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Hold Time Study of Pharmaceutical Products

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 :
  • To follow the procedure
  • To review the protocol & report.
QA Chemist and above :
  • To Prepare and review the protocol and compile the report.
  • To follow the procedure and review of  results
QC Chemist and above :
  • To Review the Protocol and compiled report.
  • Chemical testing of samples and review of results and to submit the data in QA.
Microbiologist :
  • Microbial testing of samples and review of results and to submit the data in QA.

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
Coated tablets

(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.

Note:

  1. Up to 8 Hrs study sample time shall not exceed +30 minutes of scheduled time.
  2. More than 8 hrs to 72 Hrs sample time shall not exceed +1 Hrs scheduled time.
  3. Up to 15 days sample time shall not exceed + 1 working days of scheduled time.
  4. 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.
Product Name
Batch No.
Batch Size
Effective Date:
Sr. No. Contents Page No.
1.         Approval
2.         Objective
3.         Scope
4.         Responsibilities
5.         Reference
6.         Product Details and storage condition
7.         Hold time study programme
8.         Testing Parameters & Acceptance Criteria
9.         Procedure
10.      Deviations / OOS
11.      Enclosures
12.      Abbreviations
13.      Summary, Conclusion and Recommendation

Annexure II : Template for Hold Time Study Report

Reference Protocol No.
Product Name
Batch No.
Batch Size
Effective Date:
Sr. No. Contents Page No.
1.    Approval
2.    Objective
3.    Scope
4.    Responsibilities
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
11.  Abbreviation
12.  Annexure

Annexure III : Intimation for HT Study Sample

 From: Quality Assurance                                                                           To: Quality Control

Product Batch No. Batch Size
Mfg. Date Exp. Date Days
Date Stage
Sample for analysis for :-
Test

(as per Protocol) 

Qty. of Sample Sample given by QA Sample Received By QC Report  received By QA
Remark:

Annexure IV : HT study Intimation cum Line Clearance

Intimation cum Line Clearance for HT Sample
From :   To,
  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
1.             
2.             
3.             

 

Janki Singh

Mrs. Janki Singh is the professional pharmaceuticals Blogger. She has already posted more than #1000 articles on varrious topics at different blogging plateforms. Contact : guideline.sop@gmail.com