Standard Operating Procedure for Hold Time Study Period for Dispensed Raw Materials, Inprocess and Bulk Finished Product

1.0              Objective

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

2.0       Scope

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

3.0              Responsibility

3.1              Officer QC shall be responsible for testing and generation of analytical raw data.

3.2              Executive/Officer QA shall be responsible for execution of Hold Time Study as per protocol.

3.3              Head QA & Head QC shall be responsible for approval of protocol, review of result and evaluation of quality attributes.

4.0              Accountability

Head QC and Head QA shall be accountable for the compliances of this SOP.

5.0              Procedure

5.1              Starting point of the storage period (Hold Time) shall be considered from the completion date of each processing step/stage. For example, in case of compression

started on 10/06/15 and completed on 12/06/15, the starting date of hold time shall be considered as from 12/06/15.

5.2              Material shall be stored in same condition as given in the respective BMR.

5.3              All critical operation and process parameter 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. For example:

·         Product temperature in case of temperature sensitive product.

·         Light requirement in case of light sensitive product.

·         Starch binder temperature throughout hold time period.

5.4              The containers in which hold time samples shall be stored should be same pack as shall be used in production.

5.5              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 as per Annexure-I.

5.6              For new product, establishment of hold time of bulk finished stages shall be based on its product characteristics.

5.7              Sampling at different intervals of hold time shall be done in manufacturing cubicle having status as “CLEANED”. If it is done in storage area, it shall be under the LAF and to be ensured that all other containers are in closed condition.

5.8              Hold time study shall be performed in following conditions:

·         Change in storage condition.

·         Change in formulation. For example addition or deletion of ingredient.

·         Change in manufacturing process. For example, change in granulation method.

·         For new formulation.

5.9              Storage of materials shall be as follows:

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

5.9.2                    Heat sensitive product or cold chain product shall be stored at 2°C - 8°C along with the remaining consignment.

5.9.3                    Sifted Raw Material for granulation/blending/ lubrication shall be stored in well closed IPC/SS container containing 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.

5.9.4                    Binder Solution:

·         Freshly prepared binder solution shall be used for manufacturing the batch.

·         The binder shall be stored in well closed SS container/IPCs after preparation.

·         Starch binder solution shall be used within 5 hours and other binder within 8 hours. If the storage period exceeds, the binder solution shall be discarded.

·         If composition of binder is same for different product or multiple strength of same product, then perform hold time study of binder in any one product or strength. This study shall be valid for rest of the strength or product.

5.9.5                    Sized Granules:

·         The granules after sizing shall be stored for not more than 7 days in a clean and dry IPC / SS bin / SS container containing double polythene bag. If the storage period exceeds, then LOD / Water Content shall be verified before start activity and same shall be attached with respective BMR.

5.9.6                    Lubricated Granules:

·         Lubricated granules shall be stored in controlled condition for not more than 45 days in well closed SS container/IPC with status label.

·         For blend of individual strength product, which are not dose proportional perform hold time study.

·         For blend of multiple strength product, which are dose proportional perform hold time study for blend on lower strength.

5.9.7                    Uncoated /Compressed Tablets (as a inprocess 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 hold time study on higher strength.

·         If multiple strengths of compressed tablets that are not dose proportional, then perform hold time for each strength.

·         If multiple strengths of compressed tablets are not dose proportional, but having same composition then hold time study of lower and higher strength shall be performed.

·         Hold time study is not required to perform on the tablets if there is change in description of tablets related to debossing without any alteration in the physical parameters of tablets like average weight, hardness, thickness etc.

5.9.8                    Coating suspension:

·         Freshly prepared coating suspension shall be used for manufacturing the batch.

·         Suspension shall be agitated/ stirred continuously before using.

·         Coating solution shall be used within 24 hours. If storage period exceeds 24 hours, discard the coating suspension and use freshly prepared coating suspension.

·         If composition (coating material, vehicle) of coating suspension of different products or multiple strengths of same product is same then perform hold time study of coating suspension of any one product/ strength of product. This study shall be valid for rest of all strengths/products.

·         If coating suspension is different for multiple strengths or different products, the hold time study of coating suspension shall be for individual strength/ products.

5.9.9                    Coated Tablets:

·         For coated tablets of different strengths, which are dose proportional, and having same composition of coating suspension (coating material and vehicle) then perform hold time study of coated tablets on higher strength.

·         If the multiple strength for coated tablets has different composition of coating suspension (coating material and vehicle) then hold time study shall be performed for coated tablet of each strength.

·         If the multiple strength of coated tablets are not dose proportional but having same composition, then hold time study shall be performed on lower and higher strength.

5.9.10                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 label.

5.10          Sampling Procedure for Hold Time Study:

5.10.1                Use cleaned accessories during sampling.

5.10.2                Use PPEs during sampling.

5.10.3                While sampling in the area, ensure that all stainless steel containers are closed except from which sample to be withdrawn.

5.10.4                After sampling close the polythene bag taking proper precaution to avoid contamination.

5.10.5                For sampling of microbiological test sample:

·         Use sterile accessories (spatula/ spoon) during sampling.

·         Wear sterile hand gloves while sampling.

·         Remove Aluminium wrapper of sampling accessories such as spatula/ spoon or bottle/polythene bag.

·         After sampling close the sterile polythene bag/ bottle taking proper precaution to avoid contamination.

5.11          Action in case of hold time exceeds  

5.11.1                If hold time period exceeds at any stage, a “Sample Analysis Requisition” shall be sent to QC for tests mentioned in Annexure-I (Format No. CS/QA063/F01-XX).

5.11.2                If hold time at various stages for any products and bulk finished stage for existing product exceeds during any batch manufacturing, then Production Department shall raise “Intimation of Exceed of Hold Time Period of Product” as per Annexure-II (Format No. CS/QA063/F02-XX) and send to QA and QC along with “Sample Analysis Requisition”.

5.11.3                If the inprocess/ bulk finish product fails during analysis, it shall be handled as per SOP No. CS/QA/023.

5.11.4                If the stability chamber, where the hold time samples are kept for the hold time study is malfunctioned and not rectified within 24 hours, the hold time samples shall be shifted to backup stability chamber. This shall be documented in planned deviation report, which shall be evaluated and approved by Head QA.

7.0              Reference

Annex 4: General guidance on hold-time studies: (WHO Technical Report Series, No. 992).