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WHO Guideline & Stability Protocols for Liquid Dosage Forms
This document summarizes WHO guidelines for stability testing of liquid dosage forms. It outlines the key aspects that should be covered in stability protocols, including specifications tested, storage conditions and minimum time periods for long term, intermediate and accelerated studies. Specific recommendations are provided for drug substances, oral solutions, suspensions, small volume parenterals and other dosage forms. The purpose of stability testing is to provide evidence of a product's quality over time under various environmental factors and establish a re-test period or shelf life. Ongoing stability studies are also required to monitor products throughout their shelf life.
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WHO Guideline & Stability Protocols for Liquid Dosage Forms
- 1. M.Pharm 1st SemesterSeminar Subject : Drug Regulatory Affairs & Intellectual Property Rights Topic : WHO Guideline & Stability Protocols For Liquid Dosage Forms By: Anindya Jana M.Pharm 1st Year (Pharmaceutics) Regd. No. : 1661611006
- 2. Introduction The purpose ofstability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity and light, and to establish a retest period for the drug substance or a shelf life for the drug product and recommended storage conditions.
- 3. Guidelines for DrugSubstance & Drug Product Active Pharmaceutical Ingredient Finished Pharmaceutical Product Stress Testing Selection of Batch Selection of Batch Container Closure System Container Closure System Specification Specification Testing Frequency Testing Frequency Storage Condition Storage Condition Stability Commitment Stability commitment Evaluation Evaluation Statements/Labelling Statements/Labelling In Use Stability Ongoing Stability Studies Ongoing Stability Studies
- 4. Active Pharmaceutical Ingredient 1.Stress Testing Stress testing of the drug substance can help to identify the likely degradation products. Helps to establish the degradation pathways and the intrinsic stability of the molecule. Carried out on a single batch of the drug substance. Should include effect of: o temperature e.g. 50°C, 60°C, 70°C etc. o humidity e.g. 75% or greater oxidation o hydrolysis across a wide range of pH 2. Selection Of Batch Data from stability studies should be provided on at least three primary batches of the drug substance. The batches should be manufactured to a minimum of pilot scale by the same synthetic route as production batches. Using a method of manufacture and procedure that simulates the final process to be used for the production of batches.
- 5. 3. Container ClosureSystem The stability studies should be conducted on the drug substance packaged in a container closure system is the same as the packaging proposed for storage and distribution. 4. Specification Stability studies should include testing of those attributes of the drug substance that are susceptible to change during storage and are likely to influence quality, safety, and/or efficacy. The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes. 5. Testing Frequency For long-term studies, every 3 months over the first year, every 6 months over the second year, and annually thereafter through the proposed retest period. For accelerated storage condition, a minimum of three time points, including the initial and final time points (e.g., 0, 3, and 6 months), a 6-month study is recommended. For intermediate storage condition, a minimum of four time points, including the initial and final time points (e.g., 0, 6, 9, 12 months), a 12-month study is recommended.
- 6. 6. Storage Condition (I)General Case Study Storage Condition Minimum Time Period Covered Long Term 25°C ± 2°C / 60% RH ±5%RH or 30°C ± 2°C / 65% RH ± 5%RH 12 Months Intermediate 30°C ± 2°C / 65% RH ± 5%RH 6 Months Accelerated 40°C ± 2°C / 75% RH ± 5%RH 6 Months (II) Drug Substances Intended for Storage in a Refrigerator Study Storage Condition Minimum Time Period Covered Long Term 5°C ± 3°C 12 Months Accelerated 25°C ± 2°C / 60% RH ±5%RH 6 Months
- 7. (III) Drug SubstancesIntended for Storage in a Freezer Study Storage Condition Minimum Time Period Covered Long Term --20°C ± 5°C 12 Months 7. Stability Commitment When the available long-term stability data on primary batches do not cover the proposed re- test period granted at the time of approval, a commitment should be made to continue the stability studies post-approval in order to firmly establish the re-test period or shelf-life. The stability protocol used for long-term studies for the stability commitment should be the same as that for the primary batches, unless otherwise scientifically justified.
- 8. 8. Evaluation Re-testperiod Purpose of stability studies is to establish a re-test period applicable to all further batches of the drug substance manufactured under similar circumstances. It is based on results of physical, chemical, biological and microbiological tests from three batches. No formal statistical analyses The data may show so little degradation and so little variability that it is apparent from looking at the data that the requested re-test period will be granted. Under the circumstances normally unnecessary to go through the formal statistical analyses. Statistical evaluation Data on a quantitative attribute that changes with time: Determination of the time at which the 95% one sided confidence limit for the mean curve intersects the acceptance criterion etc. 9. Statements/Labelling A storage statement should be established for the labelling in accordance with relevant national/regional requirements. The statement should be based on the stability evaluation of the drug substance. A retest period should be derived from the stability information, and a retest date should be displayed on the container label if appropriate.
- 9. 10. Ongoing StabilityStudies The purpose of the ongoing stability programme is to monitor the API and to determine that the API remains, and can be expected to remain, within specific cations under the storage conditions indicated on the label, within the re-test period in all future batches. Finished Pharmaceutical Product 1. Selection Of Batch Required are at least three primary batches. • Same formulation and in same container closure system as proposed for marketing. • Manufacturing process should simulate that applied to production batches. • Same quality and meeting specifications as that intended for marketing. Two of the three batches at least pilot scale third can be smaller Drug products should be manufactured by using different batches of the drug substance. Stability studies should be performed on each individual strength and container size of the drug product unless bracketing or matrixing is applied.
- 10. 2. Container ClosureSystem Stability testing should be conducted on the dosage form packaged in the container closure system proposed for marketing. Any available studies carried out on the FPP outside its immediate container or in other packaging materials can form a useful part of the stress testing of the dosage form or can be considered as supporting information, 3. Specification Stability studies should include testing of those attributes of the FPP that are susceptible to change during storage and are likely to influence quality, safety, and/or efficacy. The testing should cover, as appropriate, the physical, chemical, biological and microbiological attributes, preservative content and functionality tests. 4. Testing Frequency For long-term studies, every 3 months over the first year, every 6 months over the second year, and annually thereafter through the proposed retest period. For accelerated storage condition, a minimum of three time points, including the initial and final time points (e.g., 0, 3, and 6 months), a 6-month study is recommended. For intermediate storage condition, a minimum of four time points, including the initial and final time points (e.g., 0, 6, 9, 12 months), from a 12-month study is recommended.
- 11. 5. Storage Condition (I)General Case Study Storage Condition Minimum Time Period Covered Long Term 25°C ± 2°C / 60% RH ±5%RH or 30°C ± 2°C / 65% RH ± 5%RH 12 Months Intermediate 30°C ± 2°C / 65% RH ± 5%RH 6 Months Accelerated 40°C ± 2°C / 75% RH ± 5%RH 6 Months (II) FPPs packaged in semi-permeable containers Study Storage Condition Minimum Time Period Covered Long Term 25°C ± 2°C / 40% RH ±5%RH or 30°C ± 2°C / 35% RH ± 5%RH 12 Months Intermediate 30°C ± 2°C / 65% RH ± 5%RH 6 Months Accelerated 40°C ± 2°C / Not More Than75% 6 Months
- 12. (III) Drug SubstancesIntended for Storage in a Refrigerator Study Storage Condition Minimum Time Period Covered Long Term 5°C ± 3°C 12 Months Accelerated 25°C ± 2°C / 60% RH ±5%RH 6 Months (IV) Drug Substances Intended for Storage in a Freezer Study Storage Condition Minimum Time Period Covered Long Term --20°C ± 5°C 12 Months 6. Stability Commitment Submission includes data from 3 production batches, commitment to continue through proposed shelf life. Fewer than three production batches commitment continue with these studies through proposed shelf life and place additional production batches to a total of three on long term and accelerated stability testing through proposed shelf life. No Production batches commitment to place first three production batches on long term and accelerated stability testing through proposed shelf life.
- 13. 7. Evaluation Asystematic approach should be adopted in the presentation and evaluation of the stability information, which should include, as appropriate, results from the physical, chemical, biological, and microbiological tests, including particular attributes of the dosage form (e.g., dissolution rate for solid oral dosage forms). The purpose of the stability study is to establish, based on testing a minimum of three batches of the drug product, shelf life and label storage instructions applicable to all future batches of the drug product manufactured and packaged under similar circumstances. The degree of variability of individual batches affects the confidence that a future production batch will remain within specification throughout its shelf life. 8. Statements/Labelling A storage statement should be established for the labelling in accordance with relevant national/regional requirements. The statement should be based on the stability evaluation of the drug product. There should be a direct link between the label storage statement and the demonstrated stability of the drug product. An expiration date should be displayed on the container label.
- 14. 9. In UseStability The purpose of in-use stability testing is to provide information for the labelling on the preparation, storage conditions and utilization period of multidose products after opening, reconstitution or dilution of a solution. The physical, chemical and microbial properties of the FPP susceptible to change during storage should be determined over the period of the proposed in-use shelf-life. Specific parameters, e.g. for liquids and semi-solids, preservatives, per content and effectiveness, need to be studied. 10. Ongoing Stability Studies The purpose of the ongoing stability programme is to monitor the product over its shelf-life and to determine that the product remains, and can be expected to remain, within specifications under the storage conditions on the label. This mainly applies to the FPP in the container closure system in which it is supplied. The ongoing stability programme should be described in a written protocol and results formalized as a report.
- 15. Stability Protocols ForLiquid Emulsion Appearance Colour Odour Assay Degradation Product Microbial Limit pH Viscosity Preservative Content Distribution Of dispersed phase globule Oral Solution Appearance Colour Odour Assay Degradation pH Microbial Limits Preservative Content Oral Suspension Appearance Colour Odour Assay Degradation pH Microbial Limit Preservative Content Redispersibility Rheological Properties Mean Size Distribution Of Particle
- 16. Small Volume Parenteral Colour Clarity Particulate Matter pH Sterility Endotoxin PowderFor Injection Colour Reconstitution Time Water Content Suspension For Injection Particle Size Redispersibility Rheological Properties Emulsion For Injection Phase Separation Viscosity Mean Size Distribution of dispersed phase globule Large Volume Parenteral Colour Clarity Particulate Matter pH Sterility Pyrogen/Endotoxin Volume
- 17. Reference (I) S KNiazi; Handbook of pharmaceutical product (Liquid Formulation); Vol 3; 2009; P 52-57 (II) Stability Testing of active and finished pharmaceutical product; WHO technical report series No.953;2009 P 87-130 (III)S Bajaj, N Shakuja; Stability Testing of pharmaceutical product; Journal of applied pharmaceutical science02 (03), 2012; P129-138
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