Comparability of Insulins Produced by Second Generation Processes

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1 Comparability of Insulins Produced by Second Generation Processes WCBP 2009 Lene Hørlyck Novo Nordisk A/S

2 Slide no 2 Novo Nordisk at a glance More than 25,500 employees in 80 countries A world leader in diabetes care since 1923 Recombinant human insulin Rapid-acting modern insulin Long-acting modern insulin Leading position in Haemostasis management Growth hormone therapy Hormone replacement therapy

3 Slide no 3 Outline Two 2nd generation processes to be introduced Human insulin drug substance Insulin aspart drug substance Comprehensive comparability exercise planned Similar set-up for both products New drug substance expected to be comparable to current Interpretation and use of the comparability concept to be accepted world wide Lessons learned

4 Slide no 4 Strategy Late 1990 s: Increased need for human insulin drug substance Second generation process developed for human insulin Initial FDA meeting Comparability study (human insulin, pilot scale) WW meetings, main agencies (human insulin & insulin aspart) Process validation, comparability exercise & submission

5 Slide no 5 Generic Process Overview Human insulin & Insulin aspart 1st Generation Process Fermentation Intermediate 2nd Generation Process, New Facility Fermentation New precursor Intermediate Changed capture Changed process Intermediate Drug Substance Intermediate Drug Substance Changed process

6 Slide no 6 Comparability Exercise Quality comparability studies Physico-chemical properties & impurity profiles of drug substance Process comparison Drug substance stability Drug product stability (commitment) Clinical studies Immunogenicity Bioequivalence

7 Slide no 7 Drug Substance Comparability Study Specification test results 3 batch comparison Comparable levels Comparison with historical range Within range Structural properties 1 batch comparison Must be identical and conform to theoretical structure Other physico-chemical properties & impurity profiles 3 batch comparison No new impurities > predefined limit Comparable levels of well-known impurities

8 Slide no 8 Selection of Additional Tests Tests for structural and other physico-chemical properties Well-known structural tests with well-defined outputs Biological tests included for evaluation of the tertiary structure, only Focus on elucidation of impurity profiles General well-known tests Specific, highly sensitive tests Methods qualified and LOD/LOQ estimated

9 Slide no 9 Selection of HPLC Purity Tests Maximising probability of detecting new impurities by using orthogonal tests SE-HPLC, pharmacopeial test IE-HPLC, internal test RP-HPLC, four different tests Pharmacopeial test Test with alternative column and gradient Test with alternative eluent ph Test with alternative eluent components

10 Slide no 10 Structural Properties Test Amino Acid Composition N-terminal Amino Acid Sequence Primary/ Secondary Structure Tertiary Structure Position of Disulphide Bonds Peptide Mapping Circular Dicroism Nuclear Magnetic Resonance Mass Spectrometry Hypoglycaemic effect in mice (biological activity) Receptor Affinity Glucose uptake in fat cells Mass

11 Slide no 11 Other Physico-Chemical Properties & Impurity Profiles Test Size Charge Hydrophobic Properties Other Physico- Chemical Properties SDS-PAGE Isoelectric Focusing UV/VIS Spectroscopy SE-HPLC RP-HPLC (four methods) IE-HPLC

12 Slide no 12 Structural Characterisation Test Results Human insulin, Insulin aspart However Low precision of bioassays can be questioned Single batch comparison 150 Potency (%) Multi-batch comparison IA (1st generation) 100 IA (2nd generation) 50 0 Current IA (1st Production gen.) IA (2nd NN2000 generation) Bulk Drug Substance IA NN2000 (2nd gen.) Product Drug Product 7

13 Slide no 13 Insulin Aspart Evaluation of Impurity Profiles, Examples RP-HPLC Pharmacop. Method RP-HPLC Alternative Method AU Minutes 2nd gen. 1st gen. AU Minutes 2nd gen. 1st gen.

14 Slide no 14 Insulin Aspart, Conclusion Evaluation of Impurity Profiles No new impurities were detected Minor differences in levels of well-known product-related impurities Evaluated to be comparable All other tests and studies Change-over completed world-wide

15 Slide no 15 Human Insulin Evaluation of Impurity Profiles, Examples RP-HPLC Pharmacop. Method RP-HPLC Alternative Method AU nd gen. AU nd gen st gen st gen Minutes Minutes

16 Slide no 16 Human Insulin, Conclusion Evaluation of Impurity Profiles New unknown impurity detected in alternative RP-HPLC tests Identified as a product-related impurity originating from an unexpected technical failure Consequences Implementation of relevant corrective and preventive actions Repetition of Process Validation Extension of comparability study with new PV batches All batches submitted All other tests and studies Approved

17 Slide no 17 Lessons Learned In-depth process and product knowledge is essential if the comparability mindset is used for major changes Planning phase including selection of suitable complementary impurity tests Maximise probability of detecting new impurities Evaluation of data Setting of acceptance criteria No guidance levels exists for proteins Evaluate and define limits based on similar products and/or history of previous changes to the approved process Ensure that method sensitivity support the specified criteria

18 Slide no 18 Conclusions The comparability concept is applicable for introduction of complex 2nd generation processes However, it will require more extensive quality data and clinical data to support the major changes to be implemented Original strategy of consulting regulatory agencies early in the process was followed and concluded to be very valuable Good quality comparability data is the key to approval Use several orthogonal tests for impurity testing Comparable does not mean identical, explain and justify any differences