Design and Interpretation of Accelerated Stability Studies of Biologics

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1 Design and Interpretation of Accelerated Stability Studies of Biologics Sheila G. Magil, Ph.D. Cambridge Healthtech Institute s Fourth Annual The Bioprocessing Summit 2012 August 20-23, 2012 Boston, MA BioProcess Technology Consultants

2 Outline What is accelerated stability Small molecules vs. biopharmaceuticals Forced Degradation Regulatory Expectations 2 From Clone to Clinic

3 What is Accelerated Stability Stability testing is done to Provide guidance for expiry dating Evaluate how a variety of environmental conditions affect the quality of drug product or drug substance Demonstrate that Drug Product used in a clinical trial maintains suitable quality throughout the trial Accelerated stability studies include Increased temperature studies done during standard stability studies Forced degradation studies done development During analytical method development to identify stability indicating methods 3 From Clone to Clinic

4 Why Perform Accelerated Stability Studies The goals for most Drug Products is no less than 2 years of stability real time stability studies can take at least 2 years Accelerated stability studies can provide useful information on the stability of a drug earlier in development Accelerated stability also provide a way to compare different formulations during development Determine the types of degradation possible 4 From Clone to Clinic

5 Small Molecules vs. Biopharmaceuticals Small molecules degradation generally follows first order kinetics Involves only one kind of molecule Can be fit to a linear or exponential curve It is possible to extrapolate from accelerated temperature degradation to real degradation rate Arrhenius equation ) Biotherapeutics generally do not degrade via first order kinetics Second or higher order kinetics Involve more than a single kind of molecule Biopharmaceuticals are a mixture of multiple forms of the molecule Do not fit linear or exponential curves 5 From Clone to Clinic

6 Kinds of Degradation Seen in Biopharmaceuticals Chemical Degradation Oxidation Deamidation Disulfide bond rearrangement Hydrolysis or internal clipping Physical Degradation Aggregation Adsorption Loss of three dimensional structure 6 From Clone to Clinic

7 Common Conditions Examined in Forced Degradation of Biopharmaceuticals Temperature Higher and lower than proposed storage condition Supporting potential processing conditions ph Extreme ph Based on reasonable ph s to which molecule could be exposed Oxidation May use one or more oxidizing agent Different agents may have different oxidation products Agitation Impact of time Potential impact of shipping Repetitive freezing and thawing Modeling processing conditions Light Inform packaging decisions 7 From Clone to Clinic

8 Example Sample Taken Stress Condition 2H 4H 8H 1D 2D 5D 7D 14D 21D 28D Control 9 8 ph C Temperature 5 C 25 C 40 C Oxidation 10% H 2 O 2 25% H 2 O 2 8 From Clone to Clinic

9 Example continued Sample Taken Stress Condition 2H 4H 8H 1D 2D 5D 7D 14D 21D 28D Control Agitation Freeze/ Thaws Light Exposure 1 week 3 weeks 1 cycle 3 cycles 5 cycles 1.2 M lux-hr artificial daylight 9 From Clone to Clinic

10 Regulatory Guidelines FDA, Health Canada, Therapeutic Goods Administration (Australia) and EMEA have adopted ICH Q5C : Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological products Expiration dating should be based on real time/real temperature data. However it is strongly suggested that studies be conducted on the drug substance and drug product under accelerated and stressed conditions. [Q1A (R2) Stability Testing of New Drug Substances and Products] describes the conditions of the accelerated and stress study, should note that those conditions may not be appropriated for Biotechnological/biological products Conditions should be carefully selected on a case by case basis Q5C also specifies the need to examine the stability of reconstituted lyophilized products as well as drug substances, drug products and intermediates 10 From Clone to Clinic

11 Q1A(R2) Guidance For products stored in refrigerated conditions Real time 5 C ±3 C Accelerated 25 C ± 2 C/60% ±5% RH For products stored at 20 C Real time 20 C ±3 C No accelerated temperature recommended Stability to be examined for drug substances, drug products and intermediates 11 From Clone to Clinic

12 Other Regulatory Guidance WHO Refers to ICH guidances Initiated guidelines for the Eastern Mediterranean Region Accelerated stability tests provide a means of comparing alternative formulations, packaging materials, and/or manufacturing processes in shortterm experiments. As soon as the final formulation and manufacturing process have been established, the manufacturer carries out a series of accelerated stability tests which will enable the stability of the drug product to be predicted and its shelf life and storage conditions determined. Real time studies must be started at the same time for confirmation purposes. Suitable measures should be taken to establish the utilization period for preparations in multidose containers, especially for topical use 12 From Clone to Clinic

13 Summary Accelerated stability is more than examining high temperature conditions during standard stability studies Accelerated stability includes forced degradation studies Forced degradation is used to Identify stability indicating methods Identify degradation pathway Evaluate formulations Evaluate Comparability Accelerated stability supports expiry dating Regulatory guidance for biotechnology products is less prescriptive than for traditional pharmaceuticals 13 From Clone to Clinic

14 Thank You! Sheila G. Magil BioProcess Technology Consultants, Inc. 12 Gill Street, Suite 5450 Woburn, MA 01801

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