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