Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Protea Hotel Victoria Junction, Wa

1. Pharmaceutical Development Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Protea Hotel Victoria Junction, Waterfront Cape Town, South Africa Date: 16 to 20 April 2007

2. Pharmaceutical Development Stability testing of Finished Pharmaceutical Products (FPPs) Presenter: Susan Walters Email: susanw@netspeed.com.au Fax: (61) 2 6281 6948 (email is preferred)

3. Stability testing of FPPs Outline of presentation We will: • Review relevant guidelines • Define the objectives of stability testing • Outline the design & conduct of stability studies for finished products • Determine a shelf life based on study results • Discuss what to include in reports of stability studies

4. Objectives of stability testing: What is the purpose? • "…… 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 & light, & enables recommended storage conditions, re-test periods & shelf lives to be established” (ICH) 2003

5. Variables that might affect the stability of a given API & dosage form • Formulation • Packaging • Site and method of manufacture • API • Finished product • Batch size • Batch to batch variability • The importance of process validation & quality risk management • Container labelling • Changes to product

6. Stability testing • Development studies • Characterise compatibility with common excipients • Characterise stability profile of API • Eg susceptibility to acid, base, light, oxygen etc…… • Characterise stability profile of early formulations • Especially susceptibility to heat, humidity & light • Confirmatory studies • Long term & accelerated studies on the product as it is to be registered • In practice design is now largely dictated by ICH guidelines

7. What does a regulator want to see demonstrated in the registration dataset? • The product maintains relevant quality characteristics within the acceptable range: • In proposed registration formulation & container/closure system • For whole of shelf life • At permitted extremes of storage • Over all batches • When manufactured at all registered sites (API & finished product) • After any changes

8. Relevant guidelines • Many countries have their own guidelines concerning stability testing & other registration topics • But if a manufacturer wishes to market a product in several countries, it is simpler to use one of the international guidelines, such as those of WHO & ICH So how widely are WHO & ICH guidelines accepted? • Most countries will accept data generated according to ICH guidelines • Many countries will accept data generated according to WHO guidelines, & especially when the product in question has been prequalified by WHO • But possibly not ICH countries • Whilst ICH guidelines are more detailed than those of WHO, there are few ‘in-principle’ differences, except in relation to testing conditions for hot & humid climates

9. ICH stability guidelines - 1 • Q1A(R2)Stability Testing of New Drug Substances & Products • Q1BStability Testing : Photostability Testing of New Drug Substances & Products • Q1CStability Testing for New Dosage Forms Available via http://www.ich.org/cache/compo/276-254-1.html

10. ICH stability guidelines - 2 • Q1DBracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products • Q1EEvaluation of Stability Data • Q1FStability Data Package for Registration Applications in Climatic Zones III and IV Withdrawn Also available via http://www.ich.org/cache/compo/276-254-1.html

11. ICH stability guidelines - 3 • Remember that these have been adopted in the European Union, the United States, and Japan • Technically ICH guidelines apply only to new APIs & products made from them. But most regulators give ICH guidelines considerable weight when deciding requirements for non-new APIs.

12. WHO stability guidelines - 1 • “Guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms” WHO (1996) Available viahttp://whqlibdoc.who.int/trs/WHO_TRS_863_(p1-p98).pdf Note: • Applies to ‘Well established drug substances’ • Applies to ‘Conventional dosage forms’ • These guidelines are under revision : See http://www.who.int/medicines/services/expertcommittees/pharmprep/41ec_meet/en/index.html

13. WHO stability guidelines - 2 • So what are the types of product to which WHO guidelines (1996) do not apply? • New chemical entities (NCEs) • And possibly also new dosage forms of NCEs • New combinations of actives • Modified release dosage forms, including • Slow release products • Transdermal patches • Modified release injections

14. Stability guidelines for WHO’s Prequalification Program (PQP) - 1 • Stability testing: Section 3.11 of Guideline on Submission of Documentation for Prequalification of Multisource (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria & Tuberculosis • Available via http://mednet3.who.int/prequal/ • Are consistent with ICH guidelines • There are extensive cross references to ICH guidelines • Effectively the PQP text is a practical interpretation of ICH guidelines

15. Stability guidelines for WHO’s PQP - 2 “Extension of the WHO list of stable (not easily degradable ARV) APIs” WHO (2006) • Also available via http://mednet3.who.int/prequal/ • Read this carefully. It describes circumstances in which a tentative 2-year shelf life may be allocated to certain APIs & FPPs, subject to a number of strict conditions.

16. Stability report formats for WHO’s PQP • Annex 3: Model stability report of API • Annex 4: Model stability report of capsules/tablets Also available via http://mednet3.who.int/prequal/

17. Terminology – adapted from ICH 2000 (1) • Production batch: • A batch manufactured at production scale using production equipment & in a production facility as specified in the registration application • Pilot scale batch: • A batch manufactured by a procedure “fully representative of & simulating” full production scale. For tablets & capsules, this means 100,000 units or 1/10th of production scale, whichever is the larger

18. Terminology – adapted from ICH 2000 (2) • Re-test period: API • The period of time for which the API remains within specification when stored under the recommended conditions in the proposed bulk storage container • “After this period, the batch should be retested for compliance with specifications & then used immediately” [if in compliance]

19. Terminology – adapted from ICH 2000 (3) • Accelerated testing • Studies designed to increase the rate of chemical degradation or physical change by means of exaggerated storage conditions • Intermediate testing • Studies at 30degC/60%RH, intended for extrapolation to long term storage at 25degC [provided that 25degC is appropriate for the market in question] • Stress testing • API: Studies which elucidate intrinsic stab of API. Normally during development. Normally more stressful than ‘accelerated’ testing. • Finished product: Studies of effect of ‘severe’ conditions. Eg freeze/thaw cycling for suspensions & emulsions, low humidity for aqueous liquids in moisture-permeable containers.

20. Terminology – adapted from ICH 2000 (4) • In-use stability testing: • Establishes the “period of time during which a multidose product can be used whilst retaining quality within an accepted specification once the container is opened” ICH 2000 • For example: • liquids that are reconstituted prior to use • effervescent tablets in a moisture-proof container (eg Al screw-cap tube) • ophthalmic products (especially with respect to preservative efficacy)

21. Terminology – adapted from ICH 2000 (5) • Climatic zones: • Partition of the world into three temperature classes based on kinetic averaging of monthly temperatures, & subdivision of the hottest class into predominantly wet or predominantly dry • Zones (Futscher & Schumacher 1972): • I Temperate (21oC/45%RH) • II Subtropical (25oC/60%RH with possibly high RH) • III Hot & dry (30oC/35%RH) • IV Hot & wet (30oC/70%RH) • The temperatures above are kinetic averages

22. Extract of WHO Technical Report Series 937 Expert committee on specifications for pharmaceutical preparations (2006): Quality assurance: Stability testing conditions “The Secretariat reminded the Committee that the WHO guidelines had been revised in the light of harmonization efforts in collaboration with ICH. Subsequently focus had been placed within regional harmonization initiatives on the recommendations for hot and humid conditions (referred to as Zone IV). After extensive discussion the Committee reached consensus that the WHO stability guidelines be amended to reflect conditions for Zone IV as follows: — Zone IVa (30 degrees Celsius and 65% relative humidity); and — Zone IVb (30 degrees Celsius and 75% relative humidity). It was agreed that each individual Member State within the former Zone IV would need to indicate whether its territory should be classified as Zone IVa or IVb.”

23. Consequently… • Each nation within zone IV must now decide whether to adopt a stability test condition of • 30oC & 65%RH, or • 30oC & 75%RH • ASEAN nations & Brazil have adopted 30oC & 75%RH

24. Terminology – adapted from ICH 2000 (6) Reduced study designs: • Bracketing • A design in which only the extremes are tested at all time points, eg strength, pack size, container fill • Matrixing • Designs in which a selected subset of samples is tested, eg different strengths, container/closure systems, batches

25. Example of a bracketing design T = Sample is tested

26. Example of a matrixing design“One half reduction” T = Sample is tested

27. When might bracketing & matrixing be appropriate?(NB The following is not from ICH ! You must argue the case!) • Container size? • Batch size? • Formulation of coating? • With varying amounts of an excipient (eg starch, Mg stearate)?

28. The risk associated with bracketing & matrixing • If the results are not what you expected, you may have insufficient to propose an intermediate shelf life • Would be risky to use bracketing & matrixing if you did not have a good idea as to what the product’s stability will be • Consequently: Bracketing & matrixing designs are used mainly for confirmatory studies

29. ICH minimum dataset at submission - 1

30. ICH minimum dataset at submission - 2 • FPPs packaged in impermeable containers need not be stored under controlled humidity conditions • There are different minimum conditions for: • Liquid products packaged in semi-permeable containers [relating to potential loss of solvent] • Products intended for storage in a refrigerator, freezer or deep-freeze

31. Classes of degradation • Chemical • Physical • Microbiological

32. Chemical degradation Has been dealt with by Dr Elder

33. Physical degradation(≡ physicochemical degradation) • Physical properties can change too! • Important attributes vary with dosage form • Bottom line is relevance to quality, safety & efficacy • Examples for liquid formulations: • Appearance, colour, odour, pH, clarity (solutions) and freedom from visible particulate contamination, size range of particulate contamination (large volume parenterals), particle size distribution (suspensions), micelle size distribution (micellar solutions), resuspendability (suspensions), viscosity, moisture content (powders for reconstitution), phase separation (emulsions) • See other examples at http://www.tga.gov.au/pmeds/argpmap14.pdf

34. Other forms of physical deterioration may include: • Leaching • Absorption (into container walls) • Adsorption (on to container walls) • Volatilisation (eg sertraline base, glyceryl trinitrate) • Altered particle size distribution • Loss of higher order molecular structure (normally only for biological medicines) • Denaturation • Aggregation

35. Minimising physical deterioration • Some examples: • When prone to adsorption on to, or absorption into, packaging materials, use resistant packaging materials, such as good quality glass • When prone to volatilisation: • Use a non-volatile salt (if possible) • Use packaging materials that are resistant to vapour transfer • When prone to altered particle size in suspensions: • Formulate a continuous phase in which the active is less soluble

36. Microbiological deterioration • Proliferation of microbes in non-sterile products • Consequences may include: • Infection of the patient • Formation of endotoxins (≡ pyrogens) • Foul odour • Formation of gas • Change in colour • Cloudiness • Hydrolysis

37. Minimising microbiological deterioration of non-sterile products • Control the microbial load of API & excipients • Validate & monitor manufacturing conditions • Include antimicrobial preservatives in formulations • NB Normally only bacteriostatic & not bactericidal

38. Appropriate tests for stability studies - 1 • Normally test same attributes as for routine QC • May use other methodology for stability testing (avoid for dissolution rate) but must be validated • Avoid changing methodology mid-study (unless correcting a clear deficiency)

39. Appropriate tests for stability studies - 2 • Quantitate degradation products if possible, even if the assay is specific for the API • But can be difficult to quantitate impurities if there are no reference standards & relative response factors are unknown → semiquantitative estimates • Regulatory authorities usually expect an approximate mass balance • Appropriate physical tests vary with dosage form. • Remember to conduct preservative efficacy tests too, in addition to assay of any antimicrobial preservative

40. For all stability studies • Validate the analytical methodology! • See relevant guidelines, especially: • Validation of analytical procedures: Terminology • ICH Q2B 1994 • Validation of analytical procedures: Methodology • ICH Q2B 1996 • Use stability-indicating assays

41. Dissolution rate • Avoid using a method different to that in routine QC • Most regulatory authorities, including PQP, prefer dissolution profiles rather than single time points during stability testing. Better ability to detect trends.

42. Frequency of testing during a stability study - ICH • “For long term studies, frequency of testing should be sufficient to establish the stability profile of the pharmaceutical product” • “For products with a proposed shelf life of at least 12 months, the frequency of testing in the long term storage condition should normally be every 3 months over the first year, every 6 months over the second year, & annually thereafter throughout the proposed shelf life. • Other frequencies are suggested for accelerated & intermediate storage conditions. • ICH 2003

43. Some notes concerning reporting (1) • It is rarely appropriate to cite only average results • For the benefit of the manufacturer & the DRA • Dissolution results on individual tablets (not only mean results) • It’s certainly OK to cite mean & derived results as well • Assay results should be reported as absolute values • And not only as values normalised for initial results, ie % of initial • Test methods must be recorded with the study report • By the time that stability studies are conducted on finished product, is possible that more than one method has been used

44. Some notes concerning reporting (2) • Numerical results should be provided wherever possible • Not just ‘complies’ • If results are below the limit of quantitation, they should be reported as ‘below LQC’ or similar wording • ‘Not detectable’ is acceptable provided it is defined & reasonable • Results that are out of the ordinary should be discussed • Product labelling should be consistent with stability data. For example: • Solvents for reconstitution • Recommendations for mixing of injections with other injections

45. Evaluation / Interpretation of the results So what’s the shelf life?

46. First point • The validity of an assigned shelf life depends upon: • The results of stability studies, & • Whether the batches used in the stability studies accurately model those to be marketed, & • Whether analytical methodology was adequately validated

47. Assigning a shelf life • Assigning a shelf life is easier if results are available: • For the full duration of the proposed shelf life • At the maximum recommended storage conditions • For all formulations & manufacturing methods • In exactly the packaging to be registered • At all sites of manufacture of finished product & API • If these conditions are not met, that’s when shelf life assignment becomes difficult. • There will be arguments between manufacturers & registration/prequalification authorities • There will be delays in approving the product

48. Statistical estimation of shelf life - 1 • “Where the data show so little degradation & so little variability that it is apparent from looking at the data that the requested shelf life will be granted, it is normally unnecessary to go through the formal statistical analysis but only to provide a justification for the omission” • ICH 2003 & PQP 2005 In other words: If it is blindingly obvious that there is minimal change in the parameter in question, is unnecessary to conduct the numerical/statistical analysis.

49. Statistical estimation of shelf life - 2 • “An approach for analyzing data of a quantitative attribute that is expected to change with time is to determine the time at which the 95% one-sided confidence interval for the mean curve intersects the acceptance criterion” • ICH 2000

50. Statistical estimation of shelf life - 3 Is there any degradation of any relevant product characteristic? • If no, then shelf life assignment is straightforward based on the labelled storage conditions & the time for which testing has been conducted • If yes (that is there is at least some degradation/change): • Conduct a statistical analysis using a suitable software package • Consider: • Statistical pooling of results for multiple batches • Estimation of time to degrade to expiry limits using a 95% confidence interval • See the file concerning software packages • NB I am not recommending any of these software packages! • Conduct your own Internet search! Then evaluate cost against usefulness to your company.