A large number of drug products are manufactured in pharmaceutical industries using different manufacturing steps & are stored at various stages depending upon the process nature.
Good manufacturing practices demand the manufacturer to provide a system that ensures that all the dispensed raw materials, packaging materials, intermediate products, bulk & finished products are stored under controlled conditions & remain within specifications during all the stages.
The concept of hold-time studies was introduced for this.
Hold Time Reference GuidelinesÂ
WHO Technical Report Series (TRS) 992 annex 4 provides basic guide for hold time studies to the manufacturers & GMP inspectors.
- These guidelines mainly focus on the aspects which must be considered by the manufacturer during the hold time study design of nonsterile solid dosage forms.
- Different principles of these guidelines can be used for other dosage forms like creams, ointment & liquids.
- This document does not establish any process for hold time studies but focuses on the aspects to assist in the design of hold time studies.
Hold Time Duration CriteriaÂ
The above document does not restrict for final maximum holding period.
- The choice of maximum holding period depends on the risk base & must be supported by the manufacturer’s storage & testing data.
- Holding time duration can be extended or decreased depending on the risk involved to a specific stage.
- These guidelines are not bound to perform the stability studies for the duration as long as failure is observed.
What Is Hold Time
As the name indicates, hold time is the duration of holding time or the established period for which specific dispensed materials, intermediate, or bulk products awaiting for final packaging are held under suitable storage conditions & will remain within their defined specification limits.
Hold Time Studies
Hold time studies establish the time limits for holding the materials at different production stages to ensure that the quality of the product does not produce results outside the acceptance criteria during hold time.
The design of hold time studies must reflect the hold time for each stage.
Purpose Of Hold Time Studies
- Hold time studies provide us confidence that the intermediate or bulk products can be held for a defined period under suitable storage conditions before the next pending step is performed without any harmful effects.
- Hold time studies aim to demonstrate that storage conditions have no deleterious effect on the stability, safety & efficacy of the stored material.
- Hold time studies also demonstrate that storage conditions do not affect stability, safety, efficacy, or quality of the materials before final packaging.
- Hold time studies also provide us with data of storage time for various intermediate & bulk products in case of any major breakdown.
- It is the regulatory requirement.
- Hold time study data help us for investigation of any deviation.
General DefinitionÂ
For easy understanding & differentiation.
Bulk Products
Any pharmaceutical product that has completed all the required processing steps but is not finally packed.
Intermediate Products
The products that are partially processed & require further processing to become bulk product.
When To Conduct Hold Time Studies
- Hold time studies must be conducted before marketing a product.
- It can be conducted during pilot scale batches or scale up batches & must be verified during process validation of commercial batches.
- Any one batch from the first three validation batches can be selected for hold time studies & it is a good practice to conduct hold time studies on the first process validation batch.
Hold Time Protocol
Written hold time protocol must be designed for performing hold time studies & it includes following,
- Activities to be performed
- Test parameters
- Acceptance criteria
- Responsibilities
- Procedure
- Material description
- Sampling plan
- Sample quantity
- Storage conditions
- Container types
- Analytical methods
- Microbial aspectsÂ
- Results
- Recommendations
Sample Storage ConditionsÂ
- The hold time sample is stored in the same container as it is used in the manufacturing area.
- The storage container must be built of the same material as in production having the same headspace.
- It is stored at the same storage conditions as in the manufacturing or staging area.
Explanation Of Hold Time StudiesÂ
To understand the concept of hold time studies, design a flow chart for the manufacturing process & highlight the critical stages for which sampling is required based on the risk approach.
The testing is done on this sample to find out the required storage time for each critical stage.
ExampleÂ
Take the example of tablet manufacturing where a flow chart according to WHO TRS 992 annex 4 will be as followsÂ
According to this flow chart, the samples are taken for analysis at the following stages
- Binder Solutions
- Dried Granules
- Final Lubricated Blend
- Compressed Tablets
- Coating Suspension
- Coated TabletsÂ
As we know the granulation binder solution & coating suspension are consumed within the same shift or in the next shift so storage time for these is short & is taken in hours.
The remaining intermediate products may be stored for days so we perform testing for a defined number of days, usually till 90 days.
Important informationÂ
According to my observation, the hold time for granulation & coating suspension should be for 72 hours as for some coating formulations the run time may be more than 24 hours.
The solid reason for 72 hours hold time for granulation & coating suspension is to justify the quality of our prepared solution in case of any major equipment breakdown which may last for 2 to 3 days.
Tests Performed During Hold Time
Following tests are performed during hold time studies in the case of manufacturing of coated tablets.
- Physical Appearance
- Microbiological Testing
- Viscosity, pH, specific gravityÂ
- Assay, hardness, friability, disintegration, dissolution.
- Loss on drying, tape density, bulk density.
Or any other can be added depending on the risk involved.
Stage Wise Testing & HoldÂ
Time
For coated tablets manufactured by wet granulation method.
Stage NameÂ
Binder PreparationÂ
Tests Performed
The following tests are performed for the binder prepared for granulation.
- Physical Appearance
- Microbial Test
- Viscosity (If applicable)
Study Time
Testing is performed after the following time intervals.
- Initial, after 2 hrs, 5 hrs & 8 hrs.
For StarchÂ
- Initial, after 2 & 5 hrs.
Stage NameÂ
Dispersion Prepared
It includes following
- Granulation paste
- Coating Suspension
- Coating Solution
Tests Performed
Following tests are performed for this stage,
- Physical Appearance
- Microbial Test
- Viscosity (If applicable)
- Specific Gravity
- pH
- SedimentationÂ
Study Time
Testing is performed after the following time intervals.
- Initial,after 12 hrs, 24 hrs, 36 hrs 48 hrs, 60 hrs & 72 hrs.
Stage NameÂ
Dry Granules
Tests Performed
The following tests are performed for this stageÂ
- DescriptionÂ
- Assay
- Related Substance
- LOD & water contentÂ
- Particle size distribution
- Bulk & tap densityÂ
- Angle of reposeÂ
Study Time
Testing is performed after the following time intervals.
- Initial,after 15th day, 30th day & 45th day.
Stage NameÂ
Blend (Lubricated Blend)
Tests Performed
The following tests are performed for the blend stage.
- Microbial Test
- LOD
- Blend Uniformity
- Tap or bulk density
- Particle sizeÂ
Study Time
Testing is performed after the following time intervals.
- Initial,after 15th day, 30th day & 45th day.
Stage NameÂ
Compressed TabletsÂ
Tests Performed
The following tests are performed for compressed Tablets.
- Description
- Hardness, Thickness, Friability, disintegration, Dissolution.
- Assay, related substanceÂ
- Uniformity of dosage unit.
- Microbial TestÂ
Study Time
Study performed after following time intervals.
- Initial,after 30th day,45th day ,60th day & 90th day.
Stage NameÂ
Coated TabletsÂ
Tests Performed
The following tests are performed for coated Tablets.
- Description, appearance
- Hardness, Thickness, Friability, disintegration, Dissolution.
- Assay, related substanceÂ
- Uniformity of dosage unit.
- Moisture content, Microbial TestÂ
Study Time
Testing is performed after the following time intervals.
- Initial,after 30th day,45th day,60th day & 90th day.
Important Note
The batch of the product taken for hold time study manufactured from the intermediate or bulk products is placed for long-term stability testing till the end of shelf life if intermediate testing data show abnormal trends.
Revalidation Of Hold Time Studies
The hold time studies are performed again in the following cases,Â
In case of formulation change.
- Due to change in any In Process parameters.
- Due to changes in storage conditions.
Part Of BMR
The hold time of each stage for a specific product should be added to the batch manufacturing record (BMR) for better control over product quality.
Reference
WHO TRS 992 – Annex 4: General Guidance on hold time studies.
Image Credit
Image Source – Google | Image By – WHO