SOP for Hold Time Study in Pharmaceuticals

This SOP sets out guidelines for the determination and validation of in-process and bulk product holding times.

Maximum allowable hold times should be established for bulk and in-process drug products (where applicable). Typically one lot can be used for validating hold times. Data to justify the hold time can be collected during development on pilot scale batches, during process validation, via a historical review of batch data, or as part of a deviation with proper testing.

OBJECTIVE

To lay down a procedure for the Hold Time Study of intermediate products, bulk, and finished products to establish an acceptable holding time that intermediate and bulk products can be held, pending the next processing step, without producing results outside the acceptance criteria for the quality of the material.

SCOPE

This procedure is applicable to the Validation Department for performing a hold time study during the manufacturing of products (raw material, bulk, and ready-to-pack) on company premises. The other concerned department is Production, Warehouse and Quality Control.

RESPONSIBILITY

• Validation Officer/Executive QA shall be responsible for the preparation of a protocol and execution of studies as per the approved protocol and compiling the report as per the results of the analysis.
• Officer/Executive Production shall be responsible for the execution of studies as per approved protocol.
• The Head Production/ Designee shall be responsible for checking the protocol.
• Chemist QC shall be responsible for testing the material as per specification.
• Head QC/ Designee shall be responsible for review of protocol and report.
• QA Manager/ Designee shall be responsible for review of protocol and report.
• Head QA shall be responsible for the final approval of protocol and report.

ACCOUNTABILITY

• All concerned department heads
• Head QA

PROCEDURE

• 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.
• A 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 specifications for the finished products
• The starting point of Hold Time shall be considered from the completion date of each processing step/stage. Material shall be stored in the same condition as given in the respective BMR.
• All critical operation and process parameters that would affect the product quality along with room condition during hold time shall be monitored and recorded or attached during the entire hold period. 
• The containers in which hold time samples shall be stored should be the same pack as shall be used in production. All in-process stages shall be monitored for hold time. Manufacturing stage along with sampling intervals and tests to be carried out for hold time study.
• Hold time shall be conducted when, but not limited to:

1. Introduction of new product
2. As part of the investigation of a deviation that occurs during manufacturing
3. Any significant changes in process or formulation
4. Change in storage condition.
5. Change in the formulation. For example addition or deletion of an ingredient.
6. Change in the manufacturing process. For example, change in granulation method.

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• For the new product, the establishment of hold time of bulk finished stages shall be based on its product characteristics.
• A sampling at different intervals of hold time shall be done in a manufacturing cubicle having the status “CLEANED”. If it is done in the storage area, it shall be under the LAF and to be ensured that all other containers are in closed condition.
• 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.
• The Hold time study protocol shall be prepared by the Validation Officer, reviewed by the Head of Production and head QC, and then approved by the 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 and documented.
• The Hold time study report shall be prepared by the Validation Officer, reviewed by the Head of Production and head QC, and then approved by the Head QA.
• Hold time study report shall have the unique report no.
• Headspace is important the hold time samples should represent the maximum possible head space (worst-case scenario) for bulk stored in manufacturing/quarantine.
• The sample storage environmental conditions should be the 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.

Storage Procedure for Hold Time Study Samples

Dispensed Raw Material: 

• Shall not be stored for more than 5 days at controlled conditions in well closed SS container with a status label. If the storage period exceeds, reweighing of material shall be done before use either in the store or production area depending upon the quantity of material.

Heat-sensitive product or Cold Chain Product: 

• Shall be stored at 2°C - 8°C along with the remaining consignment.

Sifted Raw Material: 

• For granulation/blending/lubrication shall be stored in well well-closed IPC/SS container containing a double polythene bag, for not more than 7 days. If the storage period exceeds, sifting of material with appropriate mesh size shall be done before use and the same shall be recorded in respective BMR with sign and date.

Binder Solution: 

• Freshly prepared binder solution shall be used for manufacturing the batch. The binder shall be stored in well-closed SS containers/IPCs after preparation. The starch binder solution shall be used within 5 hours and another binder within 8 hours. 
• If the storage period exceeds, the binder solution shall be discarded. If the composition of the binder is the same for a different product or multiple strengths of the same product, then perform a hold time study of the binder in any one product or strength. This study shall be valid for the rest of the strength or product.

Sized Granules: 

• The granules after sizing shall be stored for not more than 45 days in a clean and dry IPC/ SS bin / SS container containing a double polythene bag. If the storage period exceeds, then LOD / Water Content shall be verified before starting the activity and the same shall be attached to the respective BMR.

Lubricated Granules: 

• Lubricated granules shall be stored in controlled condition for not more than 45 days in well closed SS container/IPC with the status label. For a blend of individual strength products, which are not dose-proportional perform a hold time study. 
• For the blend of multiple-strength products, which are dose-proportional perform a hold time study for a blend on lower strength.

Uncoated / Compressed Tablets (as an in-process stage for coated tablets): 

• Compressed tablets ready for coating shall be coated within 90 days.
• For compressed tablets of different strengths, which are dose-proportional perform a hold time study on higher strength.
• If multiple strengths of compressed tablets are not dose-proportional, then perform hold time for each strength.
• If multiple strengths of compressed tablets are not dose-proportional, but have the same composition then a hold time study of lower and higher strength shall be performed.
• A hold time study is not required to be performed on the tablets if there is a change in the description of tablets related to debossing without any alteration in the physical parameters of tablets like average weight, hardness, thickness, etc.

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Coating Solution:

• Freshly prepared coating solution shall be used for manufacturing the batch.
• The solution shall be agitated/ stirred continuously before use.
• The coating solution shall be used within 72 hours. If storage period exceeds, discard the coating solution and use a freshly prepared coating solution.
• If the composition (coating material, vehicle) of the coating solution of different products or multiple strengths of the same product is the same then perform a hold time study of the coating solution of any one product/strength of the product. This study shall be valid for the rest of all strengths/products.
• If the coating suspension is different for multiple strengths or different products, the hold time study of the coating solution shall be for individual strengths/ products.

Coated Tablets:

• For coated tablets of different strengths, which are dose-proportional, and have the same composition of coating solution (coating material and vehicle) then perform a hold time study of coated tablets on higher strength.
• If the multiple strength for coated tablets has a different composition of coating solution (coating material and vehicle) then a hold time study shall be performed for coated tablets of each strength.
• If the multiple strength of coated tablets are
• not dose proportional but having the same composition, then hold time study shall be performed on lower and higher strength.

Blend for Capsules:

• Blend for capsule shall be stored at appropriate condition for not more than 45 days in a well-closed IPC/SS container containing double polythene bags with status labels.

Liquid Oral:

• Liquid Oral shall be stored at the appropriate condition for not more than 7 days in a well-closed SS container with a status label.

 

Ointment/Gel/Cream:

• Shall be stored at appropriate condition for not more than 72 hours in a well-closed SS container with a status label.

Sampling Procedure for Hold Time Study Samples

• Use cleaned accessories during sampling.
• Use PPEs during sampling.
• While sampling in the area, ensure that all stainless steel containers are closed except from which the sample is to be withdrawn.
• After sampling close the polythene bag taking proper precautions to avoid contamination.
• For a sampling of microbiological test samples:

1. Use sterile accessories (spatula/ spoon) during sampling.
2. Wear sterile hand gloves while sampling.
3. Remove the Aluminium wrapper of sampling accessories such as spatula/ spoon or bottle/polythene bag.
4. After sampling close the sterile polythene bag/ bottle taking proper precautions to avoid contamination.

• “0” day sampling shall be done in the respective areas after the completion of an activity.
• Hold time sample for bulk Blend / Granules / Powder shall be stored in a simulated container in Granules quarantine and the record shall be updated accordingly.
• Sampling of Blend/Granules/Powder shall be done in the Blending area after taking the line clearance in coordination with the production chemist/section In-charge.
• After sampling details shall be updated in the status label routine area cleaning shall be done by the production chemist and records shall be updated in the 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 a double sample polythene bags, each bag shall have the sample quantity packet separately for one time complete chemical and microbial analysis.
• Such sample poly bog shall be prepared equivalent to a number of testing stations and sample for two additional testing stations.
• These packets shall be kept in an HDP container and the 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 a simulated container in the IPQA room.
• QA shall hand over the sample for analysis to QC.
• QC shall do the analysis as per the approved testing procedure following the current version of SOPs.
• Any deviation that occurs during the handling of the sample shall be handled through SOP for “Deviation Control”.
• Any out-of-specification results shall be handled through SOP for OOS.
• The approved analytical procedure shall be used for the analysis of the product.
• After compilation and approval of the hold time study report of different products stage wise recommendations of the hold time study report shall be shared with production for incorporation of the holding period of different stages in the BMR.
• After the compilation of the hold time study, QA shall destroy the remaining sample as per SOP.

Note: 

If any of the in-process materials cross the stipulated time period of hold time, then they shall be dealt with as per SOP of Deviation Management and the material shall be tested as per specification before release for further processing.

ABBREVIATIONS

SOP: Standard Operating Procedure

QA: Quality assurance

QC: Quality Control

No. : Number

% : Percentage

RH: Relative Humidity

°C: Degree Centigrade

NMT: Not More Than

HDPE: High-Density Poly Ethylene

SS: Stainless Steel

REVISION HISTORY

Nil

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