Role of LIMS in Implementing Regulatory Compliance in Cannabis Testing

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1 Role of LIMS in Implementing Regulatory Compliance in Cannabis Testing Stephen Goldman Head of R&D, EVIO Inc. Laboratory Director, PhytaTech (Denver, CO) Advisory Board Member, CloudLIMS OTCQB: EVIO

2 ABOUT EVIO LABS Provider of accredited analytical testing and industry research 10 labs and counting SERVE CONSUMER DEMAND MAINTAIN HIGH STANDARDS ADVISORY SERVICES HEALTH SAFETY EDUCATION COMPLIANCE AND R&D TESTING PROCESS OPTIMIZATION REGULATORY SUPPORT FORMULATION RESEARCH Support Health, Safety, Education ORELAP Accredited Labs in OR, plus MA, FL, CA seeking ISO 17025, CO ISO Accredited Expertise to Support R&D, Product Formulation, Grow Optimization

3 Talk Overview Significance of Cannabis Lab Testing Testing Today Regulatory Compliance in Cannabis Testing Achieving Testing Compliance Testing Tomorrow

4 Significance of Cannabis Lab Testing Screen pathogens and test risk of contamination Enable clinicians to make informed decisions by knowing exact composition of cannabis-based medicinal products, ensuring patient safety Foster cultivators interested in strategic breeding programs Public Health!

5 Cannabis is a Complex Matrix Sesquiterpenes Terpenes Flavonoids Sugars Fats Lignin Starches Cannabinoids Pigments Chlorophyll Waxes Pectins Cellulose Kenevir Research, 2016

6 Cannabis Inflorescence is a Complex Matrix Cannabis Plant Material Terpenes, Terpenoids, Flavonoids, Pigments, Sugars, Chlorophyll, Fats, Waxes, Lignin, Pectins, Starches, Cellulose Essential Oils ( Hash oil & resin concentrates) Terpenes, Terpenoids, Flavonoids, Pigments, Fats, Waxes Semi- Purified Cannabinoids THC-A, THC, CBD-A, CBD, CBN and trace cannabinoids

7 Cannabis Life Cycle

8 Analytical Testing of Cannabis

9 Cannabis Contaminants Concentrates Residual Solvents Potency Pesticides Heavy Metals Edibles Potency Homogeneity Microorganisms Flower/Trim Microorganisms Potency Heavy Metals Pesticides Processed Concentrates Residual Solvents Potency Pesticides Heavy Metals API Degradation

10 Biological Contaminants Fungi Mycotoxins Powdery Mildew Bacteria Bacterial Endotoxins Salmonella

11 Fungal Contaminants Molds Mold, potentially Aspergillus Yeasts

Agrochemical Agents - Pesticides Insecticide

central nervous system (CNS) disrupter -

synthetic compounds that mimic pyrethrins

12 Agrochemical Agents - Pesticides Insecticide Major Classes: - Carbamates: Non-persistent central nervous system (CNS) disrupter - Organochlorines (Chlorinated Hydrocarbons): persistent compounds that disrupt CNS - Organophosphates: mostly non-persistent compounds that disrupt CNS - Pyrethroids: synthetic compounds that mimic pyrethrins from chrysanthemum flowers

Azadirachtin Α-Limonene Fungicides: Myclobutanil

13 Agrochemical Agents Pesticides: Imidocloprid Bifenazate Abemectin Myclobutanil Natural Pesticides: Spinosad Azadirachtin Α-Limonene Fungicides: Myclobutanil Azoxystrobin Trifloxistrobin PGRs: Paclobutrazol Chlormequat Daminozide

Butane Ethanol Ethyl acetate Ethyl ether Heptane Hexane

14 1,2-Dichloroethane Benzene Chloroform Ethylene oxide Methylene Chloride Trichloroethylene Acetone Acetonitrile Butane Ethanol Ethyl acetate Ethyl ether Heptane Hexane Isopropyl alcohol Methanol Pentane Propane Toluene Xylenes Organic Solvents

15 POST PROCESSING CANNABIS API Degradation

16 Heavy Metal Sources Soil Past Industry contamination Non-remediated soil Water Accumulator plant Trimming equipment? Mercury Lead Arsenic Cadmium Chromium?

17 Regulatory Compliance in Testing ISO/IEC 17025:2017 Good Laboratory Practice (GLP) Document Integrity (SOPs) FDA s 21 CFR Part 11 & Audit Trail State and Local Government Regulations

18 ISO/IEC Objectives Benefits Key Features To ensure accurate testing per internationally accepted standards To ensure cannabis products are free from contaminants To accurately determine both short- & longterm effects of prescribed cannabis consumption To foster trust between producers and consumers by making test results available for public review To ensure laboratory has well-trained staff Provides formal recognition to competent laboratories Serve as a reliable indicator of technical competence Assure customers for accurate and reliable tests & calibration data Facilitate in promoting laboratory s accredited services Control of documents and records Non-conforming control Handling customer complaints Well-trained technical staffs Validated test & calibration methods Equipment's maintenance & calibration Results quality assurance and reporting

19 Maintain Chain of Custody (CoC) for Sample and Tests Chain of Custody

20 Equipment Management Along with Calibration History and Status Equipment Maintenance & Calibration

21 Cannabis Test Result Validation Generate Test Results

22 Generate Test Reports Report Test Reports to Clients/Regulators

23 Method Uncertainty Analytical target profile development & target measurement of uncertainty Error probability Risk management THC/CBD Pesticides Terpenes Microbiology Design Qualification Continuous verification Reportable result Is target measurement uncertainty attainable? Critical uncertainty variables defined Has batch/ process/ method uncertainty changed?

24 Good Laboratory Practice (GLP) Objectives Benefits Key Features To assure the quality and integrity of data submitted to FDA in support of the safety of regulated cannabis products Provide guidelines for better control of maintenance of instruments, environmental controls, & preservation of test records Facilities requirements- appropriate size, construction materials to avoid cross contamination To ensure data recording & sample retention Assures laboratory's capability to provide accurate and reproducible results Well maintained & calibrated instruments To ensure competent & properly trained staff Provide competitive advantage to GLP compliant laboratory Well-organized sample & test data and easy tracking Data acquisition by third-party instrument integrations to ensure integrity of data Well-written standard operating procedures

25 Manage and Track Your Test Data Test Data

26 Instrument Integration Integrate with Analytical Instruments

27 Document Integrity Objectives Benefits Key Features To ensure consistency of test results and prevent errors To ensure testing procedures are performed exactly the same way every time Standardized processes Consistency and quality control Increased productivity Save on training costs Reduced training time for new employees Security of the facility including the type of security in place, lock and key or security cards Organizational chart of the laboratory Training records of the staff Sampling protocols & analytical procedures for each test Quality control procedures Calibration & maintenance data for equipment Reporting of results Disposal of excess sample

28 Maintain SOP Documents Electronically Maintain SOP

29 FDA s 21 CFR Part 11 Objectives Benefits Key Features To ensure integrity & confidentiality of electronic records Help laboratories to be compliant To ensure all user interactions are audited Promotes data security Audit Trail Electronic Signature Future Cannabis Implications? Authorized access to systems and records Control Charting!

30 Authentication of Key Laboratory Activities using Digital Signatures Digital Signature

31 Automatic Audit Trail of all Laboratory Activities- Date and Time Stamp

32 Validation Documentation

36 State and Local Regulations Objectives Benefits Key Features To ensure comprehensive seed-to-sale cannabis tracking Enable laboratory to report your inventory and sales to the state and remain compliant Transfer of sample and testing data directly to the regulatory software- Metrc, SICPA, BioTrackTHC and Leaf, or ERPs like MJ Freeway To enable central control & monitoring Enables automated reporting To enhance transparency in the cannabis business To promote consumer safety

37 LIMS Integration with Regulatory Software

38 Implementing Data Systems - Benefits Easy control and visualization of the testing workflow and sample tracking Reduction in workload by automation of reporting results to customers Increase in productivity while maintaining quality Ensuring compliance with standard operating procedures Reduced transcription errors

39 Testing Why Act Now Moisture Content Potency/Homogeneity Cannabinoid Profile Terpene Profile Pesticide/Herbicide Screening Heavy Metals Microbiological Screening (Genomics) Mycotoxins Residual Solvents Stability Studies Formulation Assistance/API stability

Microbiological Screening (Genomics) Mycotoxins Residual Solvents

40 Testing Moisture Content Potency/Homogeneity Cannabinoid Profile Terpene Profile Pesticide/Herbicide Screening Heavy Metals Microbiological Screening (Genomics) Mycotoxins Residual Solvents Stability Studies Formulation Assistance/API stability Compliance Testing Value-Added Testing

41 Mycotoxins Aflatoxins and ochratoxins are secondary metabolites created by certain Aspergillus fungal species and are known carcinogens in extremely low levels. Common testing protocols exist in other industries to monitor these dangerous small molecules as food products enter to human consumption chain. The FDA mandates that food products intended human consumption must not exceed 20 ppb for aflatoxins. These molecules are heat stable and maintain their molecular structures at temperatures below 160 C. PhytaTech has detected the fungal strains known to produce these molecules in Colorado through genomic testing!

42 Water Activity Water activity is the partial vapor pressure of water in a substance divided by the standard state partial vapor pressure of water. It describes the energy status of water in a sample (how tightly bound water molecules are) and is, a thermodynamic measurement (a w increases with temperature). Water activity is represented from (dry) to (pure water). Mathematically, this is represented as: a w = P/P 0 where P is the vapor pressure of a sample and P 0 is the vapor pressure of pure water. Another way to think about water activity is with respect to the relative humidity. The molecules of water in a product can be measured either as the relative humidity at equilibrium (R.H.) expressed as a percentage or as the water activity expressed as a decimal. R.H. (%) = 100 * a w (at equilibrium) Water activity is a great way to measure shelf stability for your products, as microbes cannot grow below certain water activities. This is because all microorganisms need water to live and proliferate. If the water activity of food is controlled to 0.85 or less in the finished product, it is not subject to further regulations such as the FDA s GMP guidelines, potentially hazardous food (PHF) designations, or Hazard Analysis and Critical Control Points (HACCP) analysis. By testing the water activity and formulating your products to a water activity value of 0.85 or less and/or a ph level of 4.6 or less, products can be stored at room temperatures for a specified period of time, saving costly refrigeration space without endangering the public health and safety.

43 Stability Studies & API Stability Stability testing programs determine the rate of degradation of cannabinoids over time. Often, this is done at higher temps and humidity (accelerated stability studies). The degradation rates of the cannabinoids in your Cannabis products are determined via the following equation: k=ae-ea/rt Where k = the rate of degradation of the Cannabis product, A = a pre-exponential factor, E a = activation energy, R = gas constant, and T = absolute temperature (in Kelvin). By performing this analysis at different temperatures, we can create what is called an Arrhenius plot (hypothetical plot below):

44 Genomics Metagenomics is the study of DNA (or RNA) sequences from samples directly taken from environmental sources. The following are some of the observations made by our laboratory: The ubiquitous powdery mildew (PM) genus, Golovinomyces, begins to show up in the stem tissues, and in composited leaf/ bud tissue samples, can make up >99% for detected sequences. Despite the dominance of Golovinomyces, we also find a lot of the fungi like Penicillium and Candida responsible for failed Total Yeast and Mold tests on the leaf/bud tissue. There is often evidence of human contact with the plants often in the form of Trichsporon cutaneum, a fungus associated with human skin and responsible for dandruff. For example, we have noted at least one potential mutualism between fungal Fusarium sp. and the bacteria Xanthomonas campestris, the cause of a plant disease called black rot, which is notable for its similarities to Fusarium wilt. These two species have both shown increased abundances in diseased tissues across different grows. There is already at least one fungal species, Trichoderma viride, that is sold as a biocontrol agent for Fusarium wilt. During our survey of the diseased rhizosphere we detected this organism, but the abundance was very low, suggesting that it was insufficiently applied or had failed to thrive. Ongoing metagenomic monitoring could also be applied in such a case to gauge the efficacy of such treatments.

45 Contact Stephen Goldman OTCQB: SGBY

46 Fail Rates Early Testing Colorado 30.0 Residual Solvent Contamination - Colorado 28.5 % Total Fails April/May 2015 July-Dec

47 Fail Rates Early Testing Colorado 25.0 Microbial Contamination (TYMC) - Colorado % Total Fails Oct-15 Nov-15 Dec-15 Jan

Fail Rates Early Testing Oregon % Fails 10.00% 9.00% 8.

0% Pesticide Fail Rates - Oregon 16.7% (2016) 14.0% 12.

48 Fail Rates Early Testing Oregon % Fails 10.00% 9.00% 8.00% 7.00% 6.00% 5.00% 4.00% 3.00% 2.00% 1.00% 0.00% Pesticide Fail Rates - Oregon 8.60% 5.30% Oct-Dec % Fails 18.0% 16.0% Pesticide Fail Rates - Oregon 16.7% (2016) 14.0% 12.0% 12.0% 9.7% 10.0% 8.6% 8.0% 6.0% 3.6% 4.0% 2.0% 0.0% Bend Eugene Medford Portland Overall

49 Industry evolution Courtesy of Cindy Orser, Digipath Labs; Emerald Conference, 2016

Analytical Testing and Quality Assurance for Cannabis

Analytical Testing and Quality Assurance for Cannabis Anthony Smith, Ph.D Kenevir Research, 2016 Analytical Testing and Quality Assurance for Cannabis 1. Cannabis is a complex matrix 2. What is the role