API Stability Protocols and. Chris Byrne Tasmanian Alkaloids

Transcription

1 API Stability Protocols and Evaluations Chris Byrne Tasmanian Alkaloids

2 API Stability Overview APIs = 100% pure Limited (if any) degradation No interactions with other agents in drug products Less likelihood that shipping API to other countries will require special handling Typically 2 5 year retest dates, so long stability studies Typically not claimed to be sterile so no micro complications Straight forward protocols and reports But, all auditors ask to look at stability programs They expect to see a well run compliant program Samples pulled and testing done on time So need to follow good laboratory practices and GMP SOPs, investigations, training etc API Stability

3 API GMPs ICH Q7 : Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (2000) APIs from chemical synthesis, extraction, recovery from natural sources, cell culture/fermentation, or combination of these Common practice is to use retest dates, not an expiration date (Section 11.6) API Stability (Section 11.5): First three commercial lots used to establish retest or expiry date, then one batch per year are stability tested Guidance on testing intervals The test procedures used in stability testing should be validated and be stability indicating API Stability

4 Guidelines Core guide (ICH) for EU, USA & Japan ICH No Q1A(R2) Q1B Q1C Q1D Q1E Q1F Other countries have similar So follow ICH but check for any differences if supplying APIs to non- EU/US/Japan Guideline Stability Testing of New Drug Substances and Products Photostability of New Drug Substances and Products Stability Testing for New Dosage Forms Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products Evaluation of Stability data Stability Data Package for Registration Applications in Climatic Zones III and IV API Stability

5 ICH Q1A(R2) APIs = Drug Substances = Active Substances Note ICH Q1A(R2) is applicable to New drug substances, so should it apply to Existing drug substances? Yes, for example: EMEA (CPMP/QMP/122/02) : Guideline on Stability Testing: Stability of Existing Active Substances and Related Finished Products This Guideline is similar to ICH Q1A(R2) API Stability

6 Study Long term Stability Conditions General Case Storage Condition (ICH Q1A(R2) 25 C ± 2 C/60% RH ± 5% RH or 30 C ± 2 C/65% RH ± 5% RH Climatic Zones III & IV (ICH Q1F) 30 C ± 2 C/65% RH ± 5% RH Intermediate 30 C ± 2 C/65% RH ± 5% RH Accelerated 40 C ± 2 C/75% RH ± 5% RH 40 C ± 2 C/75% RH ± 5% RH Long term option to use 30 C instead of 25 C introduced in 2003 If use 30 C, then do not have intermediate condition For stable APIs, use 30 C to minimise samples on stability WHO Technical Report No 953, Annex 2 summarises the requirements of individual countries API Stability

7 Reasons to undertake Stability Testing New API to establish a retest date Not that common follow guidelines fully 0, 3, 6, 9, 12, 18, 24 months etc., long term & accelerated conditions Retest dates established and extended based upon available data as per Guidelines To maintain retest date on an existing API Annual testing one lot at long term conditions only Non-Typical Lot To confirm the unusual processing does not affect stability and hence retest date Consider the risk that the processing change could have on the long term stability before undertaking additional stability testing Typically use long term conditions, and consider reduced testing frequency (based upon the risk of the process change to impact stability) API Stability

8 Stability SOP Typically follows ICH Q1A(R2) Also, the Stability SOP will define: Max time between manufacture date and placing samples in chamber to initiate programs E.g. 90 days, otherwise need to retest for time zero results Window to pull samples from chambers and window to test after the pull date, e.g.: Test Date (Months) Window to pull samples Window to test < 1 month Exact day 1 M to < 3M + 3 days 3M to < 6M + 7 days 14 days > = 6M 21 days + 14 days > 24 M 28 days API Stability

9 Initiate a Stability Program For the stability protocol, select or define: Storage condition(s), Long term only, or accelerated as well? Testing frequencies, Typically every 3 months or less for first year (follow guidleines) Container closure system Must replicate API storage, e.g. same polyethylene monomer, same outer container, same seals Recommend individual packs, one pack per time point Specification & Methods API Stability

10 Select Specifications and Methods Only test those specifications which are indicative of stability Do not include identity tests Typically Appearance or Description Assay Related Substances or Impurities Solvent or water content Will consider stability indicating methods later API Stability

11 Stability Protocol Need a protocol to initiate stability program records: Defines conditions, specification, test methods, testing frequency; Manufacturing date and Approval date Time zero results (i.e. lot release data) Packaging To support a three year retest date, is 36 months stability enough? Yes, but often test for one more time point Remember: Approved by QA before can start These conditions apply through the program (e.g. if lot release specification or methods change, the historical stability programs do not change) API Stability

12 Test Results & Reports Normal QC GMPs apply E.g. Investigate all OOSs Evaluate results in real time, but formal stability report not generated till program is complete Need to interpret results considering inherent analytical variation of the methods Using a line between two data points is dangerous Consider an annual summary report for each API to collate results from all active programs Just summary results table and brief conclusions When analysing data: The data may show so little degradation it is normally unnecessary to go through the formal statistically analysis.. API Stability

13 Stability Indicating Methods Thus HPLC methods are best Do not assume an USP or EP/BP method is stability indicating you need to determine if it is or not Especially old methods unlikely to be suitable API Stability

14 HPLC Stability Method Need to show that the HPLC method: API samples exposed to stressed conditions: Active substance peak is spectrally pure by Photo Diode Array analysis Thus no degradants co-elute with main peak Degradants are assayed by the method Thus the method will show when degradation is occurring The HPLC method then relies upon a drop in assay and an increase in impurities to indicate that the API is degrading over time on stability Relying upon seeing a trend in lower assay only may not confirm trend until many data points are available due to method variability API Stability

15 HPLC Method Development Why analyse stressed samples? ICH Q1A(R2): Can help identify likely degradation products, which can in turn help establish degradation pathways and the intrinsic stability of the molecule and validate the stability indicating power of the analytical procedures used Note the text asks you to establish a scientific understanding of how your API can degrade So an analytical and synthetic chemistry study API Stability

16 Stress Conditions As per ICH Q1A The nature of the stress testing will depend on the individual drug substance and the type of drug product involved So use scientific common sense when designing experiments On solid API Photo degradation as per ICH Q1B, 1.3 Million lux hours Thermal, not more than 100 C Humidity, where appropriate In solution Oxidation, e.g. add hydrogen peroxide and heat if needed Acid & Base hydrolysis, e.g. acidic or basic solutions heated to 70 C for4 hours Typically aim for 20% degradation If API is stable, accept less 20% degradation API Stability

17 Evaluate Results Assess active substance PDA peak purity Compare the control to the degradation sample For solution experiments, before adding acid, base or peroxide Compare to any known impurity standards available Peak mass balance Sum of all peak approximately constant between control and degraded sample Treat results with caution, e.g. UV chromophore of degradant may be different to active substance API Stability

18 Additional Analysis & Method Report Recall the aim was to identify likely degradation products, so: If possible, analyse the stressed samples by HPLC- MS to propose potential structures to the main degradants In the summary report, consider potential degradation pathways API Stability

19 Stability Chambers Critical Laboratory Equipment, so full GMP required: Qualification: temperature and humidity mapping to ensure all parts of the chamber is within spec. Calibrate temperature and humidity probes Log the temperature and humidity conditions Consider power backup Investigate/document any significant outages API Stability

20 Mean Kinetic Temperature Definition (ICH Q1A(R2): A single derived temperature that, if maintained over a defined period of time, affords the same thermal challenge to a drug substance or drug product as would be experienced over a range of both higher and lower temperatures for an equivalent defined period Calculation uses the maximum and minimum average temperatures over a time period Evaluated to confirm your stability programs are being conducted at the correct conditions Frequency ICH does not specify, USP<1150> for drug products suggests weekly, so you need to define: Consider daily evaluation, review data monthly and perform the calculations Outcome Short term spikes in conditions will be compensated for Document the MKTs in a report which then supports the individual stability program reports API Stability

21 API Intermediates ICH Q7 is silent on requiring stability testing of intermediates, but this is normally done on a more limited basis Typically undertake testing programs to test initial lots to establish retest date, without further annual testing. Retest date are normally shorter than APIs Intermediates may be damp, not dried, so these are more likely to degrade, thus more critical to undertake these studies API Stability

22 References/Links ICH Guidelines EMEA Guidelines (Europe) Regulatory/Human Medicines/Scientific Guidelines/Quality/Stability 1ac eb1 WHO Report 953 Stability Testing of Active Pharmaceutical Ingredients and Finished Products, 2009, updated 1 Dec USP: New and Revised Monograph Guidance API Stability