Hold Time Studies

13,171 views
12,523 views

Published on

Good manufacturing practices (GMP) require that a maximum acceptable holding period should be established to ensure that intermediates and bulk product can be held, pending the next processing step, without any significant adverse effect to the quality of the material. Such a holding period should be underwritten by data, but need not be extended to find the edge of failure for holding. WHO has published a guideline on Hold Time Studies.
A summary of the recommendations if given in the enclosed presentation prepared by “Drug Regulations”

6 Comments
20 Likes
Statistics
Notes
No Downloads
Views
Total views
13,171
On SlideShare
0
From Embeds
0
Number of Embeds
232
Actions
Shares
0
Downloads
0
Comments
6
Likes
20
Embeds 0
No embeds

No notes for slide

Hold Time Studies

  1. 1. This presentation is compiled by “ Drug Regulations” a non profit organization which provides free online resource to the Pharmaceutical Professional. Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals. 6/25/2015 1
  2. 2. This presentation is compiled from freely available resources like the website of WHO , specifically GENERAL GUIDANCE ON “HOLD-TIME” STUDIES” “Drug Regulations” is a non profit organization which provides free online resource to the Pharmaceutical Professional. Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals. 6/25/2015 2 Drug Regulations : Online Resource for Latest Information
  3. 3.  The World Health Organization (WHO) had released the second draft of the guideline for the design of hold-time studies in March 2015  The final version was released as a part of Technical Report Series 992 (TRS 992, Annex 4) in June 2015.  This presentation is based on this final Guidance. 6/25/2015 3Drug Regulations : Online Resource for Latest Information
  4. 4.  Hold time ◦ Can be considered as the established time period for which materials (dispensed raw materials, intermediates, bulk, and finished products under quarantine) may be held under specified conditions and will remain within the defined specifications. ◦ The quality and stability of intermediate products, bulk and finished products in quarantine should be ensured at all stages of manufacture. 6/25/2015 4Drug Regulations : Online Resource for Latest Information
  5. 5.  Good Manufacturing Practices ◦ Manufacturers should ensure that the products they manufacture are  Safe  Effective  Of the quality required for their intended use  Are consistently manufactured to  The quality standards appropriate to their intended use and  As required by the marketing authorization 6/25/2015 5Drug Regulations : Online Resource for Latest Information
  6. 6.  Good Manufacturing Practices ◦ Systems should ensure that Pharmaceutical products are produced  According to validated processes  To defined procedures. ◦ Manufacturing processes should be  Capable  Consistent  Manufacture products of required quality  Manufacture products complying with their specifications 6/25/2015 6Drug Regulations : Online Resource for Latest Information
  7. 7.  Good Manufacturing Practices ◦ Arrangements should exist to ensure that the  Dispensed raw materials  Packaging materials  Intermediate products  Bulk and finished products ◦ are stored under appropriate conditions. 6/25/2015 7Drug Regulations : Online Resource for Latest Information
  8. 8.  Good Manufacturing Practices ◦ Storage should not have any significant negative effect on the  Processing  Stability  Safety,  Efficacy  Quality of ◦ Materials ◦ Intermediate products ◦ Bulk products prior to final packing 6/25/2015 8Drug Regulations : Online Resource for Latest Information
  9. 9.  Good Manufacturing Practices Require that ◦ A maximum acceptable holding period should be established ◦ Objective of Hold Time  To ensure that intermediates and bulk product can be held, without any significant adverse effect to the quality of the material till next step of processing  Such a holding period should be based on data  Studies need not be extended to find the edge of failure for holding 6/25/2015 9Drug Regulations : Online Resource for Latest Information
  10. 10.  WHO guideline ◦ Focuses on hold-time studies for solid dosage forms ◦ Many of the principles can be applied to other dosage forms such as liquids, creams and ointments ◦ Does not cover hold times in cleaning validation ◦ Does not cover manufacturing of active pharmaceutical ingredients (APIs) or Biologicals ◦ Intended as a basic guide for use by pharmaceutical manufacturers and GMP inspectors ◦ Does not intend to prescribe a process for establishing hold times, ◦ Reflects aspects that should be considered in the design of the hold-time study 6/25/2015 10Drug Regulations : Online Resource for Latest Information
  11. 11.  Gather scientific and justifiable data to demonstrate that the ◦ Dispensed raw materials and packaging materials, intermediate and bulk products:  Remain of appropriate quality before processing to the next stage;  Meet the acceptance criteria and release specification for the finished product 6/25/2015 11Drug Regulations : Online Resource for Latest Information
  12. 12.  Collect data to justify the hold time during ◦ Development on pilot scale ◦ Process validation ◦ As part of an investigation of a deviation that occurred during manufacture. 6/25/2015 12Drug Regulations : Online Resource for Latest Information
  13. 13.  Use a flow chart  Review manufacturing procedure  Break up the critical stages  Use time duration of each processing stage  Evaluate the potential impact of storage with reference to environmental and storage conditions. 6/25/2015 13Drug Regulations : Online Resource for Latest Information
  14. 14. Processing Step Product Binder preparation to granulation Granulate Wet granulation to drying Dried Granules Dried granules to lubrication/blending Lubricated Blend Compression to coating Tablet cores Coating solution to preparation Coating Solution coating to packing Bulk coated Tablets 6/25/2015 14Drug Regulations : Online Resource for Latest Information For oral tablets the following stages may be considered:
  15. 15.  Prepare a written protocol  Include following in protocol ◦ Activities to be performed ◦ Test parameters ◦ Acceptance criteria appropriate to the material or product under test 6/25/2015 15Drug Regulations : Online Resource for Latest Information
  16. 16. ◦ Title ◦ Reference number ◦ Version ◦ Date ◦ Objective ◦ Scope ◦ Responsibility ◦ Procedure 6/25/2015 16Drug Regulations : Online Resource for Latest Information ◦ Description of the material/product; ◦ Sample quantities; ◦ Sampling method and criteria; ◦ Acceptance limits; ◦ Frequency for sampling; ◦ Sampling locations; ◦ Pooling of samples; The protocol and report should generally include the following ◦ Storage conditions ◦ Type of container ◦ Methods of analysis ◦ Results ◦ Conclusion ◦ Recommendation ◦ Signatures and dates
  17. 17.  Acceptance criteria are typically more stringent than registered specifications,  This provides assurance that the material is well within control.  Consider any known stability trend when setting the specifications  Consider microbiological aspects for certain type of products  Use validated stability indicating methods for testing of bulk intermediates and product 6/25/2015 17Drug Regulations : Online Resource for Latest Information
  18. 18.  Use one or more batches of a material, intermediate or product for determining hold times.  Use a risk-based approach to determine the appropriate number of batches  Consider the characteristics of the materials and other relevant aspects.  Hold for defined period a representative sample of the batch of material or product subjected to the hold-time study 6/25/2015 18Drug Regulations : Online Resource for Latest Information
  19. 19.  Use one or more batches of a material, intermediate or product  Use a risk-based approach to determine the number of batches  Hold a representative sample for the defined hold period.  Keep the material in either original or simulated container  Containers used should be the same pack as used in production  If the pack is exceptionally large use a equivalent ◦ same material of construction and closure system to the production packaging system 6/25/2015 19Drug Regulations : Online Resource for Latest Information
  20. 20.  Reducing the size of container when necessary for testing holding time, should be justified.  Where head space is important use maximum head space (worst-case scenario) situation  In such cases, the ratio of headspace to contents in the test containers should be at least as great as the maximum that is possible in routine production (especially taking into account part-filled containers). 6/25/2015 20Drug Regulations : Online Resource for Latest Information
  21. 21.  Store samples in same environmental conditions as in manufacturing / storage  Establish a sampling plan  Calculate required sample amount based on the batch size, the intervals and tests to be performed. 6/25/2015 21Drug Regulations : Online Resource for Latest Information
  22. 22.  Keep the sample in storage container and test it  Compare results with the initial baseline data of the control sample  Samples may be pooled for analysis where appropriate  Where necessary, individual samples may be tested and compared  Identify trends & justify limits with Statistical analysis 6/25/2015 22Drug Regulations : Online Resource for Latest Information
  23. 23.  Batches of products subjected to a hold-time study should be considered for long-term stability testing if data show trending or shifting patterns during the intermediate time periods up to the end- time.  The shelf-life of the product – irrespective of hold times should be measured from the time the actives are mixed with other ingredients.  Normally intermediate and bulk products should not be stored beyond the established hold time.  All testing of bulk intermediates and product should be performed using validated stability indicating methods. 6/25/2015 23Drug Regulations : Online Resource for Latest Information
  24. 24. 6/25/2015 24Drug Regulations : Online Resource for Latest Information Stage Test Time Period for Testing Binder Preparation including granulation pastes, coating solution and coating suspension Physical appearance Specific gravity Viscosity Sedimentation pH Microbial test Initial, 12, 24, 36, 48, 60, 72 hours
  25. 25. 6/25/2015 25Drug Regulations : Online Resource for Latest Information Stage Test Time Period for Testing Granules Description Assay Moisture content (loss on drying) Water content Particle size distribution Bulk density Tap density Angle of repose Initial, 15th day, 30th day, 45th day
  26. 26. 6/25/2015 26Drug Regulations : Online Resource for Latest Information Stage Test Time period for Testing Blend Microbial test Moisture content (loss on drying) Blend uniformity Particle size Bulk/tapped density Initial, 15th day, 30th day, 45th day
  27. 27. 6/25/2015 27Drug Regulations : Online Resource for Latest Information Stage Test Time period for Testing Core tablets – uncoated (in bulk containers) Description Hardness Thickness Friability Appearance Dissolution Disintegration Assay Degradation products/related substances (where applicable) Uniformity of dosage units Microbial test Initial, 30th day, 45th day, 60th day and 90th day
  28. 28.  Examples of stages and tests that may be considered. 6/25/2015 28Drug Regulations : Online Resource for Latest Information Stage Test Time Period for Testing Coated tablets (in bulk containers) Description Hardness Thickness Friability Appearance Dissolution/dissoluti on profile Disintegration Assay Degradation products/related substances (where applicable) Uniformity of dosage units Moisture content Microbial test Initial, 30th day, 45th day, 60th day and 90th day
  29. 29. This presentation was compiled from freely available resources like the website of WHO , specifically GENERAL GUIDANCE ON “HOLD-TIME” STUDIES” “Drug Regulations” is a non profit organization which provides free online resource to the Pharmaceutical Professional. Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals. 6/25/2015 29 Drug Regulations : Online Resource for Latest Information

×