Understanding and predicting product shelf-life. Dr. Mathias Kramer

Transcription

1 Understanding and predicting product shelf-life Dr. Mathias Kramer

2 Purpose of Stability Testing What affects Stability? Evaluation of Stability Data Reasonable Stability Testing Conclusion

3 Purpose of Stability Testing Gather knowledge about the product and degradation Find interactions between excipients and API Investigate different package dresses Enables a product to be registered Establish expiration dating period Establish storage conditions, label claims Establish regulatory specifications derived from a consideration of available stability data Delivers medicines of proven quality, safety and efficacy

4 Purpose of Stability Testing What affects Stability? Evaluation of Stability Data Reasonable Stability Testing Conclusion

5 What affects Stability? (1) Storage Time Storage Condition (Temperature, Humidity, Light, Oxygen) Dosage Form (Tablet, Capsule, Vial) Manufacturing Procedure Packaging Formulation (Composition, Quantity, Quality of excipients and API)

6 What affects Stability? (2) Temperature - the kinetic of a degradation can be described by the Arrhenius equation - for evaluation you need the accelerated condition k=a*exp(-ea/r*t) k: is the rate coefficient; A: is a constant; Ea: is the activation energy R: is the universal gas constant; T: is the temperature (in Kelvin) A historically useful generalization supported by the Arrhenius equation is that, for many common chemical reactions at room temperature, the reaction rate doubles for every 10 degree Celsius increase in temperature

7 What affects Stability? (3) Humidity - may influence degradation; hydrolysis - for evaluation you need different humidity, packaging configuration Light - may influence degradation; photoreaction - for evaluation you need photo stability testing Oxygen - may influence degradation; oxidation - for evaluation you need different packaging configuration

8 What affects Stability? (4) Packaging configuration - no temperature protection - light protection - humidity protection humidity protection (water vapour permeability) of blisters PVC- < Duplex- / Triplex- < Alu- blisters humidity protection (water vapour permeability) of bottles HDPE- bottles < Glass- bottles

9 What affects Stability? (5) Formulation Fixed dose combination finished pharmaceutical product (FDC-FPP) Def.: A finished pharmaceutical product that contains two or more actives - May have an impact on the stability, the APIs may react with each other - The most sensible API will trigger the shelf-life - Testing has to take all APIs into account (assay, degradation, dissolution)

10 Purpose of Stability Testing What affects Stability? Evaluation of Stability Data Reasonable Stability Testing Conclusion

11 Evaluation of Stability Data (1) Defined in the ICH Q1E and WHO-Guideline A systematic evaluation should be performed. Stability data for each attribute should be assessed sequentially The assessment should begin with any significant change at the accelerated condition Extrapolation to extend the shelf life beyond the period covered by long-term data can be proposed if no significant change is observed at the accelerated condition

12 Evaluation of Stability Data (2) Provisional shelf-life may be established without statistical analysis if The API is known to be stable (not easily degradable) 6 month accelerated and 12 month long term data are available The accelerated and long-term data show no or little changes or variability The manufacturer will continue the long-term studies up to the proposed shelflife Results will be submitted to the health authorities

13 Evaluation of Stability Data (3) Significant change 5% change in assay from its initial value Any degradation product exceeding its acceptance criteria Failure to meet the acceptance criteria for appearance, physical attributes and functionality test (e.g. color, phase separation, caking, hardness) Also, as appropriate for the dosage form; - failure to meet the acceptance criteria for ph - failure to meet acceptance criteria for dissolution for 12 dosage units

14 Evaluation of Stability Data (4) Statistical Approach - Regression analysis (linear, non-linear) An appropriate approach to shelf life estimation is to analyze - assay - degradation products Determine the earliest time at which the 95% confidence limit intersects the proposed acceptance criterion

15 Evaluation of Stability Data (5) Proposed shelf life for Room temperature Storage Y= 2 * X but not more than X + 12 (24 month) (30 month) Y= 2 * X but not more than X + 12 (24 month) (30 month) depending on the statistical evaluation Available long-term data [X] X (12 month) (18 month) X (12 month) (18 month) Change or variability over time Available accelerated data Change or variability over time little or no 6 month little or no Showing change and / or variability over time statistical analysis 6 month Showing change and / or variability over time

16 Purpose of Stability Testing What affects Stability? Evaluation of Stability Data Reasonable Stability Testing Conclusion

17 Reasonable Stability Testing (1) What has to be tested? Basis Q1A (R2) Stability studies should include testing of those attributes of the drug product that are susceptible to change during the storage and are likely to influence quality, safety and / or efficacy.

18 Reasonable Stability Testing (2) Galenical Formulation Solid dosage forms (e.g. tablets, capsules) Ampoules Vials Powder, oral suspensions Parameter unlikely to change during storage which could be omitted Identity, Shape und Imprint etc., Uniformity of mass/fill mass/content Identity, extractable volume, sterility, endotoxine test, density Identity, extractable volume, density Identity, Uniformity of mass/content

19 Reasonable Stability Testing (3) Quality Attribute Emulsions Oral Solution and suspensions Aerosols Topical and ophthalmic Smallvolume parenterals Largevolume parenterals Strength Appearance Color Odor a Clarity Moisture + a Dissolution + ph a) + Viscosity + + Resuspendability/redispersiblity + Separation + + Weightloss b) Homogeneity + Particulate/matter/size Extractables + b) + b) Pyrogenicity + + Sterility/microbial limit Preservatives Container closure integrity + Other recommendations c). d) d) e) f) d) d) + May be required or required Not required. a) Required for reconstituted products. b) Required for products in plastic containers c) Heating/cooling cycle 4 C 45 C d) Storage on side or inverted e) Number of metered doses, delivered dose per activation, propellant pressure, valve corrosion, spray pattern, If more than 3.5 g, sample at surface, middle, bottom of container, sample tubes near crimp. [Van den Akker, C. R.; Pharm. md. 53, 483 (1991)]

20 Purpose of Stability Testing What affects Stability? Evaluation of Stability Data Reasonable Stability Testing Conclusion

21 Conclusion You have to take many parameters into account Quality is designed and built into a product and not tested in! Stability has to be planned during lifecycle of the product with standardized conditions

22 Dr. Mathias Kramer Thanks for your attention!

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