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Pharmaceutical Development. Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Tallinn 15-19th October 2007. Pharmaceutical Development. Stability testing of Finished Pharmaceutical Products (FPPs) Presenter: Susan Walters Email: susanw@netspeed.com.au

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slide1

Pharmaceutical Development

Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations

Tallinn

15-19th October 2007

pharmaceutical development
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)

stability testing of fpps
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
objectives of stability testing what is the purpose
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 Q1A (2003)

variables that might affect the stability of a given api dosage form
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
stability testing
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
what does a regulator want to see demonstrated in the registration dataset
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
relevant guidelines
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
ich stability guidelines 1
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

ich stability guidelines 2
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

ich stability guidelines 3
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.
who stability guidelines 1
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
who stability guidelines 2
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
stability guidelines for who s prequalification program pqp 1
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
stability guidelines for who s pqp 2
Stability guidelines for WHO’s PQP - 2

“Extension of the WHO list of stable (not easily degradable ARV) APIs”

PQP Guideline for generics;

Supplement 2; 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.
stability report formats for who s pqp
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/

terminology adapted from ich 2000 1
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
terminology adapted from ich 2000 2
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]
terminology adapted from ich 2000 3
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.
terminology adapted from ich 2000 4
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 Q1A (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)
terminology adapted from ich 2000 5
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
slide22

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.”

consequently
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
terminology adapted from ich q1a 2000 6
Terminology – adapted from ICH Q1A 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
slide27
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)?
the risk associated with bracketing matrixing
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
slide30

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
classes of degradation
Classes of degradation
  • Chemical
  • Physical
  • Microbiological
chemical degradation
Chemical degradation

Has been dealt with by Professor York & Dr Mills

physical degradation physicochemical degradation
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
other forms of physical deterioration may include
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
minimising physical deterioration
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
microbiological deterioration
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
minimising microbiological deterioration of non sterile products
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
appropriate tests for stability studies 1
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)
appropriate tests for stability studies 2
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
for all stability studies
For all stability studies
  • Validate the analytical methodology!
    • See relevant guidelines, especially:
      • Validation of analytical procedures: Terminology
        • ICH Q2A 1994
      • Validation of analytical procedures: Methodology
        • ICH Q2B 1996
  • Use stability-indicating assays
dissolution rate
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.
frequency of testing during a stability study ich
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 Q1A(R2) 2003
some notes concerning reporting 1
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
some notes concerning reporting 2
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
first point
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
assigning a shelf life
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
statistical estimation of shelf life 1
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.

statistical estimation of shelf life 2
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 Q1A(R2) 2003
statistical estimation of shelf life 3
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.
statistical estimation of shelf life 4
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

what are the limitations of this statistical algorithm
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?
estimation of shelf life
Estimation of shelf life
  • “Any evaluation should consider not only the assay but also the degradation products & other appropriate attributes”
  • ICH Q1A(R2) 2003

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.

estimation of shelf life54
Estimation of shelf life
  • “Where appropriate, attention should be paid to reviewing the adequacy of the mass balance & different stability & degradation performance”
  • ICH Q1A(R2) 2003
  • 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.
factors to be taken into account when assigning a shelf life based on statistical analysis 1
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
factors to be taken into account when assigning a shelf life based on statistical analysis 2
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
poolability of multiple batches
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?
slide59

Testing for poolability as described by Bolton 1997

Perform statistical test for common slope

Not significantly

different

Significantly

different

Use separate slope & intercept for each batch

Perform statistical test for common intercept

Significantly

different

Not significantly

different

Use common slope & common intercept

Use common slope but separate intercepts

Significance is on the basis of F tests (p>0.25) as modelled by Bolton 1997

extrapolation beyond real time data 1
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 Q1A(R2) 2000
extrapolation beyond real time data 2
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
slide62

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
pharmaceutical development63
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