Quality Assessments for an Organically-Complex Drug - Part 1 - PowerPoint PPT Presentation

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

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

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

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

Regulatory –

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

Single Chemical versus Botanical • Single Substance • Botanical – Single identified active – One or more actives – Full characterisation – May not be identified – Limited number of – Wide range of related substances components FID1 A, (CHEMSTOR\3940163\A417843\APB00021.D) count THC s Cannabinoids 4800 4600 Di-terpenes Sesqui-terpenes 4400 Mono-terpenes 4200 Tri-terpenes & Waxes 4000 3800 3600 0 10 20 30 40 mi

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

Cannabis Production - Weeks 1 to 3

Cannabis Production - Weeks 4 to 11

Cannabis Production - Weeks 4 to 11

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

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

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

THC BDS – Characterization % w/w % w/w THC 66.97 Non-Cannabinoids CBD 0.30 Carotenoids 0.1 THCA 0.23 Triglycerides 3.8 CBG 1.00 Sterols 2.5 CBC 1.12 Terpenes 7.2 THCV 0.55 Residual Ethanol 1.8 THC-C4 0.16 Polar Fraction 1.0 cis-CBG 0.04 Cannabinoid CBO 0.09 0.6 Esters CBO MEE 0.06 Free Fatty Acids 0.8 DHC 0.27 Others 0.99 Total Total 73.0 90.8 Cannabinoids Characterised

BDS – Total Components Identified • 400 – 500 compounds present in the BDS • >90% (w/w) identified • Challenge is the other 10% Well characterized Batch-to-batch consistency Qualitatively and quantitatively comparable

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

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

Overview – 4 methods Cannabinoids Terpenes Triglycerides Sterols & Triterpenes

QC Process THC CBD

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

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

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

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

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

Investigate Warn/Fail CBN THCV CBC

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

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

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

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

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

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

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