Stability data required by WHO-PQP Mercy Acquaye

Presentation Outline Requirements for APIs  Stress testing  Regulatory stability testing Requirements for FPPs  Stability –indicating quality parameters  Selection of batches  Container closure system  Testing frequency  Storage conditions  Evaluation  Extrapolation of data

Stress testing (forced degradation) Stress testing of the API can help to identify the likely degradation products, which can in turn help establish degradation pathways and intrinsic stability of the molecule and validate the stability indicating power of the analytical procedures used. The nature of the stress testing depends on the API and type of FPP involved Degradation paths are reactions of hydrolysis, oxidation, photolysis and/or acid-base chemistry

Stress conditions To force these reactions, the API or FPP is placed in solution for eg under the ff conditions Stress factorConditions heat60 o C humidity75% RH or more acid0.1N HCL base0.1N NaOH oxidative3% H 2 O 2 photolyticMetal halide, Hg, Xe lamp or UV- B/fluorescent

The purpose is to generate a small extent of degradation i.e about 10-30% loss of active by assay In the absence of any degradation after 10 days, the API is considered stable If degradation is present but not up to 10% stress factors and /or conditions should be increased Stress testing is carried out on 1 batch of the API Photostability testing should be included (ICH Q1B)

For solid-state degradation, a solid sample of the API is placed at elevated temperatures Results from stress testing are submitted to WHO and other DRAs

Regulatory stability testing Summary of stability testing program and report of 3 batches of the API is required Data for each parameter should be discussed, trends analyzed and a re-test date proposed Information on analytical procedures used and their validation should be submitted

The general requirements are Storage temp ( o C) Relative humidity (%) Minimum time period covered by data at submission (months) Accelerated 40±2 75± 56 Intermediate 30±2 65± 512 Long term 25± 2 60± 512

Post approval stability protocol and stability testing commitment when applicable A storage statement should be proposed for the labelling, based on evaluation of stability data

Stability requirements for FPPs The characteristics of the API and dosage form will determine the design of stability studies for the FPP Studies performed on each strength and container size unless bracketing or matrixing is applied

Stability- indicating quality parameters Include those susceptible to change during storage and likely to affect quality, safety and/or efficacy Analytical procedures should be validated and stability indicating

Parameters likely to be affected by storage and/or not routinely monitored during manufacturing but indicative of the stability of the FPP include the ff:  Physical characteristics e.g. organoleptic properties, in-vitro dissolution, moisture content and change of polymorphs  Efficacy of antimicrobial agents  Chemical characteristics e.g. assay of API, content of degradation products, content of preservatives, antioxidants as well as enantiomeric purity  Study of the container and closure interaction with the contents  In-use stability data for products to be diluted or reconstituted before use

Shelf life acceptance criteria should be based on stability data Repackaging of bulk finished products require studies in the bulk container and the final container closure system

Selection of batches Data on 3 primary batches, i.e at least 1 production scale and 2 pilot scale batches Composition, batch size, batch number, manufacturing data and COA at batch release should be submitted Where possible batches of FPP should be manufactured from different batches of API

Container closure system Stability testing should be conducted on the dosage form packaged in the container closure proposed for marketing as well as any secondary packaging and label

Testing frequency For accelerated, minimum of 3 points including the initial and final time points from a 6 month period For intermediate, a minimum of 4 time points including the initial and final time points from a 12 month period Reduced designs i.e matrixing or bracketing where the frequency is reduced or certain factor combinations are not tested can be used if justified

Storage conditions To test the thermal stability and sensitivity to moisture or potential for solvent loss. Storage conditions and length of studies should cover storage, shipment and subsequent use In-use stability testing should be done on 2 batches of re-constituted or diluted FPP one of which should be investigated close to the end of the shelf life.

Significant change For FPP significant change refers to any of the ff: 5% or more change in assay from its initial value Any degradation product exceeding its acceptance criterion Failure to meet acceptance criteria for appearance, physical attributes and functionality tests (colour, phase separation, hardness) Failure to meet acceptance criteria for pH or dissolution

Evaluation Results from physical, chemical, biological and microbiological tests Specific characteristics of the dosage form e.g. dissolution rate, hardness and LOD Stability data from a minimum of 3 batches is used to establish a shelf life and storage conditions for all future batches manufactured and packaged under similar conditions The degree of variability of the batches affect the confidence that subsequent batches will remain within specification throughout the proposed shelf life.

Extrapolation of data When long term data is supported by accelerated stability data, the re-test or shelf life may be extended up to not more than 12 months beyond the period covered by long term data