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Stability in Product Development
Andrea Baillo, PhDFeb 27th, 2020
Overview
• Background• Types of stability • Testing conditions• Common product forms• Examples • Discussion
Cannabis - One Medicine for One Hundred Conditions
Karst A. Weighing the Benefits and Risks of Medical Marijuana Use: A Brief Review. Pharmacy (Basel). 2018;6(4):128. Published 2018 Dec 6. doi:10.3390/pharmacy6040128
State Regulations and Action Limits – Lack of Uniformity
CT 0.29 ppb CT 5000 ppm CT 5 ppbFL 500 ppb FL NA FL NAIL NA IL 5000 ppm IL 20 ppbMA 500 ppb MA 5000 ppm MA 20 ppbMD 1000 ppb MD 5000 ppm MD 20 ppbNV 1000 ppb NV NA NV 20 ppbPA 1000 ppb PA 5000 ppm PA 5 ppb
Lead Action Limits Ethanol Residual Solvent Ochratoxin A
*uG/KG BW/Day
*
Pharmaceutical Product Stability
• Pharmaceutical product stability may be defined as the capability of a particular formulation in a specific container to remain within its physical, chemical, microbiological therapeutic and toxicological specification
• Assurance that the packed product will be stable for its anticipated shelf life must come from an accumulation of valid data on the drug in its commercial package
The International Council for Harmonisation (ICH)
When to Address Stability
• Early stage – stress and accelerated testing• Pre-formulation batches• Select appropriate container/package
• Stress testing on scale-up batches• Accelerated and long-term testing• On-going stability• Continuous improvement
• Follow-up stability
Factors to Consider• Stability of the active ingredients • Container for packaging• Heat/moisture condition of raw materials• Storage and shipment
• Type of dosage forms• Interaction between active ingredients and excipients
Types of Stability in Cannabis Product• Therapeutic
• Cannabinoid• Terpenoid
• Physical• Homogeneity• Physical Properties• Effect on emulsification• Rheology• Water Activity
• Chemical• Oxidation• Isomerization• Decarboxylation
• Microbiological
Shelf vs Accelerated Stability
• Shelf Life• Sample should be stored in the same conditions as product destined for
market• Samples should be stored in a controlled environment similar to how
consumer will store at home• 70F RH 50-70%
• Accelerated • Samples should be stored according to FDAs Guidance for Industry Q1A(R2)
Stability Testing of New Drug Substances and Products • Seven days of storage at 40°C ± 2°C/75% RH ± 5% RH equals one month of shelf
stability
• Inhalable• Vape Oil• Flower• Terpenes
• Sublingual• Compressed Tablets• Tinctures
• Edible• Candy (Jellies, Chocolates)• Beverages
• Topical/Transdermal• Patches• Face Cream/serum• Lotion/liniment
Product Forms
Single-source vs. Multi-source Data
• Single-source data• Data collected from following one lot/batch
• Multi-source data• Data collected from multiple lots/batches• Percent degradation denoted to normalize data
Edible/Sublingual
EDIBLE - Jellies are stable for 11 months
5.52
5.28
5.42
5.11
4.89
5.04
4.14
5.22
5.01
4.77
4.62
4.83
0
2
4
6
0 7 14 21 28 35 42 49 56 63 70 77Cann
abin
oids
/uni
t (m
g)
Days
Jellies THC potencyAccelerated Stability
THC (mg/unit)
00.20.40.60.8
1
0 7 14 21 28 35 42 49 56 63 70 77
TYM
C (C
FUs)
Days
Jellies Yeast and Mold (CFUs)Accelerated Stability
TYMC (CFUs)
65
75
85
95
0 7 14 21 28 35 42 49 56 63 70 77
Perc
ent B
rix (%
))
Days
Jellies % BrixAccelerated Stability
00.20.40.60.8
1
0 7 14 21 28 35 42 49 56 63 70 77
Wat
er A
ctiv
ity
Days
Jellies Water ActivityAccelerated Stability
Single Source Data
SUBLINGUAL - THC Degradation at 12 Months with Hash-infused Compressed Tablets
0 1 2 3 4 5 6 7 8 9 10 11 12
CBN mg/unit 1.13 1.13 1.16 1.30 1.35 1.27 1.43 1.59 1.49 1.54 1.52 1.58 1.62THC mg/unit 7.66 7.66 7.39 7.58 7.20 6.24 6.04 6.49 5.52 5.28 4.70 4.61 4.32CBD mg/unit 7.97 7.97 7.68 8.23 7.80 7.01 7.44 8.66 7.61 7.36 7.18 8.06 6.87
02468
101214161820
Pote
ncy
(mg/
unit)
Weeks
Compressed Tablets - HashAccelerated Stability
CBD mg/unit THC mg/unit CBN mg/unit Single Source Data
• 43% increase in THC degradation after 10 months
SUBLINGUAL - THC Degradation at 9 months in Distillate-infused Compressed Tablets
• 59% increase in THC degradation after 10 months
0 7 14 21 35 42 49 56 63CBN mg/unit 0.00 0.00 0.00 0.00 0.07 0.11 0.13 0.15 0.15THC mg/unit 2.95 2.68 2.48 2.40 2.02 1.76 1.61 1.53 1.22CBD mg/unit 10.64 9.57 9.85 9.91 9.38 9.07 8.82 8.54 8.08
0.00
2.00
4.00
6.00
8.00
10.00
12.00
14.00
Pote
ncy
(mg/
unit)
Days
Compressed Tablets - DistillateAccelerated
CBD mg/unit THC mg/unit CBN mg/unit Single Source Data
Serum/Tincture
WATER SERUM - Unstable at 5 Months
Color FragranceTextureFlow
pH ViscosityWeightPotency
TYMCTAMCSalmonellaE. Coli
Color Physicality
Notes/Comments ______Slightly sour taste after 3 months.__________________________________ ____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
NA
WhiteCylinder
PASS PASS
PASS
Container Physical Properties Results
PASS/FAIL
NANA
0 CFUsNANA
Critical Physical and Chemical Property Results
PASS/FAILPASS 4
NoneOpaque Tan
Slick LibeMedium Slow
NA
Critical Aesthetics Results
PASS PASS PASS PASS
PASS/FAIL
FAIL
Microbial Results
PASS/FAIL
64.19mg THC → 26.04mg THC
NAPASS
NANo loss
Length of Test _5 Weeks (5 Months)___ Humidity _75%_____ Accelerated Stability Test Date Started _9/13/2019__ Date Ended __10/18/2019____ Temp. ___95F______
• 60% total loss in THC potency
• Souring flavor• Stable micro and pH
Single Source Data
0.0%
18.3%
21.7%
15.4%
25.0%
0.0
5.0
10.0
15.0
20.0
25.0
30.0
0
10
20
30
40
50
60
70
0 1 2 3 4 5 6
Perc
etn
Loss
of m
g TH
C (%
)
Pote
ncy
of In
timac
y Se
rum
(mg
THC)
Equivalent Months in Accelearted Stability Testing
Potency of Water-based Serum Accelerated Stability Testing
Potency Percent Loss
OIL SERUM - THC Degradation 1 year Post-Production
3 month-R 6 month-R 1 year-RCBN 1.36 1.55 1.02THC9 92.4 98.51 66.49THC % Diff 11.15% 1.50% 23.43%
0.00%
5.00%
10.00%
15.00%
20.00%
25.00%
0
20
40
60
80
100
120
Oil-based Serum PotencyShelf Stability
CBN THC9 THC % Diff Multi-source data
OIL SERUM - Stable after 8 Months
0.00
104
1.36
92.4
1.55
97.09
0
104
0.00
20.00
40.00
60.00
80.00
100.00
120.00
CBN THC
mg/
g
Months
Oil-based Serum Shelf Stability
0 3 6 8 Single Source Data
Topicals
WATER TOPICAL - Stable CBD and 15% Decline in THC Potency After 5 Months
210
192
224
204
221
196
222
190
224
182
212
170
150
170
190
210
230
CBD THC
mg/
g
Months
Water-based TopicalShelf Stability
0 1 2 3 4 5Single Source Data
OIL TOPICAL - Stable After 6 months
207
0
41
226
0
45
223
0
45
220
0
44
235
0
44
229
0
43
0
50
100
150
200
250
CBD CBN THC9
mg/
g
Month
Oil-Based Topical PotencyShelf Stability
0 2 3 Single Source Data
Extended StabilityPatchesVapes
Terpenes
PATCHES – Stable THC for 1 Year & Stable CBD for 2 Years
3 month 6 month 9 month 2 Year 2.5 YearCBN 0.40 0.70 0.46 0.52 0.62THC 18.95 22.41 16.16 14.46 13.15%Diff THC 9% 7% 12% 21% 40%
0%
10%
20%
30%
40%
50%
0
5
10
15
20
25
mg/
unit
THC Patch PotencyShelf Stability
CBN THC %Diff THC
3 month 9 month 2 Year 2.5 YearCBD 11.61 9.41 8.33 9.21CBN 0.00 0.00 0.07 0.16THC 0.36 0.59 1.46 0.47%Diff CBD -3% -11% -2% 13%
-15%-10%-5%0%5%10%15%
0
4
8
12
16
mg/
unit
CBD Patch PotencyShelf Stability
CBD CBN THC %Diff CBD
Multi-source data
PATCHES - Effect of THC on CBD:THC Matrix
Multi-source data
Day 0 6 monthCBD 5.00 3.70THC 4.70 3.32%Diff CBD 0% 26%
0%
5%
10%
15%
20%
25%
30%
0.00
1.00
2.00
3.00
4.00
5.00
6.00
6 Month 1:1 THC:CBD Patch Shelf Stability
CBD THC %Diff CBD
Day 0 9 monthCBD 8.48 9.41THC 0.59 0.59%Diff CBD 0% -11%
-12%
-10%
-8%
-6%
-4%
-2%
0%
0.00
2.00
4.00
6.00
8.00
10.00
12.00
9 Month CBD Patch Stability
CBD THC %Diff CBD
VAPE - Stable for > 2 years
3 months 6 months 9 months 1 year 2 years 2.5 yearsDay 0 THC 72.20 74.30 75.70 76.00 76.8 70.4Aged THC 75.38 69.22 68.69 70.58 68.068 53.513% Diff THC 4% 7% 9% 7% 11% 24%
0%
5%
10%
15%
20%
25%
30%
40
45
50
55
60
65
70
75
80
%Di
ffere
nce
in y
ear
%Co
ncen
trat
ion
THC
in o
il
Vape Cartridge - THC PotencyShelf Stability
Day 0 THC Aged THC % Diff THC Multi-source data
TERPENES - Stability• After five weeks
30% loss of total terpenoids
• 35mL of terpene extract was contained in 40 mL volatile vial with Teflon-lined cap
• Vial was kept in 4◦C ±2◦C in the dark
• Identify optimal storage conditions
02468
1012141618
.alpha.-Pinene
Camphene
.beta.-Myrcene
.beta.-Pinene
D-Limonene
.beta.-Ocimene
Terpinolene
LinaloolGeraniol
Caryophyllene
Humulene
Nerolidol 1
Nerolidol 2
Caryophyllene oxide
Bisabolol<alpha->
Stability of CO2 Terpene Extract Snow Monster Concentration (%)
Week 0 Week 1 Week 3 Week 4 Week 5
Single Source Data
Discussion
• Benefits to understanding stability• Optimize Storage Conditions• Define acceptable cannabinoid loss• Assure micro stability
• Purchase quality raw materials • Infusion material – not all cannabis concentrates are equal• Equipment stability• Process Control • Co-man
Next Steps
• Address homogeneity due to process/equipment• How does THC interact in CBD:THC matrix• Effect on stability
• Use this data to guide regulations• Extended shelf life
Acknowledgements
Cheri PearsonAnalytical Chemist
Alexandra DePalmaProduct Developer
Project Manger
Barbara FisherAnalytical Chemist
Laura Brown – VP OPX, Continuous Improvement
Michael Giroux – Research and Development Tech
Michael Armstrong – Production Ops Manager
Sarah Lundfelt – Stability Scientist
Greg Flickinger – SVP Ops
Questions?
Nano-particle distribution and diameter monitoring for stability
Single Source Data
Stable CBD and 15% decline in THC potency after 5 months
210
192
224
204
221
196
222
190
224
182
212
170
150
170
190
210
230
CBD THC
mg/
g
Months
Water-based TopicalShelf Stability
0 1 2 3 4 5
3
192
4
204
5
196
5
190
7
182
7
170
0
50
100
150
200
250
CBN THC
mg/
g
Months
Water-based Topical Shelf Stability
0 1 2 3 4 5
00.20.40.60.8
1
0 7 14 21 28 35 42 49 63 70 77 84
TYM
C (C
FUs)
Days
Water-based Topical Yeast and Mold (CFUs)Accelerated Stability
TYMC (CFUs) Single Source Data
SUBLINGUAL - Stability is lost after 6 months in compressed tablets infused with a carrier
0 7 14 21 28 35 42 49 56 63 70
CBN mg/unit 0.00 0.00 0.00 0.00 0.03 0.12 0.12 0.16 0.16 0.18 0.17THC mg/unit 2.87 2.61 2.62 2.37 1.69 1.97 1.54 1.43 1.40 1.08 0.85CBD mg/unit 11.05 10.30 10.38 10.41 8.77 10.15 8.93 9.35 9.67 8.49 8.61
0
2
4
6
8
10
12
14
Pote
ncy
(mg/
unit)
Days
Compressed Tablets – With CarrierAccelerated
CBD mg/unit THC mg/unit CBN mg/unit
• 5 months• 22% difference
@10 months
Single Source Data
SUBLINGUAL - THC degradation at 10 months in distillate infused compressed tablets
0 7 14 28 35 42 49 56 63 70
CBN mg/unit 0.00 0.00 0.00 0.00 0.07 0.11 0.13 0.15 0.15 0.12THC mg/unit 2.95 2.68 2.48 1.70 2.02 1.76 1.61 1.53 1.22 0.89CBD mg/unit 10.64 9.57 9.85 8.41 9.38 9.07 8.82 8.54 8.08 6.87
0
2
4
6
8
10
12
14
Pote
ncy
(mg/
unit)
Days
Compressed Tablets - DistillateAccelerated
CBD mg/unit THC mg/unit CBN mg/unit
• 70% increase in THC degradation after 10 months
Single Source Data