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Slide 1 Walters April 2007 Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Protea Hotel Victoria Junction, Waterfront.

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Presentation on theme: "Slide 1 Walters April 2007 Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Protea Hotel Victoria Junction, Waterfront."— Presentation transcript:

1 Slide 1 Walters April 2007 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 Pharmaceutical Development

2 Slide 2 Walters April 2007 Pharmaceutical Development Stability testing of Finished Pharmaceutical Products (FPPs) Presenter: Susan Walters Fax: (61) ( is preferred)

3 Slide 3 Walters April 2007 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 Slide 4 Walters April 2007 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 Slide 5 Walters April 2007 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 Slide 6 Walters April 2007 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 Slide 7 Walters April 2007 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 Slide 8 Walters April 2007 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 Slide 9 Walters April 2007 ICH stability guidelines - 1 Q1A(R2) Stability Testing of New Drug Substances & Products Q1B Stability Testing : Photostability Testing of New Drug Substances & Products Q1C Stability Testing for New Dosage Forms Available via html html

10 Slide 10 Walters April 2007 ICH stability guidelines - 2 Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products Q1E Evaluation of Stability Data Q1F Stability Data Package for Registration Applications in Climatic Zones III and IV Withdrawn Also available via html html

11 Slide 11 Walters April 2007 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 Slide 12 Walters April 2007 WHO stability guidelines - 1 “Guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms” WHO (1996) Available via p98).pdf p98).pdf Note: –Applies to ‘Well established drug substances’ –Applies to ‘Conventional dosage forms’ –These guidelines are under revision : See armprep/41ec_meet/en/index.html armprep/41ec_meet/en/index.html

13 Slide 13 Walters April 2007 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 Slide 14 Walters April 2007 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 –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 Slide 15 Walters April 2007 Stability guidelines for WHO’s PQP - 2 “Extension of the WHO list of stable (not easily degradable ARV) APIs” WHO (2006) –Also available via –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 Slide 16 Walters April 2007 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

17 Slide 17 Walters April 2007 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 1/10 th of production scale, whichever is the larger

18 Slide 18 Walters April 2007 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 Slide 19 Walters April 2007 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 Slide 20 Walters April 2007 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 Slide 21 Walters April 2007 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 (21 o C/45%RH) IISubtropical (25 o C/60%RH with possibly high RH) IIIHot & dry (30 o C/35%RH) IVHot & wet (30 o C/70%RH) –The temperatures above are kinetic averages

22 Slide 22 Walters April 2007 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 Slide 23 Walters April 2007 Consequently… Each nation within zone IV must now decide whether to adopt a stability test condition of –30 o C & 65%RH, or –30 o C & 75%RH ASEAN nations & Brazil have adopted 30 o C & 75%RH

24 Slide 24 Walters April 2007 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 Slide 25 Walters April 2007 Example of a bracketing design T = Sample is tested

26 Slide 26 Walters April 2007 Example of a matrixing design “One half reduction” T = Sample is tested

27 Slide 27 Walters April 2007 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 Slide 28 Walters April 2007 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 Slide 29 Walters April 2007 ICH minimum dataset at submission - 1

30 Slide 30 Walters April 2007 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 Slide 31 Walters April 2007 Classes of degradation -Chemical -Physical -Microbiological

32 Slide 32 Walters April 2007 Chemical degradation Has been dealt with by Dr Elder

33 Slide 33 Walters April 2007 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

34 Slide 34 Walters April 2007 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 Slide 35 Walters April 2007 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 Slide 36 Walters April 2007 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 Microbiological deterioration

37 Slide 37 Walters April 2007 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 Slide 38 Walters April 2007 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 Slide 39 Walters April 2007 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 Slide 40 Walters April 2007 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 Slide 41 Walters April 2007 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 Slide 42 Walters April 2007 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 Slide 43 Walters April 2007 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 Slide 44 Walters April 2007 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 Slide 45 Walters April 2007 Evaluation / Interpretation of the results So what’s the shelf life?

46 Slide 46 Walters April 2007 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 Slide 47 Walters April 2007 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 Slide 48 Walters April 2007 “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 Statistical estimation of shelf life - 1 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 Slide 49 Walters April 2007 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 Slide 50 Walters April 2007 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.

51 Slide 51 Walters April 2007 Statistical estimation of shelf life - 4 Superimposition of a 95% confidence interval on to the regression line for stability data from Bolton 1984 NB This is an old graph & it describes a very unstable product

52 Slide 52 Walters April 2007 What are the limitations of this statistical algorithm? -It applies only to quantitative attributes -Does not apply for example to colour tests, or to semiquantitative comparisons such as TLC limit tests -It may be unreliable for physical attributes -Such as dissolution tests & discoloration -Use your judgement! Look at the slope of the curve. Does the change accelerate with time?

53 Slide 53 Walters April 2007 “Any evaluation should consider not only the assay but also the degradation products & other appropriate attributes” ICH 2003 Estimation of shelf life In other words: If evaluation of different (but relevant) attributes leads to different conclusions as to shelf life, the shortest of these shelf lives should be chosen.

54 Slide 54 Walters April 2007 “Where appropriate, attention should be paid to reviewing the adequacy of the mass balance & different stability & degradation performance” ICH 2003 Estimation of shelf life –In other words: If the loss of active is not of the same order (=approximately the same) as formation of degradation products, more investigation is needed. –Note however that mass balance will always be approximate; it is rarely exact.

55 Slide 55 Walters April 2007 Factors to be taken into account when assigning a shelf life based on statistical analysis - 1 -Release limits -Expiry limits -Results of stability studies -Is there any desired safety margin? -This is largely a matter for the manufacturer/supplier

56 Slide 56 Walters April 2007 Factors to be taken into account when assigning a shelf life based on statistical analysis - 2 A batch may be released with a result anywhere in range of release limits Consequently a prudent manufacturer will take into account the lower limit of release when estimating shelf life

57 Slide 57 Walters April 2007 Combining results for several batches Poolability

58 Slide 58 Walters April 2007 Poolability of multiple batches  A statistical concept that allows the results for several batches to be combined  If we estimated stability based on results for individual batches, we would have to select the shortest estimate of shelf life  Pooling usually leads to a longer shelf life as compared with the results for one batch only  But we must first test whether the batches can legitimately be pooled  Are the batches statistically homogenous?

59 Slide 59 Walters April 2007 Testing for poolability as described by Bolton 1997 Perform statistical test for common slope Perform statistical test for common intercept Use common slope & common intercept Use separate slope & intercept for each batch Use common slope but separate intercepts Significance is on the basis of F tests (p>0.25) as modelled by Bolton 1997 Significantly different Significantly different Not significantly different Not significantly different

60 Slide 60 Walters April 2007 Extrapolation beyond real-time data - 1 “Limited extrapolation of the real time data from the long term storage condition beyond the observed range to extend the shelf life can be undertaken at approval time, if justified. This justification should be based on what is known about the mechanisms of degradation, the results of testing under accelerated conditions, the goodness of fit of any mathematical model, batch size, existence of supporting stability data, etc. However, this extrapolation assumes that the same degradation relationship will continue to apply beyond the observed data.” ICH 2000

61 Slide 61 Walters April 2007 Extrapolation beyond real-time data - 2 “If long term data are supported by results from accelerated studies the retest period/shelf life may be extended beyond the end of the long- term studies. The proposed retest period or shelf life can be up to twice, but should not be more than 12 months beyond, the period covered by long-term data”. ” PQP 2005

62 Slide 62 Walters April 2007 References References in your CD may be useful: -Regulatory guidelines -Sources of climate-controlled cabinets -Software for processing stability data -Most include laboratory information management for the data

63 Slide 63 Walters April 2007 Pharmaceutical Development Summary and conclusion Stability data submitted during the registration process should confirm that all batches of the FPP will remain of acceptable quality when stored in the marketing container, at the most extreme storage conditions permitted by container labelling & prescribing information, for the duration of the shelf life Any subsequent variations (for example to site or method of manufacture of the API or FPP) should be shown not to reduce the shelf life as defined above


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