Committee Blog: Manufactured Product Safety – 2021 Series Premier

by NCIA’s Cannabis Manufacturing Committee

Product safety isn’t an endpoint, it’s a journey. And let’s face it, there is years-worth of research left to do on the safety of cannabis products. That’s why it’s important to stay up to speed on the latest thinking from leaders in the industry. In 2021, the National Cannabis Industry Association’s Cannabis Manufacturing Committee intends to help you do just that by providing information and approaches aimed to help you continue to improve the safety of your manufactured cannabis (marijuana and hemp) products while providing your customers with increasingly trusted experiences. This Manufactured Product Safety Series will consist of blogs, podcasts, and expert panel discussions focused on providing insight into topics relevant to a wide range of manufacturers.

Over the course of the next several months, we’ll bring you content with the following working titles.

Vapor Liquid Formulations

The Importance of Testing Vapor Products as a System

Edibles Stability – Microbial Growth Due to Insufficient Packaging

Terpene Limits Across Multiple Product Formats

But while we’re busy crafting these new pieces, we want to take advantage of our past publications to keep important safety topics front and center. Back in January of 2020, in response to the then-emergent EVALI outbreak, NCIA’s Policy Council created a whitepaper to provide guidance to the industry and regulators. We’re republishing portions of this whitepaper starting with the Vaporizer Liquid Formulations section below. We’ve learned more about EVALI since its original publication, and while some of the specifics may be a little dated, the principles remain relevant to helping you understand product safety.

Disseminating our knowledge of this topic also helps promote better regulation. Examples of what can go wrong are the Oregon Liquor Control Commission’s (OLCC) recently adopted regulations that effectively ban the use of propylene glycol (PG). Granted, they were addressing a difficult issue and made some good decisions, but had they read this piece, they might have better understood that PG “degradation has been shown only with temperatures in excess of what is typically produced by well-controlled hardware.” Even in studies where the temperature was not well controlled, thermal degradants were detected in amounts that are lower in the vapor stream when compared to combustion and inhalation of plant products, such as cannabis flower. And given that PG has been “used at up to 90% concentration in e-cigarette products for the past decade without reports to date of significant health issues,” it is unwise to ban an ingredient option that may turn out to have a better safety profile than even certain native terpenes, some of which may have to be added at abnormally high concentrations in order to achieve the desired viscosity, without further research.

So with that in mind, stay tuned for the next piece in the series and enjoy the excerpt below!

Excerpted from THE KEY TO CONSUMER SAFETY: DISPLACING THE ILLICIT CANNABIS MARKET RECOMMENDATIONS FOR SAFE VAPING

Access the full report and citations.

Cannabis Ingredients

The cannabis-derived ingredient in cannabis oil vaporizers is a concentrate that is produced by extracting the cannabinoids and other compounds from the plant. With the exception of supercritical CO2 extraction, most other common extraction methods use butane, alcohol, or hexane as solvents for the extraction of cannabis oils used in vape pens. Extraction processes using these solvents may result in a small presence of the solvent in the extracted oil. Any residual solvent must ultimately be removed prior to any product being sold to consumers. States that have legalized and regulated cannabis typically have specific requirements regarding allowable concentration levels of these solvents. These states also require full analytical testing by licensed independent labs, including reporting of residual solvents, to ensure that only safe levels of any solvents are present in the final formulation of cannabis vape products.

The type of cannabis concentrate used in a vaporizer is important to consider. Some require diluents or other additives to be effectively vaporized while other types of concentrates (eg: live resin) have the appropriate viscosity to be used in vaporizers without adding any diluting non-cannabis ingredients.

Non-Cannabis Ingredients

Propylene Glycol (PG), Vegetable Glycerin (VG) aka Glycerol, and Polyethylene Glycol (PEG)

Similar to what we are seeing in the commercial e-cigarette industry, some manufacturers of cannabis extract-containing vape pens choose to add ingredients that help adjust the viscosity of the cannabis oil. This allows the oil to flow evenly through the atomizer when heated. Some of these additives may also contribute to a vapor “cloud” when exhaled. PG, VG, and PEG are the most commonly used cosolvents or diluents. PG and VG are on the FDA’s Inactive Ingredient List for inhalable drug products and are allowable only at fairly low concentrations in drug products, but have been used at up to 90% concentration in e-cigarette products for the past decade without reports to date of significant health issues. PEG is not on the FDA’s list and less is known about its inhalation toxicity. Therefore, PEG should be viewed with more caution, even at lower concentrations.

The state of Colorado has paved the way for the industry on forward-thinking cannabis regulations and remains an industry leader. Governor Polis, his cannabis advisor, and the Marijuana Enforcement Division should be commended for creating an environment in the state that fosters business development while simultaneously protecting consumers. After discussions between Colorado regulators and stakeholders about additives, and given the lack of sufficient safety reviews of these ingredients, the state of Colorado prohibited Polyethylene glycol (PEG); Vitamin E Acetate; and Medium Chain Triglycerides (MCT Oil) in inhalable concentrates and products effective January 1, 2020. Colorado further banned non-botanical terpenes, any additive that is toxic, and any additive that makes the product more addictive, appealing to children, or misleading to patients or consumers. Other states should consider following Colorado’s lead.

The creation of degradants through overheating is also an important consideration. For example, overheating PG and VG may result in their degradation into molecules with established toxicity profiles such as glyceraldehyde, lactaldehyde, dihydroxyacetone, hydroxyacetone, glycidol, acrolein, propanal, acetone, allyl alcohol, acetic acid, acetaldehyde, formic acid, or formaldehyde. However, this degradation has been shown only with temperatures in excess of what is typically produced by well-controlled hardware. Because PEG is a polymer of glycerin, its degradation upon heating is similar to that of VG and it forms the same unwanted toxic molecules.

Vitamin E Acetate and Tocopherols Inhalable Safety Profile Has Not Been Evaluated

Investigators at the FDA and CDC recently found that some cannabis-containing vape products from the illicit market contain a molecule called vitamin E acetate (VEA), also known as Tocopheryl acetate. Vitamin E is a common name for several similar types of chemicals called “tocopherols.” Vitamin E occurs naturally in certain foods, such as canola oil, olive oil and almonds, but also can be made synthetically. Tocopherols are used as nutritional supplements, and manufacturers put tocopherols in food and cosmetics. VEA is the acetic acid ester derived from vitamin E and is also not known to cause harm when ingested as a supplement or applied to the skin.

VEA’s safety when inhaled has not been evaluated. Numerous published studies indicate that the inhalation of vaporized oils, including certain tocopherols, are harmful to the lungs and numerous cases of lung injury after their inhalation have been documented since 2000. Tocopherols such as VEA adhere to an important fluid in the lungs called lung surfactant. Lung surfactant enables oxygen to transfer from air into your body. Studies have shown that tocopherols impair gas transfer in the lungs. Currently, it is believed that inhalation of significant amounts of certain tocopherols can lead to the death of lung cells and initiate a massive inflammatory reaction that can further contribute to lung damage and functional impairment. Accordingly, VEA should not be used as an additive in any inhaled product. Following the FDA and CDC’s investigation, Colorado added VEA to their list of prohibited ingredients in inhalables to their regulations effective January 1, 2020.

Artificial Flavorings Have Not Been Fully and Scientifically Evaluated.

Some manufactures of cannabis extract-containing vape pens choose to add flavoring agents to the cannabis oil to give them a distinctive flavor, similar to products in the electronic cigarette industry. These additives tend to produce flavorings that are appealing to some consumers. While a number of flavorings have been used for many years without incident, the safety of the majority of flavorings when added to vaporized products – alone or in combination with cannabis extracts – have not been fully and scientifically evaluated.

In one study, certain chemicals that are used in flavorings for vanilla, cherry, citrus, and cinnamon can create compounds called acetals when they are mixed with solvents such as PG and VG. Acetals are known to cause irritation when inhaled and can lead to chronic inflammation in the lung. The long-term

effects of these flavoring agents on lung function are unknown. A separate study showed that some popular flavorings may increase the risk of cardiovascular disease when inhaled, although several other studies show no negative effects.

As approximately 17 million Americans use vape products, many of which contain flavors, and only around 2,000 cases of e-cigarette, or vaping, product-use associated lung injury (EVALI) are currently being reported, it appears unlikely that all flavoring agents in all hardware devices are linked to EVALI. However, until more detailed safety studies have been completed on these product lines, manufacturers should proceed with caution.

Some Terpenes are Safe (GRAS); Some Can be Harmful When Heated

Terpenes are a class of molecules found in many plants, including cannabis, that are responsible for the aroma of the plant. Plants evolved to make terpenes to attract pollinators and to deter herbivores and unwanted pests. Terpenes are biologically active and help contribute to many of the physiological effects of inhaled cannabis. Isolated terpenes have been widely used as fragrances in perfumes in the cosmetic industry and in medicine, such as aromatherapy. Although many terpenes are considered “Generally Regarded As Safe” (GRAS) by the FDA, some terpenes are toxic when inhaled/ingested at high concentrations. While most cannabis goods on the market contain levels of terpenes similar to those that occur naturally in the cannabis plant (~1-5%), some products contain terpenes at much higher concentrations (upwards of 25%). High levels of terpenes and other molecules can also occur if chemical procedures such as distillation are used to concentrate cannabis or hemp oil.

In general, terpenes are benign at low concentrations; however, overexposure to concentrated terpenes has the potential to lead to negative effects, including hypersensitive (allergic) reactions in chemically sensitive people. Additionally, some vape pens do not have the means to adequately control the temperature and can heat the cannabis oil to a very high temperature. In certain instances, this has been shown to lead to thermal decomposition of some molecules in cannabis extracts, such as terpenes, resulting in the formation of new molecules with established toxicities. It is also worth noting that even when these new molecules have been shown to form, they have been detected in amounts that are lower in the vapor stream when compared to combustion and inhalation of plant products, such as cannabis flower, or tobacco leaf.

Cannabis-derived Terpenes

Cannabis contains terpenes, such that cannabis oil extracts used in vape products typically also contain these molecules, depending on the extraction method. Typically, the distillation process causes a loss of terpenes. Some vape manufacturers now recover cannabis-derived terpenes during the distillation process and then re-introduce them back into the final formulated product. Because of poor process control, one potential safety concern from this procedure is that these cannabis-derived terpenes have an undefined molecular composition and the specific concentration of any terpene in the crude mixture likely varies from batch-to-batch due to numerous experimental variables. For example, many manufacturers that are producing large volumes of vape products by necessity must make the oil extracts from a mixture of cannabis strains. Since every cannabis strain contains different terpene profiles, this means that formulated products made from these strains will also vary in their terpene profiles from batch-to-batch.

The potential for terpene profiles changing during the manufacturing process could pose a potential safety concern. Additionally, new isomers, oxidative by-products, or degradative terpenes may be present in these captured terpenes, which could possibly present hazards never presented by merely combusting and smoking the cannabis plant. Some states that have regulations on cannabis require analytical testing of formulated products, including the reporting of terpene concentrations, but this is not yet the universal standard. Vape manufacturers must exercise caution and be required to analyze terpene profiles of products they make in order to begin to develop a better understanding of this subject. Adhering closely to terpene concentrations known to be present in cannabis flower is a good practice.

Non-Cannabis Derived Terpenes Can Contain Residual Solvents and Pose Dangers

One widespread misconception in the cannabis vape industry is that cannabis-derived terpenes are somehow safer or better for you than non-cannabis-derived terpenes. There are few cannabis-specific terpenes because most terpenes are also present in other plants. Most cannabis vape manufacturers that operate at a large scale, therefore, prefer to use terpenes isolated from non-cannabis sources to introduce into their formulated products. There are several reasons why this is popular in the industry. High purity terpenes (e.g. >99% pure) are sold by numerous retailers, which allows these terpenes to be re-introduced into cannabis vape products at defined and safe concentrations. Also, the cost of using non-cannabis-derived terpenes is far lower than the cost of isolating and using cannabis-derived terpenes.

For example, the terpene D-Limonene is present at extremely high levels in citrus fruits, and therefore can be isolated to high purity easily and inexpensively from them. In contrast, in most cannabis strains D-Limonene is only found at relatively low concentrations, and therefore one would have to use massive amounts of cannabis material to isolate significant quantities of this terpene required for companies that are operating at scale.

The origin and concentration of non-cannabis-derived terpenes that manufacturers use in their formulations is nevertheless important. Non-cannabis-derived terpenes from overseas often have several residual solvents in them, including ethanol, hexane, xylenes, benzene, butane, and toluene. Moreover, some retailers of non-cannabis-derived terpenes do not list the actual concentration or purity of terpenes in their products. It is imperative that cannabis vape manufacturers purchase and use non-cannabis derived terpenes that are accompanied by a COA that reports the purity of the terpene, any solvent(s) that may carry the terpene, and be required to adhere to the same purity standards and mandatory analytical testing requirements as cannabinoids. Reputable companies will also supply a safety data sheet (SDS) that describes the known toxicities of that terpene by different routes of ingestion, including inhalation.

Cannabis manufacturers that make formulated vape products should be aware of any toxic liabilities of non-cannabis-derived molecules introduced into these products. Vape products should also undergo analytical testing for cannabinoids, terpenes, and contaminants. Finally, analytical tests for aerosolized cannabis, similar to those used in the e-cigarette industry, should be developed, implemented, and mandated to address safety concerns. The industry needs to build the volume of inhalation safety data required for all of these ingredients, hardware, and end product combinations.

Committee Blog: First The Vaping Crisis, Now COVID-19 – A Cannabis Physician’s Perspective

by Cynthia Shelby-Lane, MD
Member of NCIA’s Scientific Advisory Committee

The vaping crisis was first reported in June 2019. In October 2019, the U.S. Centers for Disease Control and Prevention (CDC) coined a new medical term describing the cases of severe pulmonary disease that have occurred among e-cigarette and vape users, E-Cigarette and Vaping Associated Lung Injury, or EVALI. EVALI’s primary cause was determined by the CDC to be vitamin E acetate contamination, mostly in illicit market vaping products, although research into this condition continues.

By the early fall of 2019, the National Cannabis Industry Association (NCIA) formed a Safe Vaping Task Force to respond to the crisis. Together with NCIA’s Policy Council, they released a white paper in January 2020 detailing information about vaporizer components, formulations, testing, governmental response, and recommendations for the industry.

As the COVID-19 health pandemic takes front and center stage on the world scene, vaping related issues and EVALI, becomes even more of a health concern as the novel coronavirus causes respiratory issues. While reported cases of EVALI are slowing down, this public health crisis still looms over us, and it’s been very challenging to fully solve this mystery illness associated with vaping e-cigarettes, and other electronic nicotine delivery systems (“ENDS”). Furthermore, it’s been more difficult to stop the primary root cause: the illicit market.

VAPING, EVALI, AND COVID-19

We’re experiencing a worldwide public health crisis with coronavirus and it’s also affecting the Marijuana industry, as we face “stay at home” orders, slower production or reduced access in some areas, and fear from the community about vaping related respiratory illnesses, EVALI, and death due to COVID-19. It begs the question: Is vaping safe and could vaping put you at greater risk of severe illness during this coronavirus pandemic?

Some health experts say vaping can increase the risk of developing COVID-19 complications and spreading the virus to others because many people share vaping devices. A Bloomberg article was published last month, stating the FDA says “vaping could compound health risks tied to virus.” The Attorney General of Iowa along with scientists sent the FDA a letter commenting that they should be more careful giving advice at a time like this, especially given “the pronounced difference in risk between smoking and vaping.”

The Food and Drug Administration (FDA) has supported both positions on vaping but now says there is a lack of evidence to support the worsening of health in conjunction with vaping and COVID-19, while also considering that underlying conditions could be the real culprit.

According to the CDC, those with chronic lung disease are at higher risk for severe illness. The conditions listed with the CDC do not include EVALI, but perhaps vaping behaviors should be considered when determining risk. I am a member of Doctors for Cannabis Regulation (DFCR), an organization that supports the legalization and use of cannabis. DFCR cautions against smoking and vaping during the COVID-19 pandemic because we just don’t have enough research yet.

After reviewing the limited literature, it must be noted that “e-cigarette use” and vaping have cardiovascular risks. Buchanan and colleagues reviewed the limited available preclinical and clinical data and concluded that “E-cigarette use is associated with inflammation, oxidative stress, and haemodynamic imbalance leading to increased cardiovascular disease risk.” Current evidence is available primarily from acute studies and the effects of chronic exposure remain an urgent research question.

PERSONAL PHYSICIAN RESPONSE

As an emergency physician, functional medicine specialist, and medical cannabis doctor, I’ve examined, certified, and managed patients for medical marijuana use in Michigan since 2014. As a cannabis physician, I routinely review cannabis-related science and research and its therapeutic effects, based on forms of consumption, frequency of use, and limited data on patient dosing. I evaluate patients for their therapeutic benefits and patient outcomes obtained by using marijuana in various forms of consumption, in conjunction with their other medications.

As a cannabis physician, I work very hard to get to the source of my patients’ medical issues or problems related to their medical need for cannabis. This also means giving them direction about the use of cannabis, cannabis products, and noting any side effects related to their method of consumption and use of marijuana, hemp, and CBD.

Perceiving the same thing as the general public, my patients frequently say, “I thought vaping was safe.” This is still the case even during this ongoing public health crisis with EVALI and now, COVID-19.

Pertinent health questioning should always involve asking patients about their forms of usage of cannabis, their daily intake, and noting if a person has any side effects related to cannabis usage or any other medications. Since vaping related illnesses were first reported, I continue to educate patients about the possible side effects of vaping. For some people, problems related to vaping may have been present since they started vaping, but were disregarded because they thought it wasn’t serious or of much concern. We need more research to better inform educational programs so patients and consumers can make better-educated decisions on which marijuana products they should use.

HEALTHCARE, THE CDC. AND COMMUNITY RESPONSE

“Do you vape? Do you smoke? Do you have an underlying lung disease such as asthma, chronic obstructive pulmonary disease (COPD, e.g. emphysema), heart disease, or any respiratory problems?” These are the most important questions doctors and healthcare providers should ask patients who present with respiratory symptoms, especially during the worldwide COVID-19 pandemic. All healthcare providers, whether on the frontlines or not, must change their assessment of patients to ask about their lifestyle and any respiratory-related health conditions (past and present). This includes addressing smoking, vaping, and potential side effects.

Patients often delay seeking treatment and the biggest challenge doctors face is that patients might lie about vaping out of fear they will be identified publically or criminally charged if they procured their vaping products from the illicit market. Doctors and other health care providers need accurate information to make a diagnosis and should maintain a non-judgmental attitude and confidentiality when asking patients about their lifestyle and social history.

Detailed information has been created by the CDC for ongoing updates regarding EVALI and related illnesses. Specific information for healthcare providers can be found here.

New tools for physicians include an updated algorithm for the management of patients with suspected EVALI and a Discharge Readiness Checklist. These documents are recommended for use by doctors, hospitals, clinics, and health care professionals and should be followed to help with systematic care and prevention. These tools have been used for EVALI. There have been major updates since the COVID-19 pandemic as of December 2019.

THE FUTURE OF EVALI: CONTAMINANTS AND CONSUMER RESPONSE

According to the CDC and available data, it appears that vitamin E acetate is primarily associated with EVALI, but there could be other substances that are responsible. We now know the illicit market is using vitamin E acetate to dilute their products, but they could use other harmful chemicals in the future. To reduce the risk of lung injury, consumers should purchase vaping products from the regulated market, where products are tracked and tested.

Because there is still so much research to be done, I recommend that anyone who continues to use e-cigarettes or vaping products should monitor themselves for symptoms related to EVALI and see a healthcare provider as soon as possible, especially if you are experiencing the symptoms below.

Patients have reported symptoms such as:
- Respiratory symptoms, including cough, shortness of breath, or chest pain;
- Gastrointestinal symptoms, including nausea, vomiting, stomach pain, or diarrhea; and
- Nonspecific constitutional symptoms, like fever, chills, or weight loss.
- Exposure to COVID-19, testing positive or hospitalized and placed on a ventilator
Some patients have reported that their symptoms developed over a few days, while others have reported that their symptoms developed over several weeks.

The American College of Cardiology also released Cardiac Guidelines for cardiac implications of COVID-19, which may mimic respiratory symptoms.

As I mentioned earlier, the FDA previously stated that vapers were at an elevated risk of developing complications tied to COVID-19. However, the FDA also admitted there is actually no “evidence” that vaping makes COVID-19 outcomes worse as noted in this article outlining the FDA’s stance on vaping and COVID-19.

So the jury is out and we are still waiting for evidence on the long term safety of vaping. As a member of NCIA and the Scientific Advisory Committee, I believe that vaping and it’s long term effects due to acute and chronic exposure remains an urgent and ongoing research question. Is vaping safe, does vaping cause higher risk if you contract the novel coronavirus, and do synthetic flavorings, diluents, or possible contaminants within vaping devices cause harm? More research is warranted.

NCIA Policy Council Publishes New Safe Vaping Recommendations Report

by Morgan Fox, NCIA Director of Media Relations

In September of last year, reports began surfacing of mysterious respiratory illnesses generally associated with the use of vape cartridges, including those containing cannabinoids. Over the following months, reports of these cases climbed to more than 2000 nationwide, including more than 50 deaths. The Center for Disease Control and state health agencies struggled to determine the proximate causes, but it became increasingly clear that the vast majority of these cases were linked to unregulated cannabis vape products. As the focus began to narrow on the presence of Vitamin E acetate and other additives in unregulated products, NCIA and members of the industry urged producers, regulators, and lawmakers to take steps to prevent the use of these substances in vape cartridges and enact changes that would make legal, licensed, and tested products competitive with illegal market products that were making people sick.

New reports of this illness – called EVALI – have slowed, and the CDC has ended its official state of emergency related to vaping. However, there is still significant confusion on the part of stakeholders and the government about how to avoid similar issues in the future and the huge causal role prohibition played in this outbreak. In an incredibly misguided statement earlier this month, the CDC even lumped all “commercial” sources for vape cartridges together as a source for one sixth of the harmful products, despite only a handful of links to regulated businesses out of thousands of cases. This is especially troubling for states like California, where no cases were linked to regulated businesses and where unlicensed storefronts greatly outnumber those with licenses. Equating licensed, regulated businesses to those operating without oversight or regulations completely misses the mark and creates a dangerously inaccurate set of assumptions that could lead to even worse public health issues in the future.

As such, NCIA is proud to be releasing a thorough report on EVALI this week entitled “The Key to Consumer Safety: Displacing the Illicit Cannabis Market – Recommendations for Safe Vaping” which was produced by our Policy Council and informed by a variety of subject experts. This paper explores not only the additives that were the primary culprit but also potential areas for future concern such as heavy metals in vape cartridge manufacturing, potential problems caused by poor temperature control, and the use of certain types of flavorings and terpenes. It clearly lays out suggestions for both producers and regulators that will help avoid potentially dangerous products in the legal market, as well as ways to make sure that unregulated counterfeit products don’t make it into the hands of consumers. Just as important, this paper offers a guide on how states – as well as the federal government – can combat the illicit market by removing the onerous burdens placed on legal businesses, lowering barriers of entry to the industry and creating easier pathways for legacy businesses to become licensed, and exploring non-criminal methods to shut down illicit operators.

Whether you are a producer, regulator, policymaker or just concerned with public health and cannabis policy, this paper is an important tool for you. We ask that you please read and share it with your networks and urge your elected representatives at every level to explore and implement these evidence-based recommendations.

As members of the responsible cannabis industry, it is our duty to look out for the safety of cannabis consumers and shine a light on the policies that are bolstering the unregulated market.

As this paper concludes, the American consumer clearly wants cannabis products to be both accessible and legal. It’s time for the federal government to deschedule marijuana and regulate it like alcohol. Legalization through descheduling, regulation, and testing is the best path forward to keeping consumers safe. In the end, sensible regulation and a clear path to licensure and compliance will be the most compelling force in driving people from the illicit market to the state-legal market.