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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