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

– IND in the US

• Botanical

– extracts from specific Cannabis sativa plants

THC

CBD

27mg/ml

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

– Single identified active

– Full characterisation

– Limited number of related substances

• Botanical

– One or more actives

– May not be identified

– Wide range of components

mi0 10 20 30 40

counts

3600

3800

4000

4200

4400

4600

4800

FID1 A, (CHEMSTOR\3940163\A417843\APB00021.D)

Mono-terpenes

Sesqui-terpenes Di-terpenes

Tri-terpenes & Waxes

Cannabinoids THC

Process Overview

Botanical Raw Material (BRM)

Botanical Drug Substance

(BDS)

Botanical Drug Product (BDP)

Sativex

THC BRM

CBD BRM

THC BDS

CBD BDS

GACP

GMP

Cannabis Production - Weeks 1 to 3

Cannabis Production - Weeks 4 to 11

Cannabis Production - Weeks 4 to 11

BRM to BDS

Milling

Decarboxylation

CO2 Extraction

Partial Purification

Isolation

CBD BRM THC BRM

CBD BDS THC BDS

Sativex Finished Product

BDS to Sativex

Bulk Solution

Filling

Packaging

CBD BDS THC BDS

BDS Characterization

Cannabinoids Non-cannabinoids

70 to 75% w/w 25 to 30% w/w

% w/w

THC 66.97

CBD 0.30

THCA 0.23

CBG 1.00

CBC 1.12

THCV 0.55

THC-C4 0.16

cis-CBG 0.04

CBO 0.09

CBO MEE 0.06

DHC 0.27

Others 0.99

THC BDS – Characterization % 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 Cannabinoids

73.0 Total Characterised

90.8

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

Sterols & Triterpenes

Triglycerides

Terpenes

Cannabinoids

QC Process

THC

CBD

Specification – Priority Flow

Quantitative Cannabinoid/Non Cannabinoid

Cannabinoid Profile PCA Model

Non-Cannabinoid Profiles PCA Models

Ranking in importance

Terpenes 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 Cannabinoids

Compare new batch

Pass/Warn/Fail

Pass/Warn/Fail Qualitative Fit of Batch

PCA Model Terpenes

Compare new batch

Pass/Warn/Fail

PCA Model Sterols

Compare new batch

Pass/Warn/Fail

PCA Model Triglycerides

Compare new batch

Pass/Warn/Fail

Cannabinoids (LC) Sterols (GC) Terpenes (GC) Triglycerides (LC)

THC or CBD or Sativex

Align Signals

CDF

CDF

CDF

CDF

CDF

CDF

CDF

CDF Compare Fingerprint to model

Report

Scoresheet

QC Analysis Schema – the Profiler

MD & Q

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

THCV CBC

CBN

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

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

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

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

Results - Contamination

99.5:0.5 THC:CBD 99:1 THC:CBD 98:2 THC:CBD

CBD CBD 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