Standard Operating Procedure & Guideline for Hold Time Study of Drug Product at different manufacturing stages like bulk granules/powder, blend, bulk liquids, core tablets, coated tablets, filled capsule, binder and coating solution etc.
Hold Time Study Procedure
1.0 Objective :
- To lay down the procedure for conducting the hold time study of pharmaceutical products during manufacturing at every stage.
2.0 Scope :
- The SOP is applicable to conduct the hold time study of bulk granules/powder, blend, bulk liquids, core tablets, coated tablets, filled capsule, binder and coating solution in production at pharmaceuticals drug manufacturing plant.
3.0 Responsibility :
|Production Chemist & above||:||
|QA Chemist and above||:||
|QC Chemist and above||:||
4.0 Procedure – Hold Time Study :
Definition of Hold Time Study:
- Hold-time studies establish the time limits for holding the materials at different stages of production to ensure that the quality of the product does not deteriorate significantly during the hold time.
- Hold time study shall be conducted to demonstrate that the bulk products and intermediates.
- Retain the appropriate quality before processing to the next stage.
- Meet the acceptance criteria and release specification for the finished products
Hold time shall be conducted when, but not limited to:
- Introduction of new product
- As part of the investigation of a deviation that occur during manufacturing
- Any significant changes in process or formulation
- A written protocol shall be prepared which includes the activities to be performed, test parameters and acceptance criteria appropriate to the material or product under test.
- Annexure-I shall be followed to prepare the hold time study protocol.
- The Hold time study protocol shall be prepared by QA, reviewed by Head Production & Head QC and then approved by Head QA.
- Protocol for Hold time study shall have the unique protocol no.
- Hold time study shall be conducted on one batch and if not justified can be extended to other batches.
- After completion of the hold time study a report shall be prepared on Annexure-II.
- The Hold time study report shall be prepared by QA, reviewed by, Head Production & Head QC, and then approved by Head QA.
- Hold time study report shall have the unique report no.
- The containers used in which hold-time samples are stored should have the same MOC in which the material is hold in production area.
- Where head space is important the hold-time samples should represent the maximum possible head space (worst-case scenario) to bulk stored in manufacturing/quarantine.
- The sample storage environmental conditions should be same as that of the quarantine area/manufacture stage.
- Batches of finished products made from intermediates or bulk products and subjected to a hold-time study should be considered for long-term stability testing.
Follow the given below table for collection of sample, testing frequency and test parameters(But not limited):
|Stage||*Test Parameter||*Study time|
|Starch paste||Microbial test, Appearance ,Viscosity (If applicable)||Initial, 2hrs, 5hrs|
|Binder preparation||Microbial test, Appearance ,Viscosity (If applicable)||Initial, 2hrs, 5hrs, 8hrs|
|Coating solution||Physical appearance, Specific gravity, Viscosity, Sedimentation rate, pH & Microbial test||Initial, 24, 48, 72 hours|
|Bulk Granules / Powder||Description, Assay, Related substances, Loss on drying, Water content, particle size distribution, Bulk density, Tap density, Angle of repose and Microbial test||Initial, 15th 30th, 45th day|
|Blend||Microbial test, Loss on drying, blend uniformity, particle size, Bulk/Tapped density, Assay||Initial, 15th, 30th, 45th day|
|Core tablets (in bulk container)||Description, Hardness, Thickness, Friability, Disintegration, Dissolution, assay, Degradation products/ related substance, Microbial tests.||Initial, 15th, 30th, 45th , 60th, 90th day|
(in bulk container)
|Description, Hardness, Thickness, Friability, Disintegration, Dissolution, Assay, Degradation products/ related substance, Moisture content, Microbial tests.||Initial, 15th, 30th, 45th , 60th, 90th day|
|Filled Capsules||Description, Disintegration, Dissolution, assay, Degradation products/ related substance, Microbial tests.||Initial, 15th, 30th, 45th , 60th, 90th day|
|Bulk Oral Liquids||Description, pH, weight/ml, Preservative, Assay, Viscosity, Impurities and Microbial Test.||Initial, 3rd day, 7th and 10th day|
*Test parameter and study time point shall be defined in HT study protocol. Acceptance criteria from release specification shall be followed. Study time point can be changed as per product nature and customer requirement and shall be defined in hold time study protocol.
- Up to 8 Hrs study sample time shall not exceed +30 minutes of scheduled time.
- More than 8 hrs to 72 Hrs sample time shall not exceed +1 Hrs scheduled time.
- Up to 15 days sample time shall not exceed + 1 working days of scheduled time.
- More than 15 days sample time shall not exceed + 3 working days of scheduled time.
Storage and sampling procedure for Hold Time Study Samples:
- “0” day sampling shall be done in respective area after completion of activity.
- Hold time sample for bulk Blend/ Granules/ Powder shall be stored in simulated container in Granules quarantine and record shall be updated accordingly.
- Sampling of Blend/Granules/Powder shall be done in Blending area after taking the line clearance as per Annexure-IV in coordination of production chemist / section In-charge.
- After sampling details shall be updated in status label and routine area cleaning shall be done by production chemist and record shall be updated in process area log.
- Sampling for chemical and microbiological examination shall be done separately.
- Sample for Core/Coated tablets and filled capsules shall be packed in double sample polythene bag, each bag shall have the sample quantity packet separately for one time compete chemical and microbial analysis.
- Such sample poly bog shall be prepared equivalent to number of testing station and sample for two additional testing stations.
- These packets shall be kept in HDP container and record shall be updated accordingly.
At sampling interval one complete packet shall be taken & handed over to QC for Chemical and microbial analysis.
- Hold time sample for bulk oral Liquid shall be stored in simulated container in IPQA room.
- QA shall hand over the sample for analysis to QC.
- QC shall do the analysis as per approved testing procedure following current version of SOPs.
- Annexure-III shall be followed for Intimation for HT Study sample.
- Any deviation occurred during handling of sample shall be handled through SOP for “Deviation Control”.
- Any out of specification results shall be handled through SOP for OOS.
- Approved analytical procedure shall be used for analysis of product.
- After compilation and approval of hold time study report of different product stage wise recommendation of hold time study report shall be shared to production for incorporation the holding period of different stage in the BMR.
- After compilation of hold time study, QA shall destroy the remaining sample as per SOP.
- Issuance record of protocol number shall be maintained as per format attached as Annexure-V
Cleaning of Hold time container:
- Cleaning record of hold time study container maintained as per Annexure-VI.
- Hold time study Planner shall be prepared as per Annexure No. VII and updated annually.
5.0 Reference :
- General Guidance ON “Hold-Time” Studies: Working document QAS/13.521/Rev.2
6.0 Annexure – Hold Time Study Guideline :
Annexure I : Template for Hold Time Study Protocol
|Reference Protocol No.|
|Sr. No.||Contents||Page No.|
|6.||Product Details and storage condition|
|7.||Hold time study programme|
|8.||Testing Parameters & Acceptance Criteria|
|10.||Deviations / OOS|
|13.||Summary, Conclusion and Recommendation|
Annexure II : Template for Hold Time Study Report
|Reference Protocol No.|
|Sr. No.||Contents||Page No.|
|5.||Hold time study team|
|6.||Product Details and storage condition|
|7.||Procedure and Acceptance Criteria|
|8.||Observation and results|
|9.||Deviation / OOS|
|10.||Summary, Conclusion and Recommendation|
Annexure III : Intimation for HT Study Sample
From: Quality Assurance To: Quality Control
|Product||Batch No.||Batch Size|
|Mfg. Date||Exp. Date||Days|
|Sample for analysis for :-|
(as per Protocol)
|Qty. of Sample||Sample given by QA||Sample Received By QC||Report received By QA|
Annexure IV : HT study Intimation cum Line Clearance
|Intimation cum Line Clearance for HT Sample|
|Quality Assurance Department||Production Department|
|Kindly provide the area for sampling of hold time sample of the details are :|
|Product Name||Batch No.||Stage||Date|
|Intimation Given By||
Intimation Received By
|Area Line Clearance|
|Sr. No.||Check List||Observation||Checked By||Verified by|
|1.||Check and ensure identification of the area and the equipments with status label||Identified / Not Identified|
|2.||Check & ensure that all the equipments in the lubrication area are cleaned properly||Cleaned / Not Cleaned|
|3.||Check & ensure that all the powder transfer pipes are cleaned properly||Cleaned / Not Cleaned|
|4.||Ensure that all the transfer pipes are properly connected.||Yes / No|
|5.||Ensure the waste bins for cleanliness||Cleaned / Not Cleaned|
|6.||Ensure that gowning system is followed properly.||Complies / Doesn’t comply|
|7.||Check the riser filters for Cleanliness||Cleaned / Not Cleaned|
|Verification of Area Cleaning After Sampling|
|1.||Area Cleaned as per SOP|
Annexure V : Hold time study protocol number issuance log
|Sr. No.||Date||Product Name||Batch size||Protocol No.||Issued By||Remark|
Annexure VI : Template for Cleaning Record of HT Sample Container
|Date||Product name||Batch No.||Cleaned By||Checked By||Remark|
Annexure VII : Format for HT study planner
Document No.: Section: Dosage Form: Effective Date:
|Sr. No.||Product Name||Composition||Reason for study||Batch No.||Batch size||Status||Remark|