Inform production officer and QA 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.

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.

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 QA.

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

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

Continue the packing activity.

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 QA.

Rechecking after rectification by production officer and QA officer.

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

Continue the packing activity.

Bottle    

filling

Bottle washing, fill weight, cap/closure placement, Stop the operation

Isolate the bottles and label it “Under Hold”, QA shall investigate.

Corrective actions to rectify the problems.

Line clearance by QA.

Rechecking after rectification by production officer and QA officer.

Continue the filling activity.

Annexure-II

In-Process Tests Including the Frequency of Testing

S.

No.

Test

parameters

Sample

quantity

Procedure
1.

 

 

Appearance

/ Description

for tablets

20 tablets 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.
2. Average Weight 20 tablets Weigh individually all tablets, calculate the average weight.
Weight variation

(For tablets)

20 tablets Weigh one by one 20 tablets and determine the weight variation by subtracting the individual weight of tablets with average weight of each tablets.
3. Disintegration

time testing for tablets

6 tablets Operate the disintegration tester as per SOP. 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.
4. Hardness

Testing

6 tablets Hardness test shall be performed with the help of tablet hardness tester as per SOP number _____________
5. Thickness testing for compressed/ coated tablets 6 tablets Thickness shall be determined using vernier caliper/ digital tablet hardness tester as per SOP number _________.
6. 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 SOP number ­­­­__________

7. Weight gain of coated tablets 100 tablets Take weight of 100 pre warmed tablets and Weigh the 100 coated tablets. Calculate the weight gain.
8. 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.
9. Disintegration

time testing for capsules

6 capsules Introduce 1 capsule in to each tube and operate the disintegration tester as per SOP number _______. 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.
10. 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.

11. Appearance /

Description for

Syrup & suspension

Bottle from every head Examine for lump formation, caking, quality of suspension odour. The appearance should comply with that mentioned in the individual specification.
12. Lock length of the capsules 6 capsules Lock length of the capsules shall be determined using vernier caliper

 

13. 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 respective SOP
14. Fill weight of syrups No. of bottles filled while single rotation of dosing wheel Take Bottles directly from the syrup filling machine and check the fill weight of powder
15. 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 SOP number ____
16. Bottle Cleanliness Two bottles/Jar Visually check the bottles/Jar for their cleanliness
17. Overprinting details Random sampling Visually check the blister, strips, carton, label for batch details, wrinkles, proper pasting, appearance, etc.
18. Labeling Random sampling Visually check the labeling for any defects like Wrinkles/ crumpled/ slanted/ stained or any other abnormal observations.
19. Leaflet Placement Two bottles/jars Visually check whether the leaflet is placed correctly on the bottle cap/ inside the cartons.(as applicable)
20. Measuring Cup Placement Two bottles Visually check whether the Measuring Cup is placed correctly on the bottle.
21. 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.
22. Carton packing Random sampling Visually check for the correct coding, Product details, and weight of the Carton.
23. 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.
24. 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.

Annexure-III

In-Process Control: Tablet

     Stage: Compression

   1.0 Description:

     Frequency for Description:

For Production: Initial, every 1 hours and at the end of the batch.

     For QA: Initial, every 2 hours and at the end of the batch. Every 2 hours)

 

Test

Date/ Time Observations Done by

Description

 2.0 Tablets Size Verification:

Frequency for Tablets Size Verification (By Production & QA): Initial Machine setting 

SNo. Length Width Diameter
1    
2      
3      
4      
5      
6      
7      
8      
9      
10      
Average      
Maximum      
Minimum      
Limit      

3.0 AVERAGE WEIGHT AND UNIFORMITY OF WEIGHT RECORD:

     Date           :                       Location        :                       Equipment ID No.      :

Product Name        :                                                           B. No.                         :

  1. Size :

Temperature °C      :                                                           RH                              :           %

 Frequency:

For Production: Initial, every 1 hours and at the end of the batch.

     For QA: Initial, every 2 hours and at the end of the batch. Every 2 hours).

   Sample size=20 tablets                             Analytical Weighing Balance ID No.:………………

Date  
Time  
Wt. of 20 Tab.  
Av. Wt. (mg)  
1  
2          
3          
4          
5          
6          
7          
8          
9          
10          
11          
12          
13          
14          
15          
16          
17          
18          
19          
20          
Max. Wt. (mg)          
Min. Wt. (mg)          
Variation + %          
Variation–– %          
Checked By          

4.0 Hardness & Friability:

Parameter Time→          
Limit↓ Observation
Hardness

(Unit:____)

           
Friability (%)            

5.0Thickness

 

Tablets

Thickness
Time
         
1  
2          
3          
4          
5          
6          
7          
8          
9          
10          
Average          
Maximum          
Minimum          
Limit  

 6.0 Disintegration time

 

Tablets

Disintegration Time
Time
         
1  
2          
3          
4          
5          
6          
Maximum          
Minimum          
 Checked By          
Limit  Not More Than 30 minutes

      Frequency for Hardness, Friability, thickness & Disintegration test:

For Production: Initial, every 1 hours and at the end of the batch.

     For QA: Initial, every 2 hours and at the end of the batch. Every 2 hours

Stage: Coating

                      Date    :                       Location        :                       Equipment ID No.      :

Product Name        :                                                                       B. No.                         :

  1. Size :

Temperature °C      :                                                                       RH                              :           %

Frequency:

For Production: Initial, every 1 hours and at the end of the batch.

   For QA :Initial, every 2 hours and at the end of the batch. Every 2 hours)

1.0 Description

Test Date/ Time Lot No. Observations Done by
Description

(At the end of each lot)

2.0 Disintegration Test:

Test Date/ Time Lot No. Observations Done by
Disintegration Test (At the end of each lot)

3.0 Weight gain of coated tablets:

Weight gain of coated tablets (At the end of each lot)

Weight gain in % = B – A x 100 = ……… % (Limit……………..)

A

 

Limit :

 

Lot number        
Date/ Time        
Actual Weight of 100 pre-warmed Tablets in g (A)
Actual Weight of 100 coated tablets in g (B)  

 

 

 

 

 

Actual % weight gain of 100 coated tablets
Thickness in mm (At the end of each lot) Limit (mm):
Lot number
Date/ Time
Minimum (mm)
Maximum (mm)
Done by/ date

4.0 AVERAGE WEIGHT AND UNIFORMITY OF WEIGHT RECORD:

Sample size=20 tablets                              

Date
Time
Wt. of 20 Tab.
Av. Wt. (mg)
1 6 11 16
2 7 12 17
3 8 13 18
4 9 14 19
5 10 15 20
Max. Wt. (mg)  
Min. Wt. (mg)  
Variation + %  
Variation–– %  
Checked By  

 

 

 

 

 

 

 

 

 

 

 

 

 

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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