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

Objective

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

Scope

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

Responsibility

Quality Assurance department.

Accountability

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

Procedure

• In-process specifications and test procedures along with the acceptance criteria shall be prepared for each product.
• 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.
• In-process sampling and analysis are basically divided into two sections:

1. In-process, semi-finish, and finish sample intimation slip generated by production/pilot plant.
2. In-process analysis is carried out by quality assurance during routine production activity.

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

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. 
2. Before proceeding with the sampling activity, the QA person shall ensure the preparatory setup for a sampling of semi-finished product, finished product, and rinse water/swab test samples to be carried out as per respective SOPs.
3. For process validation, the 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.
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 After sampling for QC analysis, the details of the samples withdrawn shall be entered in the in-process logbook as per Annexure-I and respective batch manufacturing/packing records.
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.
6. All Sampling Intimation slips shall have a 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.
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.
8. After completion of analysis, results shall be recorded in the sampling intimation slip by QC.
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 and then hand over the report to the production department.

• In-process tests carried out during routine work:

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.
2. Sampling and testing shall include in-process tests during granulation, tablet compression, coating, capsule filling, powder filling, packing operations etc.
3. All the tests conducted during the above-mentioned processes shall be recorded in the respective formats as mentioned under List of Annexures. Critical parameters during in-process check are LOD, weight variation, filled weight, hardness, thickness, DT, weight gain, leak test, batch overprinting detail.

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

Sr. No.	Test Parameters	Sample Quantity	Procedure	Sample Frequency
1.	Appearance /Description for tablets	5 tablets from each batch	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.
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
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
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
5.	Disintegration time testing for tablets	6 tablets	Operate the disintegration tester as per SOP. Place 1 dosage unit in each of the six tubes of the basket and, if prescribed add a disk. Operate the apparatus, using water or the specified medium as the immersion fluid, and maintain the temperature at 37±2ºC or given in the 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 1 or 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
6.	Disintegration time testing for capsules	6 capsules	Introduce 1 capsule into each tube and operate the disintegration tester as per the respective SOP. Insert disk over each capsule. Operate the apparatus, using water or the specified medium as the immersion fluid, and maintain it at 37±2ºC. At the end of the time limit,   specified Capsules pass the test if all of them disintegrate completely. Result reporting is the same as for tablets.	Initial, every 2 hours and at the end of the batch
7.	Friability test	For 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.
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.
9.	Thickness testing for compressed/ coated tablets	6 tablets	Thickness shall be determined using an 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
10.	Weight variation (For uncoated tablets)	1 tablet from each station of the compression machine	Weigh individually all tablets, and calculate the average weight. Using analytical balance as per respective.	Initial, every 2 hours and at the end of the batch
11.	Weight gain of coated tablets	100 tablets	Take the weight of 100 pre-warmed tablets and weigh the 100 coated tablets. Calculate the weight gain.	At the end of each coating lot
12.	Weight variation (For capsules)	20 capsules	Weigh 20 intact capsules individually and determine the average weight. Remove the contents of each capsule with the aid of a 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 the respective gross weight, and determining the average net content from the sum of the individual net weights.	Initial, every 2 hours and at the end of the Batch.
13.	Lock length of the capsules	6 capsules	Lock length of the capsules shall be determined using an vernier caliper as per respective SOP.	Initial, every 2 hours and at the end of the batch
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
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
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.
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.
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
19.	Bottle / Jar Cleanliness	Two bottles/Jar	Visually check the bottles/Jar for their cleanliness	Initial and every 2 hrs.
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.
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.
22.	Induction sealing	Two bottles/jars	Visually check for the induction sealing and ensure that it is okay.	Initial and every 2 hrs.
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.
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.
25.	Measuring Cup Placement	Two bottles	Visually check whether the Measuring Cup is placed correctly on the bottle.	Initial and every 2 hrs.
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.
27.	Carton packing	Random sampling	Visually check for the correct coding, Product details, and weight of the Carton.	Initial and every 2 hrs
28.	Tests to be conducted during shipper packing	Random sampling	Visually check for the correct coding, a 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.
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
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
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

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