Quality Assessments for an Organically-Complex Drug - Part 1 Background and the Chemometrics Role

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Spencer Lionel Gaines
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1 Quality Assessments for an Organically-Complex Drug - Part 1 Background and the Chemometrics Role Dr Peter Gibson Technical Director Sovereign House, Vision Park, Histon, Cambridge, CB24 9BZ

2 Global leaders in prescription cannabinoid medicines Develop pharmaceutical products which address clear unmet medical needs

3 Lead Products Sativex for the treatment of MS Spasticity and Cancer Pain Epidiolex for the treatment of Childhood Epilepsy

4 Sativex Oromucosal Spray Spasticity in multiple sclerosis Pain in advanced cancer Neuropathic pain Approved in 26 countries IND in the US Botanical extracts from specific Cannabis sativa plants THC 27mg/ml CBD 25mg/ml

5 Regulatory

6 FDA Botanical Guidelines (2004) For Phase III prior to NDA submission: Well characterized Batch-to-batch consistency Fingerprints based on multiple methods Qualitatively and quantitatively comparable

$of components FID1 A, (CHEMSTOR\3940163\A417843\APB00021.$

7 Single Chemical versus Botanical Single Substance Single identified active Full characterisation Limited number of related substances Botanical One or more actives May not be identified Wide range of components FID1 A, (CHEMSTOR\ \A417843\APB00021.D) count s 4800 Cannabinoids THC Mono-terpenes Sesqui-terpenes Di-terpenes Tri-terpenes & Waxes mi

8 Process Overview THC BRM Botanical Raw Material (BRM) CBD BRM GACP THC BDS Botanical Drug Substance (BDS) CBD BDS GMP Botanical Drug Product (BDP) Sativex

9 Cannabis Production - Weeks 1 to 3

10 Cannabis Production - Weeks 4 to 11

11 Cannabis Production - Weeks 4 to 11

12 BRM to BDS THC BRM CBD BRM Milling Decarboxylation CO 2 Extraction Partial Purification Isolation THC BDS CBD BDS

13 BDS to Sativex THC BDS CBD BDS Bulk Solution Filling Packaging Sativex Finished Product

14 BDS Characterization Cannabinoids Non-cannabinoids 70 to 75% w/w 25 to 30% w/w

15 THC BDS Characterization % w/w THC CBD 0.30 THCA 0.23 CBG 1.00 CBC 1.12 THCV 0.55 THC-C cis-cbg 0.04 CBO 0.09 CBO MEE 0.06 DHC 0.27 Others 0.99 Total Cannabinoids 73.0 % w/w Non-Cannabinoids Carotenoids 0.1 Triglycerides 3.8 Sterols 2.5 Terpenes 7.2 Residual Ethanol 1.8 Polar Fraction 1.0 Cannabinoid Esters 0.6 Free Fatty Acids 0.8 Total Characterised 90.8

16 BDS Total Components Identified compounds present in the BDS >90% (w/w) identified Challenge is the other 10% Well characterized Batch-to-batch consistency Qualitatively and quantitatively comparable

17 Specification Quantitative 10 cannabinoids 14 non-cannabinoid components Class totals Qualitative Chromatogram comparison Routine use of 4 methods

18 Qualitative Compare Chromatograms THC BDS Batch 1 THC BDS Batch 2 THC BDS Batch 3

19 Overview 4 methods Cannabinoids Terpenes Triglycerides Sterols & Triterpenes

20 QC Process THC CBD

21 Specification Priority Flow Quantitative Cannabinoid/Non Cannabinoid Cannabinoid Profile PCA Model Ranking in importance Non-Cannabinoid Profiles PCA Models Terpenes Sterols Triglycerides

assays Scoring System Based on 2 outlier diagnostics Values

22 Qualitative Evaluation Chromatogram alignment Statistical algorithms Peak Marker sets PCA Model Comparison 4 separate assays Scoring System Based on 2 outlier diagnostics Values associated with CI Primary & secondary scores PASS, FAIL or WARN

batch Compare new batch Compare new batch Pass/Warn/Fail

23 Model Development PCA Model Cannabinoids PCA Model Terpenes PCA Model Sterols PCA Model Triglycerides Compare new batch Compare new batch Compare new batch Compare new batch Pass/Warn/Fail Pass/Warn/Fail Pass/Warn/Fail Pass/Warn/Fail Pass/Warn/Fail Qualitative Fit of Batch

24 QC Analysis Schema the Profiler THC or CBD or Sativex Cannabinoids (LC) Sterols (GC) Terpenes (GC) Triglycerides (LC) CDF CDF CDF CDF Align Signals CDF CDF CDF CDF Compare Fingerprint to model MD & Q Report Scoresheet

25 Batch Scoring For MD, Q if metric < 95% cutoff, score = 0 if metric > 95% cutoff, score = 1 if metric > 99% cutoff, score = 3 Cannabinoids Fail if (primary) score >= 3 Warn if score > 0 Non-cannabinoids Fail if composite (secondary) score >= 9 Warn if composite score >= 3

26 Investigate Warn/Fail CBN THCV CBC

27 Validation Samples were generated to test the sensitivity of the models Models need to satisfy the Goldilocks criteria Not too sensitive, not too insensitive but just right Aim to confirm suitability for use in QC release Chemotype Genotype Cross Contamination Stability Process Change

28 Results - Chemotypes Sample Profiler Model Expected Result Result THCV BDS THC BDS Profiler will generate a FAIL FAIL CBDV BDS CBD BDS Profiler will generate a FAIL FAIL THC BDS (Sativex) THC BDS Profiler will generate a PASS PASS CBD BDS (Sativex) CBD BDS Profiler will generate a PASS PASS

29 Results - Genotypes Sample Profiler Model Expected Result Result CBD BDS (M250) CBD BDS Profiler will generate a FAIL FAIL THC BDS (M333) THC BDS To be determined FAIL

30 Results - Contamination Evaluation of cross-contamination of BRM when producing BDS Sample Profiler Model Expected Result Result THC BDS: CBD BDS (98:2) & (99:1) THC BDS Profiler will generate a FAIL FAIL THC BDS: CBD BDS (99.5:0.5) THC BDS Profiler will generate a WARN WARN

31 Results - Contamination CBD CBD CBD 99.5:0.5 THC:CBD 99:1 THC:CBD 98:2 THC:CBD

32 Summary Routine QC Procedure Based on strong data set Demonstrates can identify batches Absence of expected constituents Presence of the unexpected peak Variation in the expected relative abundance Chromatographic changes beyond the scope of the training set

33 Thanks to: Infometrix Inc Brian Rohrback Scott Ramos Marlana Blackburn Analytical R&D team at GW Pharma Alan Sutton Emma Lennon James Dean-Hughes

Pharmaceutical Quality Control of Complex Botanicals

Pharmaceutical Quality Control of Complex Botanicals Dr Peter Gibson Technical Director Porton Down Science Park, Salisbury, SP4 0JQ, United Kingdom GW Pharmaceuticals To be the global leader in prescription