1 TG Dekker – WHO, UkraineOctober 2005 Stability Studies (emphasis on FPPs) World Health Organization Training Workshop on Pharmaceutical Quality, GMP and Bioequivalence Kiev - Ukraine 3 to 7 October 2005 Theo Dekker, D.Sc., consultant to WHO Research Institute for Industrial Pharmacy North-West University, Potchefstroom, South Africa

2 TG Dekker – WHO, UkraineOctober 2005 Topics for discussion 1.Objective of stability studies 2.Glossary / definitions  Included for completeness - self reading 3.Study protocol/requirements 4.TB and ARV FDC examples to show  Expression of degradants  Assay / degradation analytical requirements 5.Reporting of stability data  See Annex 3 and 4 of main guidelines – self reading 6.Evaluation of stability data 7.Closing remarks Note: 25ºC/60%RH = 25ºC ± 2ºC / 60% RH ± 5% RH

3 TG Dekker – WHO, UkraineOctober 2005 The objective of stability studies The purpose of stability testing is to provide evidence on how the quality of a drug substance [API] or drug product [FPP]  varies with time  under the influence of a variety of environmental factors such as temperature, humidity, and light and  to establish a re-test period for the API or a shelf life for the FPP and  to recommend storage conditions ICH QA1(R2)

4 TG Dekker – WHO, UkraineOctober 2005 Glossary [ICH QA1(R2)] (1) Re-test period  The period of time during which the API is expected to remain within its specification and, therefore, can be used in the manufacture of a given drug product, provided that the API has been stored under the defined conditions  After this period, a batch of API destined for use in the manufacture of a FPP should be re-tested for compliance with the specification and then used immediately  A batch of drug substance can be re-tested multiple times and a different portion of the batch used after each re-test, as long as it continues to comply with the specification  For most biotechnological/biological substances known to be labile, it is more appropriate to establish a shelf life than a re- test period. The same may be true for certain antibiotics

5 TG Dekker – WHO, UkraineOctober 2005 Glossary [ICH QA1(R2)] (2) Re-test date The date after which samples of the API should be examined to ensure that the material is still in compliance with the specification and thus suitable for use in the manufacture of a given drug product [if stored under defined conditions] Expiry (expiration) date The date placed on the container label of an FPP designating the time prior to which a batch of the FPP is expected to remain within the approved shelf life specification  if stored under defined conditions, and after which it must not be used {no re-testing !!}

6 TG Dekker – WHO, UkraineOctober 2005 Glossary [ICH QA1(R2)] (3) Stress testing (API)  Studies undertaken to elucidate the intrinsic stability of the IPA. Such testing is part of the development strategy and is normally carried out under more severe conditions than those used for accelerated testing. Stress testing (finished product)  Studies undertaken to assess the effect of severe conditions on the finished product. Such studies include photostability testing (see ICH Q1B) and specific testing on certain products, (e.g., metered dose inhalers, creams, emulsions, refrigerated aqueous liquid products).

7 TG Dekker – WHO, UkraineOctober 2005 Glossary [ICH QA1(R2)] (4) Accelerated testing  Studies designed to increase the rate of chemical degradation or physical change of an API or FPP by using exaggerated storage conditions as part of the formal stability studies. Data from these studies, in addition to long term stability studies, can be used  to assess longer term chemical effects at non-accelerated (real-time) conditions &  to evaluate the effect of short term excursions outside the label storage conditions such as might occur during shipping  Results from accelerated testing studies are not always predictive of physical changes Current accelerated conditions for solid orals: 40ºC/75%RH

8 TG Dekker – WHO, UkraineOctober 2005 Example of shipping conditions (possible excursions outside storage requirements) UNICEF ↔ Kampala (1989): Temperature Relative humidity

9 TG Dekker – WHO, UkraineOctober 2005 Stability batches (FPPs)  Stability data for three primary batches by time of submission  One batch should at least be of production scale, the remaining 2 batches at least pilot scale  The formulation and manufacturing process should be the same as proposed for marketing  In container-closure system as proposed for marketing  Preferably manufactured from different API batches  Full info on batches tested (tabulated format)  Next slide

10 TG Dekker – WHO, UkraineOctober 2005 Information on stability batches required Tablets as example 1 st 2 nd 3 rd Batch number Manufacturing date Manufacturing site Batch size (kg) Batch size (number of units) Batch type (full-scale, pilot, etc.) Primary packaging Date initial analysis Batch number of API

11 TG Dekker – WHO, UkraineOctober 2005 Stability specifications Stability studies should include testing of those attributes (parameters) of the FPP that are  susceptible to change during storage and thus  are likely to influence quality, safety, and/or efficacy  The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes, preservative content (e.g., antioxidant, antimicrobial preservative), and functionality tests (e.g., for a dose delivery system) From ICH Q1A(R2)

12 TG Dekker – WHO, UkraineOctober 2005 Example - FPP specs – uncoated tablets AttributeRelease limitsStability limits AppearanceFull descriptionSame as release IdentificationAt least 1 method Not required for stability studies. Not regarded as variables for product. DimensionsDiameter, etc Average massw.r.t. theoretical Mass uniformityPh.Eur/USP/Int.Ph Water contentProduct specificSame as release? Tablet hardness*Product specificSame as release

13 TG Dekker – WHO, UkraineOctober 2005 Example of FPP specs – uncoated tabs (con.) AttributeRelease limitsStability limits Friability *≤ 1 % (normally)Same as release DissolutionSet per productSame as release DisintegrationNot required if dissolution is done Related subs. (degradants) Only if formed during production Required. Limits to one/two decimal Assay (content) %, unless justified May be % if justified Microbial limitsSkip-testingEnd-of-shelf * Tests not necessary at release if done in-process

14 TG Dekker – WHO, UkraineOctober 2005 FPP stability specifications Special for FDCs  Degradation products must be calculated in % with reference to the parent API, not the sum of APIs, e.g.  Rifampicin / isoniazid tablets Rifampicin quinone (degradant) as % of rifampicin.  Lamivudine + Stavudine + Nevirapine tablets Thymine (degradant) as % of stavudine  If 2 APIs react with each other, then the degradant to be stated with respect to worst case, e.g.  Rifampicin / isoniazid tablets. Isonicotinyl hydrazone forms from the 2 APIs. Specification: % hydrazone with respect to rifampicin (worst-case in mass balance).  Unknown degradants – with respect to worst case

15 TG Dekker – WHO, UkraineOctober 2005 Stability indicating analytical methods  Analytical methods must be suitable for the purpose of stability testing (stability indicating), particularly in the case of  Assay of the API(s) in the FPP  Determination of the degradants  Determination of preservatives  Compendial methods  May not be suitable (e.g. non-specific like titration)  May not exist for the particular purpose (e.g. degradants)

16 TG Dekker – WHO, UkraineOctober 2005 Rifampicin containing FDC products assay/degradation methods (1) Particular degradants to consider: 1.Isonicotinyl hydrazone 2.Rifampicin quinone 3.Rifampicin N-oxide 4.3-Formyl rifamycin (present in FDCs?) 5.25-Desacetyl rifampicin  All to be determined & expressed with respect to rifampicin

17 TG Dekker – WHO, UkraineOctober 2005 Rifampicin containing FDC products assay/degradation methods (2) Examples of methods:  USP 28 (2, 3, 4 FDC capsules/tablets)  Assay method (stability indicating when tested in our lab)  No specification/test for degradants  S. Singh et al. (NIPER)  Various HPLC methods, mainly related to isonicotinyl hydrazone determination, simultaneously with rifampicin and isoniazid (one example given here)  In-house HPLC analysis  For assay of rifampicin and degradants  Other APIs with a separate method

18 TG Dekker – WHO, UkraineOctober 2005 Rifampicin containing FDC products A NIPER HPLC method S. Singh et al., Pharm. Pharmacol. Commun., 6, (2000)

19 TG Dekker – WHO, UkraineOctober 2005 Rifampicin containing FDC products In-house HPLC chromatogram (spiked) C-18: methanol/phosphate buffer pH 7.0 : 6/4 Signals well separated rifampicin N-Oxide Hydrazone Quinone 3-Formyl rifamycin

20 TG Dekker – WHO, UkraineOctober 2005 Lamivudine + Stavudine + Nevirapine tablets 150 mg 40 mg 200mg According to the WHOPAR of TRIOMUNE  Lamivudine and nevirapine are compatible (stable)  Stavudine shows incompatible with both APIs  The main degradation product was found to be  thymine (degradant of stavudine)  HPLC (modified from literature) for sample stored at 30°C/60%RH for 12 months is shown on next page  Hypothetical example & signal for thymine  Assumption: all substances show similar response factor  Calculate the percentage degradation for thymine  How would you express the “identified related substances”

21 TG Dekker – WHO, UkraineOctober 2005 Lamivudine + Stavudine + Nevirapine tablets HPLC chromatogram (modified from lit.) mAU SubstancePeakArea (mAU)% degradation Stavudine Lamivudine Thymine →? Nevirapine Sum of areas 1800 Thymine

22 TG Dekker – WHO, UkraineOctober 2005 Testing frequency & storage conditions Example: Tablets and capsule  Zone IV is real-time condition for prequalification project, unless otherwise justified  Zone II only if justified (may be fall-back for zone IV)  ASEAN proposal for zone IV: 30ºC / 75% RH  Real-time data to cover minimum of 12 months  However, see Supplement 2 of guideline 6 month data for certain FPPs containing stable APIs Condition▼ Month► ºC / 65% RH (zone IV)XXXXXXXX 40ºC / 75% RH (accel) XX 25ºC / 60% RH (zone II)XXXXXXX

23 TG Dekker – WHO, UkraineOctober 2005 Significant changes during stability 1.A 5% change in assay from its initial value 2.Any degradation product exceeding its acceptance criterion 3.Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., colour, resuspendibility, hardness) 4.and, as appropriate for the dosage form:  Failure to meet the acceptance criterion for pH; or  Failure to meet the acceptance criteria for dissolution for 12 dosage units Dissolution specifications for release and stability must be the same (otherwise possible BE change)

24 TG Dekker – WHO, UkraineOctober 2005 Pitfall  The assay value is still within the limits  but the change during stability is more than 5.0%  Example  Release assay limit:95.0 – 105.0%  Stability assay limit: 92.5 – 105.0%  Release assay:101.0% (within spec)  24-Month assay:93.0% (within spec)  Loss in potency:8.0% !! This is a significant change !!

25 TG Dekker – WHO, UkraineOctober 2005 Evaluation of stability data 1.The data show no/little variation with time  Statistical analysis is not required  Proposed shelf-life = 2 x real-time data (R), but not more than R + 12 months (30 months max) Exception to rule: see Supplement 2 of Guideline 2.The data show trend(s)  Statistical analysis required [see ICH Q1A(R2)]  Proposed shelf-life depends on the statistical analysis 3.Commitment  For confirmation of provisional (tentative) shelf-life, real- time data are required  First 3 production batches on stability  Follow up stability testing (FUST) – one batch per year

26 TG Dekker – WHO, UkraineOctober 2005 Closing remarks  Stability testing is an essential part of the process of ensuring that the patient receives a product that meets established standards of safety, efficacy and quality  Sound planning and execution of stability studies are important  Valuable time may be lost if the data are insufficient  Always include all attributes which may change with time (e.g. water content, friability & tablet strength in the case of uncoated tablets) – pay upfront and save later  Give attention to analysis and calculation of degradation products in FDCs