HOLD TIME FOR DISPENSED MATERIAL, INTERMEDIATES AND FINISHED PRODUCTS

HOLD TIME FOR DISPENSED MATERIAL, INTERMEDIATES, AND FINISHED PRODUCTS

PURPOSE

The purpose of this SOP is to describe the systematic procedure to establish the hold time of Dispensed materials, intermediate and bulk products prior to final packing

SCOPE

This SOP is applicable for Dispensed materials, intermediate as well as bulk products that hold time to study.

REFERENCE

WHO Technical Report Series No. 992, Annexure 4, 2015(General Guidance on Hold time studies)

ATTACHMENTS

Hold Time Study Sampling Register

DEFINITION

Dispensed Material: A set of Dispensed active & excipient raw materials as per the approved formula comes under dispensed material.

Intermediate: A partly processed product that must undergo further manufacturing steps before it becomes a bulk product.

Bulk Product: Any pharmaceutical product that has completed all processing stages up to, but not including final packaging.

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. Or 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

RESPONSIBILITY

QA Department Person:

QA shall be responsible to collect the hold time samples as per the hold time study Protocol/Datasheet and shall send duly filled “Sample request slip” to the QC department.

QA shall be responsible to maintain the hold time register and soft copy of the hold day’s record.

QA shall be responsible to investigate in case of failure/discrepancies 

QC Department Person:

QC shall be responsible to make entries of the sample as per the defined procedure and analyze the sample as per the defined procedure.

QC shall be responsible to share the report and investigate in case of failure/discrepancies.

Production Department Person:

Production shall be responsible to prepare the Test Requisition cum report and intimate to QA for sampling.

Quality Head and Plant head Responsible for:

Quality Head and Plant Head shall be responsible for review and approve the SOP.

Responsible for implementation of defined system.

PROCEDURE

Hold time study shall be performed in one batch, which shall represent the respective product.

Hold Time study of Product shall be performed as per customize protocol.

Separate protocol shall be prepared and followed for different dosage forms and customize as per formulation.

Each protocol shall cover hold time study at different stages during manufacturing i.e. raw materials (dispensing), granulation fluid & granular blend (granulation), core tablet (compression), coating suspension & coated tablet (coating). 

Storage condition of the product shall be mention in protocol as per dosage form for hold time study. The containers in which hold time samples are stored shall be the same pack (i.e. HDPE or S.S. container) as is used in production. Reducing the size of container, when this is necessary for testing holding time, shall be justified.

The environmental conditions for sample storage shall be the same as those of quarantine area/manufacturing stage and mentioned in the respective protocol.

A sampling plan shall be established and defined in the protocol for taking samples for testing at different intervals.

The amount of sample required shall be calculated based on the interval, the test required in respective product/material specification or analytical test procedure and quantity will be mentioned in the respective protocol sampling plan.

StageTest to be carried out

(can be customized as per the requirement)

Study time as per guidelineIn house
Granulating fluid & Coating suspensionPhysical appearance, specific gravity, sedimentation,  viscosity, pH, Microbial testInitial, 12, 24, 36, 48, 60 & 72  hoursThe frequency may vary as per protocol but not exceeded the frequency as per recommendations in guidelines.
Liquid suspension & syrupsPhysical appearance, specific gravity, sedimentation,  viscosity, pH, Microbial test

(For holding & Manufacturing vessels)

Initial, after 24, 48 & 72 hours
Granular blend/PelletsDescription, assay, Loss on drying, Water content, blend uniformity, particle size, bulk/tapped density, Microbial testInitial, 15th, 30th  &  45th day
Core tablets-uncoatedDescription, hardness, thickness, Friability, Average  Weight, Disintegration, dissolution, related substances, uniformity of dosage unit, Assay, Microbial test,Initial, 30th, 45th, 60th & 90thday.
Coated tabletsDescription, appearance & Visual examination, hardness, thickness, Friability, Average  Weight, Disintegration, dissolution, related substances, Assay, Microbial test,Initial, 30th, 45th, 60th & 90thday.

Hold time study shall be performed in following cases:

  • Change in storage condition
  • Change in a formulation like addition or deletion of ingredients.
  • Change in manufacturing process like change in granulation method etc.
  • For new formulations.
  • Change in API Source.

The hold time study for tablet, liquid, and Dry Powder shall be performed up to:

For blend, granulating fluid, coating suspension & tablet:

  • Hold granulating fluid/coating suspension for 72 hours (samples send to QC at initial, end of 24 & 48 hours).
  • Hold blend for 45 days (sample send to QC at Initial, 15th 30th & 45thday)
  • Hold core tablet for 90 days (sample send to QC at Initial, 30th, 45th, 60th & 90th)
  • Hold coated tablets for 90 days (sample send to QC at Initial, 30th, 45th, 60th & 90thday).

Hold time samples (Granulating fluid, Blends, Core tablets, coated tablets & Coating Suspensions) handling during tablet manufacturing:

Raw Materials:

QA person shall collect the required quantity of samples of starting materials as per the protocol and store them in the HDPE container in quarantine.

The entry of hold time samples collected should be made in the hold time sampling register

On completion of hold time, the ‘Test Requisition Cum Report’ should be filled by QA and sent to QC along with the sample.

Granulating Fluid:

QA person shall collect the required quantity of sample of granulating fluid (binder) as per the protocol and store it in the S.S. container in a controlled area.

The entry of hold time samples collected should be made in the hold time sampling register.

On completion of hold time, the ‘Test Requisition Cum Report’ should be filled by QA and sent to QC along with the sample.

Blend Stage:

QA person shall collect the required quantity of the sample of blend/granules/pellets as per the protocol or as specified in BMR/MPS and stored them in the HDPE container in blend Quarantine.

The entry of hold time samples collected should be made in the hold time sampling register.

On completion of hold time, the ‘Test Requisition Cum Report’ should be filled by QA and sent to QC along with the sample.

Compression Stage:

QA person shall collect the required quantity of the sample of the core tablet as per the protocol and store it in the HDPE container in tablet Quarantine.

The entry of hold time samples collected shall be made in the hold time sampling register.

On completion of hold time, the ‘Test Requisition Cum Report’ shall be filled by QA and sent to QC along with the sample.

Coating Stage:

QA person shall collect the required quantity of the sample of the coated tablet as per the protocol and store in the HDPE container in tablet Quarantine.

The entry of hold time samples collected should be made in the hold time sampling register.

On completion of hold time, the ‘Test Requisition Cum Report’ should be filled by QA and sent to QC along with the sample.

Coating Suspension:

QA person shall collect the required quantity of coating suspension as per the protocol and store it in the S.S. container in the tablet Quarantine.

The entry of hold time samples collected should be made in the hold time sampling register.

On completion of hold time, the ‘Test Requisition Cum Report’ should be filled by QA and sent to QC along with the sample.

Hold time (Tablets/sachets/bottle) handling at the packing stage :

For Tablets/sachets/bottles/pouches kept in factory premises at specified storage conditions beyond the hold time data specified, the sample shall be sent to QC for analysis before the release of the batch.

Head QA/Quality head shall recommend the testing parameter for re-testing, Preferably stability indicating test shall be considered for retesting (Assay, Average weight, Fill weight, Related Substances (impurities) dissolution, etc.).

“Test requisition cum report” slip shall be prepared by the packing officer and shall be forwarded to the IPQA officer for collection of sample.

For chemical testing 50 units for tablets/capsules and for bottles/sachets 50 gm or as per QC requirement.

For microbiology testing required 10 gm. or as per microbial requirement from each dosages form separately shall be sent to QC.

The certificate of analysis of the Hold time stage received from the QC department shall be attached with respective BMR/BPR and the hold time shall be updated in soft copy for future reference soft copy shall be password protected by the concerned QA officer.

The batch will be transferred only after ensuring compliance with the QC result.

If hold time sampling skip or forget at the defined frequency, then raise QMS & justify the reason then Sampling shall be done in the next hold time frequency to be analyzed.

If any finished/ semi-finished product crosses its defined hold time frequency then raise QMS Document for justification, semi-finished/Finished product shall be retested before proceeding to the next stage or the final decision shall be taken by QA Head.

Hold time sample shall be withdrawn on the next working day in case of holiday.

In case a batch /product is retested and the result found the complying then the existing hold time shall be updated accordingly for future reference.