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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
Quality Assessments for an Organically-Complex Drug - Part 1 - - PowerPoint PPT Presentation
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
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Lead Products
Sativex for the treatment of MS Spasticity and Cancer Pain Epidiolex for the treatment
- f Childhood Epilepsy
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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
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Regulatory –
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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
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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
mi 10 20 30 40 count s 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
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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
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Cannabis Production - Weeks 1 to 3
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Cannabis Production - Weeks 4 to 11
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Cannabis Production - Weeks 4 to 11
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BRM to BDS
Milling Decarboxylation CO2 Extraction Partial Purification Isolation CBD BRM THC BRM CBD BDS THC BDS
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Sativex
Finished Product
BDS to Sativex
Bulk Solution Filling Packaging
CBD BDS THC BDS
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BDS Characterization
Cannabinoids Non-cannabinoids
70 to 75% w/w 25 to 30% w/w
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% 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
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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
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Specification
- Quantitative
– 10 cannabinoids – 14 non-cannabinoid components – Class totals
- Qualitative
– Chromatogram comparison – Routine use of 4 methods
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Qualitative – Compare Chromatograms
THC BDS Batch 1 THC BDS Batch 2 THC BDS Batch 3
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Overview – 4 methods
Sterols & Triterpenes Triglycerides Terpenes Cannabinoids
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QC Process
THC CBD
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Specification – Priority Flow
Quantitative Cannabinoid/Non Cannabinoid Cannabinoid Profile PCA Model Non-Cannabinoid Profiles PCA Models
Ranking in importance
Terpenes Sterols Triglycerides
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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
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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
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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
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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
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Investigate Warn/Fail
THCV CBC CBN
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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
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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
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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
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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
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Results - Contamination
99.5:0.5 THC:CBD 99:1 THC:CBD 98:2 THC:CBD CBD CBD CBD
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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
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