In part I of this series I made the case for how US Food and Drug Administration (FDA) regulation will help our industry make safer and effective medicines profitably. In this and upcoming installments I will take a detailed look at how FDA regulation will impact cannabis businesses. Expect to see changes in how we manufacture, formulate, and test our products. Regulation will also mean increased record keeping, and will impact how employees are hired and trained. In this installment, I discuss how the need for increased testing will impact extractors.

In a previous column I made the case for “cannabis is medicine, test it like medicine,” and promoted the use of the pharmaceutical industry testing paradigm in our industry (1). This paradigm requires what I call “cradle-to-grave” testing, meaning testing is not just required at the end of the manufacturing process, but at every point in the supply chain and at every manufacturing step.

If we were to follow the journey of a cannabidiol (CBD) molecule from being synthesized inside a cannabis plant to its presence in a tincture bottle, it might look something like this:

Grower ➡ Extractor ➡ Dispensary ➡ Customer

Of these four stages, the one where the most testing will be required is the extractor.

Many in this industry don’t like to think of it this way, but an extractor is a chemical manufacturer. They perform operations including extraction, precipitation, distillation, and dissolution, all of which are chemical processes. And yes, extractors are pharmaceutical manufacturers because they are making cannabis medicines. Let’s walk through the process that a typical manufacturer might go through to turn hemp into a medium-chain triglyceride (MCT) oil tincture and discover when and where testing will be done. If your process differs from this one, please try to imagine at which steps in your process testing should be done.

What Cradle-To-Grave Testing Looks Like for Extractors

The incoming hemp biomass will need to be analyzed by the full complement of tests that states have in place for final products. You should perform a cannabinoid profile on your raw plant material, to make sure you are getting what you paid for and to make sure this material is appropriate for the processing you are about to perform on it. You should also obtain a terpene profile on this biomass as terpenes are an important part of the user experience, and to make medicines consistently you need to know the amount of all the active ingredients in your raw material including terpenes. There exist methods for analyzing for cannabinoids and terpenes in biomass that are appropriate for in-house testing (2).

You will also want to test the biomass for pesticides. These materials are of course highly regulated (3). The problem with inhalable products is that it introduces pesticides directly into the bloodstream. Also, it is well known that some pesticides can concentrate during the manufacturing process. So, even if biomass has acceptable levels of pesticides, an extract or distillate made from it may be above legal limits, which is why it is important to test biomass for pesticides. Some methods for pesticide analysis in cannabis can be found in the literature (4–7).

Biomass should also be tested for heavy metals. Most states regulate the concentrations of the “four metals of the apocalypse:” arsenic, cadmium, mercury, and lead (8). These metals are highly toxic and have no useful biological function, hence the need to limit human exposure to them. The problem with cannabis is that it has been shown to bioaccumulate metals. So even if the water, soil, and other agricultural inputs have acceptable levels of metals, the plant may concentrate them until they are at unacceptable levels. This is why you can’t assume that metals testing on water and soil will predict the metals content of biomass, you have to test the plant material as well. There exist methods for analyzing for metals in cannabis plant material (9).

Biomass should also be tested for mold, fungi, mycotoxins, moisture, water activity, and anything else your state regulations require. In the pharmaceutical industry, incoming raw materials are tested extensively for identity, potency, and purity. We need to do the same in our industry. Why? Because the products we make are going into and onto human beings, so we need to do all within our power to protect the health and well being of our customers.

After purchasing biomass a processor will then typically extract it with a solvent to concentrate the cannabinoids and terpenes. Amongst the solvents used are hydrocarbons such as butane, ethanol, and supercritical CO

. Since the Food and Drug Administration (FDA) will require you to test after every manufacturing step, raw extracts need to be tested before being further processed. At this point a cannabinoid profile should be measured to see how efficient the extraction was. I have seen extractors use this data to optimize their extractions and increase yield by 10% to 20%. So not only is cradle-to-grave testing the right thing to do, it is also the profitable thing to do. There exist analyzers and methods for measuring cannabinoids and their stability in cannabis extracts (10,11).

Raw extracts are then often dissolved in ethanol and the resultant solution is placed in a freezer to precipitate the fats and waxes. These are then filtered out. While working as a laboratory director for a cannabis extractor, we found that the filtered fats and waxes contained 20–30% cannabinoids. That is a lot potential product and money to be throwing away. Testing the precipitate at this point allows optimization of the winterization process, reducing the amount of cannabinoids thrown away, ethanol used, and freezing conditions, thus increasing profitability.

After winterization we have a solution of cannabinoids in ethanol. We of course need to get rid of the ethanol, which is often times removed by rotary evaporation. The concern here is that we get rid of all the ethanol. Having the ability to test for residual solvents at this point is important to insure compliance with extant regulations. Also, when we go to distill a winterized extract if there is residual solvent present it will form bubbles and cause the liquid in the pot to “burp,” sending undistilled material up into the distillation column. This is best avoided. Methods exist for determining residual solvents in cannabis (12). After evaporation of the solvent, the winterized extract should be tested for cannabinoids to insure the process has been performed according to standard operating procedures.

Winterized extracts are often times heated to decarboxylate them. This reaction involves the carboxylic acid functional group of an acid cannabinoid splitting off a molecule of CO2 to yield the non-acid form. Here are two of the more important reactions:

The reason we do this is that the cannabis plant does not give us much tetrahydrocannabinol (THC) or CBD, the economically important cannabinoids, but their acid precursors tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA). The FDA will require testing throughout this process to make sure that decarboxylation is done in a controlled, safe, and reproducible fashion. It also makes economic sense to test for cannabinoids during this reaction to make sure it is performed to completion, and if you know when it is done you can save time, energy, and money. So, yet again testing is the profitable thing to do. Mid-infrared (IR) spectroscopy can be used to follow this reaction to completion (13).

At some extractors decarboxylation is performed by heating the biomass. As a chemist I have reservations about this as the plant material is chemically complex, and heating will produce all kinds of side reactions that may adversely affect the color and flavor of extracts made from this biomass. That is why I recommend to my extraction customers that they heat the winterized extract to decarboxylate rather than the biomass.

After winterization and decarboxylation our extract is now ready to be distilled to concentrate the cannabinoids. Winterized and decarboxylated extracts should be tested prior to distillation because they are a starting material and we want to know what we are putting in the pot to make sure it is of appropriate composition. Small amounts of distillate can be drawn off during the process and tested to make sure the distillation is going according to plan. Lastly, the final batch of distillate should be tested for potency to make sure the product made is within specifications. Methods exist to test distillate for cannabinoids (14).

Let’s imagine at this point we have a distillate that is 90% CBD and we want to make an MCT oil tincture out of it. First, the MCT oil itself must be tested for identity. My own work with IR spectroscopy has shown that the chemical composition of MCT oil varies greatly from vendor to vendor and batch to batch. Therefore, you need to invest in the ability to test MCT oil to make sure you are getting a quality and reproducible starting material. And since MCT oil is a raw material that goes into a product that will be ingested by human beings, the FDA will require it to be tested as well.

To make your tincture you may either weigh out the ingredients or dispense them by volume. In the case of weighing, you will need to have a balance that has been calibrated using what are called National Institute of Standards and Technology (NIST) traceable standards. NIST is the Federal government agency tasked with issuing standards and standard reference materials for US industry. There exist well established standards and methods for calibrating balances, or devices that dispense liquids by volume. You will need to make sure your balances and dispensers are calibrated in a NIST-consistent fashion to pass muster with the FDA.

Let’s say we finally have an MCT oil tincture that according to the weights used is 5 weight % CBD. At this point you will be expected to test this final product to make sure you have the CBD amount right. You will be required to test each batch of tincture, and you should test a representative sample of the tincture bottles you make as well. In-house compatible methods exist for tincture analysis (15).

As I have pointed out in the past, third party testing is not a substitute for in-house testing because it is too slow (1). Imagine you make a batch of extract and it must be tested before you can process it further. You could take a sample, send it out for testing, and wait days or weeks for results. In the meantime your extract is losing potency, taking up space, and not making you any money. If you had your own in-house cannabis analyzer you could get results in a few minutes, streamlining your manufacturing process.

However, third party cannabis laboratories still have a role to play. Regulations require that your final product be tested by a third party laboratory for testing to make sure it is compliant with applicable laws and label claims. This battery of tests may include a cannabinoid profile, terpenes, pesticides, heavy metals, and so forth.

A recent informal survey I saw showed that upwards of 2/3 of extractors are not doing any in-house testing. This is crazy for two reasons. First, by not doing in-house testing you are losing money as indicated above. Secondly, by not testing you will not produce a consistent product. This product will more often disagree with your label claims, meaning it will more often fail compliance testing. This will drive up your costs since you have to re-test, remediate, or scrap your product.

Be Prepared to Set Up a Testing Laboratory

Because of the need for significant amounts of in-house testing, all extractors should set up an in-house testing laboratory. In a perfect world where money is no object, I would like to see all cannabis businesses have the ability to test for cannabinoids, terpenes, pesticides, and heavy metals amongst other things. The reality of course is that this is terribly expensive. Pesticide analyzers can cost more than $500k, and heavy metals testers can cost over $200k, so these are not practical for most cannabis businesses. However, there exist cannabis potency analyzers that cost around $25k that are capable of giving a cannabinoid profile on a wide variety of samples (16). When advising cannabis businesses who are building out an in-house laboratory, I recommend that they start with a potency analyzer. As you saw above, potency testing is the most informative and most often type of in-house testing performed. In fact, advice on how to build out a laboratory would make for a good future column.

FDA regulation means that cannabis extractors need to think of themselves as pharmaceutical manufacturers and act accordingly. This includes cradle-to-grave testing. We walked through a typical extraction process, and saw the need for testing biomass, raw extract, winterized extract, the decarboxylation reaction, distillates, and final products. We also discussed the role of third party laboratories in all this, and the practicality of cannabis businesses setting up their own analytical laboratories.

California Bureau of Cannabis Control Regulations, Section 5719.

R. Jordan, L. Asanuma, D. Miller, and A. Maherone, 

A. Dalmia, E. Cudjoe, T. Astill, J. Jalali, J. Weisenseel, F. Qin, M. Murphu, and T. Ruthenberg, 

https://govt.westlaw.com/calregs/Document/I1362951A423B4B44BCD7D0698108A1D4?viewType=FullText&originationContext=documenttoc&transitionType=CategoryPageItem&contextData=(sc.Default)&bhcp=1

https://www.perkinelmer.com/lab-solutions/resources/docs/app_nexion_icp_ms_titan_mps_heavy_metals_in_cannabis_014714_01.pdf

https://www.agilent.com/en/solutions/cannabis-hemp-testing/residual-solvents-testing-for-cannabis-hemp

B.C. Smith, C. Fucetola, K. Erhmentraut, and T. Hagan, 

,is Founder, CEO, and Chief Technical Officer of Big Sur Scientific. He is the inventor of the BSS series of patented mid-infrared based cannabis analyzers. Dr. Smith has done pioneering research and published numerous peer-reviewed papers on the application of mid-infrared spectroscopy to cannabis analysis, and sits on the editorial board of 

. He has worked as a laboratory director for a cannabis extractor, as an analytical chemist for Waters Associates and PerkinElmer, and as an analytical instrument salesperson. He has more than 30 years of experience in chemical analysis and has written three books on the subject. Dr. Smith earned his PhD on physical chemistry from Dartmouth College.

Articles

Cannabis Analysis 

How will the need for increased testing impact extractors?

The FDA is Coming…Will the Cannabis Industry Be Ready? Part II: In-House Testing for Extractors

As refinement methods grow in the world of cannabis extracts, here we explore various refinement methods for removal of plant waxes from cannabis extract.

More than 400 chemical compounds have been identified in the cannabis plant (Figure 1). Some of these compounds are targeted during extraction and others, such as waxes, are extracted alongside the targeted compounds. Plant waxes are composed of a variety of compounds, such as fatty acids, hydrocarbons, esters, lactones, and alcohols (1). Most plants, including cannabis, produce waxes that exist on the plant’s surface. The purpose of the plant’s wax layer is to modulate hydration and protect the plant’s exposed surface (2). The cannabis wax layer is easily soluble in many solvents that are used for cannabis extraction, such as supercritical CO

, ethanol, and hydrocarbon extraction. While waxes prove to be useful to plants, they are often an undesirable by-product of extraction methods. Waxes dramatically impact the viscosity as well as the complex chemical profile of cannabis extract.

The viscosity, clarity, and flavor of cannabis extracts are all distinct characteristics of the various concentrate products found in the cannabis marketplace. Currently, the primary wax fractionation process in the industry is called 

Winterization is the process of removing fats and waxes from botanical oils to prevent crystallization of certain compounds in the oil.

Not only does the winterization process reduce the viscosity of an extract, it also increases the concentration of other desirable compounds such as cannabinoids and terpenes. The winterization process involves mixing crude extract with organic solvents like high-proof ethanol over heat to dissolve the extract (Figure 2). Once dissolved, the ethanol–extract solution is frozen to facilitate crystallization of the waxes. Once thoroughly frozen, the solution is processed through vacuum filtration to separate wax solids from the oil–ethanol solution.

As cannabis and hemp operations have begun to scale up, pressure has increased on advancements in winterization and filtration technology. Winterization continues to be a bottleneck in the refinement process. Extraction operators have continuously developed more selective extraction methods to fractionate the wide range of cannabis compounds. These methods are moving closer to selective separation of desirable from undesirable components. However, refinement processes of some fractions are still used to meet quality, consistency, and efficiency standards. For example, “wax fractions” would be winterized to extract any cannabinoids that may still be in the fraction to ensure all cannabinoids are captured in the process. The various desirable fractions would then be mixed together or used separately to create final products.

Ethanol extraction equipment manufacturers have innovated by significantly lowering extraction temperatures as well as sequentially linking extraction and post-processing steps into one unified system. Reducing extraction temperature has increased the extraction efficiency by selectively extracting cannabinoids and leaving behind undesirable compounds such as wax and chlorophyll. Full service processing equipment, which would sequentially complete extraction, winterization, filtration, and solvent evaporation in one piece of equipment, has continued to rise in popularity. This significantly reduces hands-on labor and has amplified efficiency from start to finish.

The aforementioned full service ethanol processing equipment model has not yet been successfully implemented in other extraction methods. However, I believe in the very near future supercritical CO

 extraction equipment manufacturers will have the technical capability to selectively filter wax from the raw CO

 cannabis extract within the supercritical CO

 system itself. This may be implemented via in-line filtration paired with improved selective fractionation capability, but all of this has yet to be seen.

Finally, centrifuge technology has continued to surface as an option for selective separation of waxes from cannabinoid and terpene fractions. Using centrifugal force, heavy waxes are pulled to the bottom of the vessel physically separating the chemical components. However, the cost of a centrifuge large enough for efficient operations is a significant investment. This technology requires massive up-front capital costs with a long return on investment (ROI) time line.

After reviewing the various methods of wax fractionation, it is clear that time, equipment costs, and operating costs play a significant factor in deciding which method to implement in daily operations at cannabis and hemp facilities. Due to the relatively minimal investment in standard vacuum filtration, it continues to be the primary wax fractionation method to date. I am eager to see the technology strive to improve wax fraction purity and overall process efficiency as this industry develops.

(5), 539-48 (2005). doi: 10.1016/j.lfs.2005.09.011. Epub 2005 Sep 30. PMID: 16199061.

(2), 1120-1129 (2012). doi:10.1104/pp.112.198473.

H. Zhong‚ M. Watanabe, H. Enomoto‚ F. Jin‚ A. Kishita‚ T.M. Aida, and R.L. Smith, Jr., 

https://doi.org/10.1021/acs.energyfuels.6b00310

 is the founder, CEO, and Chief Extractor of Heylo. With a background in chemistry and clinical research, Lo was inspired to explore cannabis as a medicine and to enter the emerging industry. She joined Eden Labs, a leading CO

 extraction equipment manufacturer to support and expand a Research and Development department. There she managed the development of their latest and greatest CO

 extraction system. In 2017, after working with Eden Labs and another cannabis processor, Lo launched Heylo with a mission to help people get more out of life with cannabis.

Extraction Science

Here we explore various refinement methods for removal of plant waxes from cannabis extract.

Methods and Advancements in Wax Fractionation from Cannabis Extract

Given the magnitude of the energy use in cannabis cultivation operations, resource benchmarking is especially important. Benchmarking is commonly performed for commercial and industrial buildings and is a crucial tool for determining baseline and efficient facility performance, allowing building managers and operators to measure facility performance year over year, and compare against similar properties. Cannabis operations are challenging to benchmark, but there are specialized tools that can measure key performance indicators (KPIs) for production and resource efficiency. By monitoring, quantifying, and ranking KPIs, cannabis businesses can become more efficient and competitive in changing markets. Understand what information to gather for cultivation operations, which KPIs are important, and how to interpret a performance benchmark.

Here you will learn what information to gather for benchmarking cultivation operations, which key performance indicators (KPIs) are important, and how to interpret a performance benchmark report.

Benchmarking is commonly performed for commercial and industrial buildings and is a crucial tool for determining baseline and efficient facility performance, allowing building managers and operators to measure facility performance year over year, and compare against similar properties. Given the magnitude of the energy use in cannabis cultivation operations, resource benchmarking is especially important. Just like financial benchmarking enables a comparative assessment of a firm’s performance, so does resource benchmarking for production processes.

Cannabis operations are challenging to benchmark, but there are specialized tools that can measure KPIs for production and resource efficiency. By monitoring, quantifying, and ranking KPIs, cannabis businesses can become more efficient and competitive in changing markets.

Resource Benchmarking Evaluates Competitive Performance

Established cultivators in various markets may be managing high operational expenses because of geographic region and real estate costs, site location and associated energy sources and suppliers, building type, and building systems such as lighting, heating, ventilation, and air conditioning (HVAC), and dehumidification. As businesses evaluate the cost-effectiveness of their 

 (1), resource benchmarking is a key pathway to assessing the operating capabilities of growers and cannabis businesses. With energy and water costs making up almost half of the total operating expenses and consumer interest in corporate action on climate change and environmental and social responsibility increasing, measuring and reporting resource efficiency is increasingly critical.

What gets measured gets managed. Resource benchmarking is the process of tracking and reviewing a property’s annual energy and water use over time in relation to itself or other buildings. Like stepping on a scale, energy benchmarking is the first step in a strategic energy management process (2).

Cannabis cultivation facilities are industrial and agricultural buildings, and are challenging to benchmark using traditional tools because of the diverse production activities performed within. Effective benchmarking for productive and profitable cannabis cultivation operations requires a specialized and vetted tool offering KPIs with a transparent and standardized calculation methodology. In commercial buildings, the U.S. Department of Energy’s 

 is often used to measure energy use intensity (EUI), a KPI measuring whole-building energy use in units of kBtu per gross square foot of building area.

To walk the walk of efficient production, operators must learn how efficiently they currently produce cannabis and use energy and water to establish a baseline. Continuously measuring against baselines on a recurring basis enables operators to measure and report performance as they improve efficiency over time. Benchmarking EUI for buildings and processes is crucial for determining baseline and efficient facility performance. Controlled environment agriculture processes are more challenging to assess using a metric based on building area alone (EUI), and production-oriented metrics are essential to include so competitive performance from operation to operation can also be understood on a basis of resource consumption per unit of final product.

Operators engaged in strategic energy management processes can compare facility energy and water efficiency and productivity values year-over-year for the same building—comparing you against yourself—and between buildings of the same type—comparing you against your peers to learn how changes in operational procedures, retrofit projects, and expansion into new space is affecting your bottom line.

Cannabis PowerScore: Specialized Benchmarking for Cannabis

As a non-profit advocacy organization, Resource Innovation Institute (RII) cultivates resource efficiency for a better agricultural future, and part of our mission includes providing objective, brand-agnostic education to the cannabis industry (3). A key element of RII’s market transformation work is our Cannabis PowerScore resource benchmarking platform (4). In 2017, RII brought together its initial Technical Advisory Council of cultivators, design and construction partners, and energy efficiency engineers to determine how to quantify the energy performance of cannabis cultivation operations. The group advised the development of the Cannabis PowerScore benchmarking platform and established cannabis-centric KPIs evaluating resource efficiency and productivity.

The Cannabis PowerScore benchmarking platform is a free, non-profit, peer-reviewed, and confidential suite of tools designed by and for cultivators and their construction partners. Detailed facility information is never sold or shared with anyone without consent. RII has built trust as an objective source of information about resource efficiency in cultivation operations and Cannabis PowerScore is used by hundreds of facilities throughout North America.

While individual facility information is anonymized, RII analyzes the aggregate Ranked Data Set to inform governments, utilities and industry leaders who share an interest in advancing producer efficiency with quarterly resource benchmarking reports (5). Ultimately, trends from PowerScore and these reports will help the industry establish standards and a leadership recognition system.

Key Performance Indicators for Efficiency and Productivity

The PowerScore platform includes a survey, visualizations, and dashboards for competitive performance reporting at the facility and portfolio level. The survey calculates comparative efficiency performance metrics using submitted facility details including building construction, building systems, and annual resource usage and production.

At the facility level, PowerScore provides a Performance Benchmark report for each year of facility performance that summarizes resource efficiency and productivity KPIs and an overall Facility Ranking against operations from the Ranked Data Set growing in similar environments (see Figure 1). Facility Ranking is a proxy for overall resource efficiency performance, and provides a holistic apples-to-apples comparison of cultivation facility competitiveness across similar cultivation approaches.

Performance Benchmarks report calculated KPIs for energy, water, waste and, soon, carbon emissions. Energy KPIs modify traditional EUI by using flowering canopy area instead of gross building area. Annual cannabis flower production is used to create new productivity KPIs by dividing production totals by annual consumption of energy and water and generation of waste.

Facility energy and water efficiency and productivity are critical KPIs that can measure both business competitiveness and brand risk:

 Annual energy use per square foot, in units of kBtu/sq. ft. of flowering canopy; energy use includes all energy sources such as electricity, natural gas, delivered fuels, backup generation, and renewable energy generation. A lower value is better; a higher value is worse.

 Efficiency of annual produced grams of dried cannabis flower per kBtu of total (all fuels) annual energy use using a facility’s annual production and whole-facility energy consumption totals. A higher value is better; a lower value is worse.

 Annual water use per square foot, in units of gal/sq. ft. of flowering canopy. A lower value is better; a higher value is worse.

 Efficiency of annual water use
in units of annual produced grams of dried cannabis flower per gallon. A higher value is better; a lower value is worse.

At the portfolio level, groups of facilities using similar cultivation approaches can be grouped together and compared against peer operations in the Ranked Data Set using competitive performance reports. Figure 2 is summarizing electric facility energy efficiency for several indoor, greenhouse, and outdoor operations (orange bars) and comparing them against the relevant groups of facilities in the Ranked Data Set (green bars).

Baselines for Electric Facility Energy Efficiency and Productivity

The Ranked Data Set of PowerScore helps cultivators understand baseline resource efficiency and productivity, and describes average performance among US producers in early regulated states to establish baselines for KPIs for comparisons and competitive reports. As more facilities benchmark with PowerScore, comparisons by climate zone will become feasible for even more accurate KPI comparisons across peer groups. Table I lists the 151 operations currently recorded in the Ranked Data Set and their average KPIs in October 2020.

Benchmarking Operations Using High-Performance Equipment

Success stories from the PowerScore Performance Benchmark reports are revealing the promise of efficiency investments. KPIs for some facilities seem to validate that certain techniques and technologies are driving efficiency. As one leading-edge example, an Oregon facility underwent a retrofit from high pressure sodium vapor (HPS) to light emitting diode (LED) lighting, which resulted in a 68% improvement in electric facility energy efficiency (g/kBtu).

Analysis of the aggregate Ranked Data Set suggests that most facilities, regardless of legacy equipment installed, have the opportunity to save at least 30% of energy expenses through efficiency measures. A recent RII benchmarking report showed that indoor cannabis cultivation operations growing with LED for flowering achieve 34% better average electric facility efficiencies and 80% better average electric production efficiencies than indoor facilities using double-ended (DE) HPS lighting for the flowering growth stage. However, some operations using LED lighting solutions perform better than other LED facilities due to cultivator techniques and actual environmental conditions in grow rooms.

Performance variability results from contributions of several factors including the quality of the lighting system, lighting controls, the limitations of the site, or the actions of the cultivator. Most long-term cannabis cultivators need to learn how to evaluate the state-of-the-art LED lighting solutions available on the market today and adapt to effectively install and operate them. Others are bound by the ability of their building’s HVAC systems to condition the internal space despite the quality of the building envelope, ductwork and piping, and ventilation equipment.

Producing cannabis efficiently with high-performance equipment like LED lighting systems is possible if cultivators and facility operators measure KPIs on a quarterly or annual basis. Benchmarking helps cultivators learn how they currently perform, and how they compare against their baseline performance benchmark and the average performance benchmarks of cultivators growing like them to quantify the benefits of efficient technology and prove the value of projects to investors. Get started on your efficiency journey at CannabisPowerScore.org.

https://www.cannabissciencetech.com/view/hvacd-controls-for-plant-health-product-quality-and-energy-efficiency-in-cultivation-and-drying-processes

https://www.burlingtonelectric.com/benchmarking

https://resourceinnovation.org/press-release/study-of-cannabis-energy-use-shows-indoor-cultivation-operations-using-led-lighting-demonstrate-better-efficiency/

, is the Technical Director of RII and manages the organization’s Technical Advisory Council. She is an LED-lit home cultivator. While serving Burlington Electric Department customers, she incentivized horticultural LED lighting equipment through energy efficiency programs, and has commissioned LED lighting designs and installed systems in commercial and industrial buildings, including greenhouses used for academic research on hemp and other cultivars. She authored the RII 

Best Practices Guides on HVAC and LED Lighting for Cannabis Cultivation and Controlled Environment Agriculture.

 She has a B.S. in Architectural Engineering from the University of Wyoming and an M.S. in Civil Engineering from Stanford University. She is a licensed Civil Professional Engineer in California and Vermont.

The Cultivation Classroom

Understand what information to gather for cultivation operations, which KPIs are important, and how to interpret a performance benchmark.

Resource Benchmarking for  Competitive and Efficient Cannabis Cultivation and Production Processes

Since the introduction of the first commercially available flame atomic absorption spectrophotometer (FAAS) in the early 1960s, there has been an increasing demand for better, faster, easier-to-use, and more flexible trace element instrumentation. A conservative estimate shows that in 2019, the market for atomic spectroscopy-based instruments was well in excess of $1 billion in annual revenue, and that doesn’t include after-market sales and service costs, which could increase that number by an additional $500 million. As a result of this growth, we have seen a rapid emergence of more sophisticated, easier-to-use equipment. Moreover, with an increase in the number of manufacturers of atomic spectroscopy instrumentation and its sampling accessories, together with the availability of traditional solid sampling techniques—such as X-ray fluorescence (XRF) and newer techniques such as microwave-induced optical emission spectroscopy (MIP-OES), laser induced breakdown spectroscopy (LIBS), and laser ablation laser ionization time-of-flight mass spectrometry (LALI-TOFMS)—the choice of which technique to use is often unclear. It also becomes even more complicated when budgetary restrictions allow only one analytical technique to be purchased to solve a particular application problem. This article takes a look at the major atomic spectroscopy techniques and compares their performance characteristics and, in particular, examines the limits of quantitation for the four heavy metals (lead [Pb], aresnic [As], cadmium [Cd], and mercury [Hg]) currently being regulated in cannabis and hemp by most states in the US. Note: A more expanded version of this article can be found in my book, 

Measuring Heavy Metal Contaminants in Cannabis and Hemp

To select the best technique for a particular analytical problem, it is important to understand exactly what the problem is and how it is going to be solved. For example, if the requirement is to monitor copper at percentage levels in a copper plating bath and it is only going to be done once per shift, flame atomic absorption (FAA) would adequately fill this role. Alternatively, when selecting an instrument to measure 24 elemental impurities in pharmaceutical products according to 

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use

) Q3D Guidelines (4), this application is clearly better suited for a multielement technique such as inductively coupled plasma-optical emission spectrometry (ICP-OES) or inductively coupled plasma-mass spectrometry (ICP-MS). However, if the demand is for four heavy metals in cannabis or hemp the decision is not so clear. ICP-MS could be the most suitable technique, but depending on the state maximum limits, the cannabis product being tested, the sample workload, or budgetary restrictions, other techniques such as graphite furnace atomic absorption (GFAA) or vapor generation atomic fluorescence (VGAF) might be the best fit.

So when choosing a technique, it is important to understand not only the application problem, but also the strengths and weaknesses of the technology being applied to solve the problem. However, there are many overlapping areas between the major atomic spectroscopy techniques, so it is highly likely that for some applications, more than one technique would be suitable. For that reason, it is important to go through a carefully thought-out evaluation process when selecting a piece of equipment (5).

The main intent of this article is therefore to look at measuring the big four heavy metals in cannabis and cannabis products to offer some insight as to which might be the most suitable atomic spectroscopic approach. We will not be discussing XRF, MIP-OES, LIBS, or LALI-TOF-MS techniques in this evaluation. They are all very useful techniques for many sample types and have been described at length in the open literature (6, 7). Chapter <233> does allow the use of an alternative technique, as long as it meets the validation and verification protocols described in the analytical procedure section. In fact it has been shown that XRF is a valid technique to use as a screening tool to reduce the number of samples that need to be analyzed by one of the spectrochemical techniques (8). However for the purpose of this comparison, we will be focusing on the most commonly used atomic spectroscopy techniques—flame atomic absorption (FAA), GFAAA, hydride generation atomic absorption (HGAA), VGAF, ICP-OES, and ICP-MS.

The fundamental principles of these four techniques are represented in Figure 1.

FAA is predominantly a single-element technique that uses a flame to generate ground-state atoms. When light in the form of a hollow cathode or electrodeless discharge lamp is passed through this atom cloud, specific wavelengths of light are absorbed that are characteristic of the metal of interest. The amount of light absorbed is indicative of the amount of analyte present. Flame AAS is capable of low parts per million (ppm) detection limits.

HGAA is a very useful analytical technique to determine the more volatile, hydride forming metals, such as As, Bi, Sb, Se, and Te. In this technique, the analytes in the sample matrix are first reacted with a very strong reducing agent, such as sodium borohydride to release their volatile hydrides, which are then swept into a heated quartz tube for atomization. The tube is heated either by a flame or a small oven that creates the ground state atoms of the element of interest, which are then measured by atomic absorption. HGAA is capable of approximately three orders of magnitude lower detection limits than FAA for the hydride forming elements.

Cold vapor atomic absorption (CVAA): The determination of elemental mercury can also be carried out using reduction chemistry. This is known as the cold vapor (CV) technique and by generating elemental mercury in the form of a vapor; it can improve the detection for mercury over FAA by up to 4 orders of magnitude. It should also be pointed out that dedicated mercury analyzers using atomic fluorescence are capable of even lower detection limits.

Atomic fluorescence (AF) coupled with hydride generation (HG) or cold vapor generation (VG) can also be used to improve the detection capability of the volatile elements. Atomic fluorescence shares properties with atomic absorption in that it has a light source, atomizer, monochromator, and detector. The element specific light energy is absorbed, taking the element through excitation. However, rather than determining the amount of light being absorbed by the element in the atomizer, as the excited atoms return to ground state, they emit photons of light and the emission (or fluorescence) resulting from the decay is measured. The major difference is the element specific light source is at an angle so as not to interfere with the fluorescence process. To carry out multielement analysis using AFS, many lamps are positioned around the atomization or excitation source. Atomic fluorescence coupled with hydride or vapor generation can improve the detection limits compared to FAA by up to 3–4 orders of magnitude, but with the added benefit of being multi-element, based on the number of lamps around the excitation source. There are in fact commercially-available vapor generation AF systems on the market, which are being used for the measurement of Pb, Cd, As, and Hg in cannabis samples (9, 10).

GFAA is also a single element technique, although some multielement instrumentation is now available. GFAA works on exactly the same principle as FAAS, except that the flame is replaced by a small heated graphite tube to generate the source of atoms. Because the ground state atoms are concentrated in a smaller volume than a flame, more light absorption takes place resulting in detection limits approximately 100–1000 times lower than for FAAS.

ICP-OES is a multielement technique that uses an extremely hot plasma source to excite atoms to the point where they emit wavelength-specific photons of light, characteristic of each particular element. The number of photons produced is directly related to the concentration of that element in the sample. ICP-OES instrumentation comes in two configurations, radial and axial. The radial configuration uses a traditional vertical plasma source where the emitting light is viewed from the side, whereas the axial configuration uses a horizontal plasma, where the light is viewed directly down the center. The benefit of the axial design is that more photons are seen by the detector and as a result offers 5–10 lower detection limits than the radial configuration. ICP-OES is capable of low parts-per-million to parts-per-billion detection limits.

ICP-MS also uses a plasma source. However, the fundamental difference between ICP-OES and ICP-MS is that the plasma is not used to generate photons of light, but to generate positively-charged ions. The ions produced in the plasma are transported and separated by their atomic mass to charge ratio, using a mass spectrometer. The generation of such large numbers of positively charged ions allows ICP-MS to achieve detection limits for most elements at the parts-per-trillion level.

There is no question that the multielement techniques like ICP-OES and ICP-MS are better suited for the determination of the elements defined in 

Chapter <232>, especially in laboratories that are expected to be carrying out the analysis in a high throughput, routine environment. If the best detection limits are required, ICP-MS offers the best choice followed by GFAA. Axial ICP-OES offers very good detection limits for most elements, but generally not as good as GFAA. Radial ICP-OES and FAA show approximately the same detection limits performance, except for the refractory, rare earth, and transuranic elements, for which performance is much better by ICP-OES. For Hg and those elements that form volatile hydrides, such as As, Bi, Sb, Se, and Te, the HGAA or VGAF techniques offer exceptional detection limits. Figures 1 and 3 and Table I show an overview of the detection capability, working analytical range and sample throughput of the major atomic spectroscopy approaches, which are three of the metrics most commonly used to select a suitable technique.

This is not meant to be a detailed description of each technique, but a basic understanding as to how they differ from each other. Let’s now turn our attention to selecting the best technique based on the demands of the cannabis and hemp testing community.

Comparing an instrumental technique based on its performance specifications with simple standards is important, but it bears little relevance to how that instrument is going to be used in a real-world situation. For example, instrument detection limits (IDL) are important to know, but how are they impacted by the matrix and sample preparation procedure? So, what are the real-world method detection limits (MDL) and is the technique capable of quantifying the maximum concentration values expected for this analysis? And what kind of precision and accuracy can be expected if working close to the limit of quantitation (LOQ) for the overall methodology being used? Additionally, on the sample throughput side, how many samples are expected and at what frequency will they be coming into the laboratory? How much time can be spent on sample preparation and how quickly must they be analyzed? Sometimes the level of interferences from the matrix will have a major impact on the selection process or even the amount or volume of sample available for analysis.

Understanding the demands of an application is therefore of critical importance when a technique is being purchased, and particularly if there is a minimum amount of expertise or experience in house on how best to use it to solve a particular application problem. This could be the likely scenario in a cannabis testing laboratory that is being asked to check the four elemental contaminants in cannabis, or one of its many cannabinoid products. Because there are currently very few regulated methods available, the industry is turning to the highly regulated pharmaceutical industry for guidance. As a result, they use the new 

 Q3D Guidelines to carry out the measurements, which recommend the use of a plasma-based spectroscopic technique or any other atomic spectroscopy technique as long as it meets the validation protocols described in 

The expertise of the operator should never be underestimated because, if ICP-MS is being seriously considered, it generally requires an analyst with a higher skill level to develop rugged methodology free of interferences that can eventually be put in the hands of an inexperienced user to operate on a routine basis. It also requires someone with the knowledge of working in the ultra-trace environment where understanding contamination issues and laboratory cleanliness is of the utmost importance. This again is a real concern if the technique is being used by novice users who have limited expertise in running analytical instrumentation, which may be the case in the cannabis industry. So let’s take a closer look at the permitted daily exposure (PDE) limits defined in 

 Guidelines to understand what atomic spectroscopy techniques might best meet the demands of measuring the four heavy metals in cannabis. Note: PDE is defined as the maximum acceptable intake of elemental impurity in a pharmaceutical product per day.

 Chapter <233> is being adopted by most cannabis testing laboratories as the standardized methodology to test cannabinoid-based products for heavy metals. To get a better understanding of the suitability of the technique being used and whether its detection capability is appropriate for the samples being tested, it’s important to know the PDE limits for each of the four target elements and, in particular, what the 

 calls the J-value, as described in Chapter <233>. The 

 is defined as the PDE concentration of the element of interest (based on the suggested maximum dosage per day), appropriately diluted to the working range of the instrument, after the sample preparation procedure is completed. Let’s take Pb as an example. The PDE limit for Pb in an oral medication (or an orally-delivered cannabinoid product) defined in Chapter <232> is 5 µg/day.

Based on a suggested dosage of 10 g of the product/day, that’s equivalent to 0.5 µg/g Pb. If 0.2 g of sample is digested or dissolved and made up to 100 mL (typical for many cannabis samples), this equals a 500-fold dilution, which is equivalent to 1.0 µg/L. So the J-value for Pb in this example is equal to 1.0 µg/L.

The method then suggests using a calibration made up of two standards: Standard 1 = 1.5J, Standard 2 =
0.5 J. So for Pb, that’s equivalent to 1.5 µg/L for Standard 1 and 0.5 µg/L for Standard 2.

The suitability of a technique is then determined by measuring the calibration drift and comparing results for Standard 1 before and after the analysis of all the sample solutions under test. This calibration drift should be <20% for each target element. However, once the suitability of the technique has been determined, further validation protocols described in Chapter <233> including accuracy, detectability, specificity, repeatability, and ruggedness must be carried out to show compliance to the regulatory agency if required.

It should also be pointed out that no specific instrumental parameters are suggested in Chapter <233>, but only to analyze according to the manufacturer’s suggested conditions and to calculate and report results based on the original sample size. However, it does say that appropriate measures must be taken to correct for interferences, such as matrix-induced wavelength overlaps in ICP-OES and argon-based polyatomic interference with ICP-MS.

Let’s exemplify this by taking an analytical scenario of measuring four elemental contaminants (Pb, Cd, As, and Hg) in a cannabis product that is being regulated according to the 

 Q3D inhalation PDEs (many states use the inhalation maximum limits even though a cannabis product might be consumed orally because the inhalation values are much lower) and calculate the J-values for each heavy metal and compare them with the limits of quantitation (LOQ) for each technique to give us an assessment of their suitability. For this analytical scenario, we’ll take the LOQ for the technique as 10x the IDL. These LOQs were calculated by taking the average of published IDLs from three instrument vendors’ application material and multiplying them by 10 to get an approximation of LOQ. In practice, a method limit of quantitation is typically determined by processing the matrix blank through the entire sample preparation procedure and taking 10 replicate measurements. The method LOQ, sometimes referred to as the method detection limit (MDL), is then calculated as 3–7x standard deviations of these 10 measurements, depending on the % confidence level required.

To make this comparison valid, the sample weight was adjusted for each technique, based on the detection limit and analytical working range. So for AA, VGAF, and ICP-OES we based the calculation on a dilution of 2 g/100 mL (or 0.5 g/25 mL), whereas for ICP-MS we used 0.2 g/100 mL. AA and ICP-OES could definitely use larger sample weights, but for high throughput routine analysis, we are probably at the optimum dilution for ICP-MS. Tables II, III, and IV show the comparison of AA (FAA and GFAA), VGAF, ICP-OES, and ICP-MS, respectively, for four elemental contaminants in an inhaled cannabis product according to Chapter <232>. The relevant comparative data to consider is in the final column, labelled “Factor Improvement,” which is the J-value, divided by the LOQ. Generally speaking, the higher this number, the more suitable the technique is.

It should be emphasized again that LOQ in these examples is just a guideline as to the real-world detection capability of the technique for this method. However, it does offer a very good approximation as to whether the technique is suitable based on the factor improvement number compared to the J-values for each elemental impurity. Clearly, if this improvement number is less than 1, as it is with Pb and Cd by FAA, the technique is just not going to be suitable. Although, As and Hg could be improved using hydride or cold vapor techniques. On the other hand, GFAA would be suitable for all the heavy metals. However, the GFAA technique is very time-consuming and labor intensive, so it probably wouldn’t be a practical solution in a high throughput cannabis testing laboratory. On the other hand, VGAF looks to be very promising as the factor improvement for all four heavy metals is between 40 and 600. The comparison between FAA, GFAA, and VGAF is exemplified in Table II.

Table III shows that axial-ICP-OES doesn’t look to be a good candidate because aside from Cd, the factor improvements are all around 1 or less. These numbers could be further improved by using a higher sample weight in the sample preparation procedure without compromising the method, or possibly using a sampling accessory such as an ultrasonic nebulizer, which could improve the detection capability by a factor of 5–10 fold. (Note: As most commercial ICP-OES instrumentation offers both axial and radial capability, it was felt that the axial performance was most appropriate for this comparison.)

However, it can be seen in Table IV that ICP-MS shows significant improvement factors for all contaminants that are not offered by any other technique. The added benefit of using ICP-MS is that if and when the elemental suite expands to include other heavy metal contaminants, the additional workload should not pose too much of a problem. Additionally, if arsenic or mercury levels were found to be higher than the PDE levels, it would be relatively straight-forward to couple ICP-MS with high performance liquid chromatography (HPLC) to monitor the speciated forms of these elements if required.

It is important to understand that there are many factors to consider when selecting a trace element technique most suited to the demands of your application. Sometimes one technique stands out as being the clear choice, whereas other times, it is not quite so obvious. And as is true with many applications, more than one technique is often suitable. However, the current state regulations for cannabis products are based on a mix of 

 Chapter <232> inhalation and oral PDEs which presents some unique challenges, not only from a perspective of performance capability, but also because testing laboratories have to meet the validation protocols defined in 

 Chapter <233> to show suitability of the technique to the analytical procedure being used. From a practical perspective, there is no question that to meet the lowest limits for inhaled products (used by many state regulators) ICP-MS is probably the most appropriate technique, followed closely by VGAA. For oral cannabis products or transdermal applications, where the maximum limits are higher, axial-ICP-OES combined with performance enhancing sampling accessories could offer a more cost-effective approach. And if the sample workload requirements are not so demanding, GFAA could provide a solution, particularly as solid samples can be analyzed. However, ICP-MS has shown it has the detection limits and throughput capability to be the optimum technique of choice for these types of samples, particularly if the suite of required heavy metals expands at a later date because of stricter federal regulations.

 (CRC Press, Boca Raton, Florida, 2020) ISBN 9780367417376.

General Chapter <232> “Elemental Impurities – Limits,” 1st supplement to 

United States Pharmacopeia 40–National Formulary 35 (USP40–NF35)

 (United States Pharmacopeial Convention, Rockville, Maryland, 2017). 

https://www.usp.org/chemical-medicines/elemental-impurities-updates

General Chapter <233> "Elemental Impurities – Procedures," Second Supplement to 

United States Pharmacopeia 38–National Formulary 33

 (United States Pharmacopeial Convention, Rockville, Maryland, 2015). 

International Conference on Harmonization, 

ICH Guideline Q3D on Elemental Impurities: Step 5

https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-13.pdf

R.J. Thomas, "Choosing the Right Trace Element Technique: Do you know what to look for," 

Lumina 3500 Atomic Fluorescence Spectrometer, Aurora Illuminating Systems Elemental Analysis Instruments, 2020, 

https://www.aurorabiomed.com/wp content/uploads/2019/07/LUMINA_3500.pdf

PF7 Heavy Metals Analyzer, Persee Analytics Inc., 

http://perseena.com/index/prolist/pid/33/c_id/43.html

 is the principal of Scientific Solutions, a consulting company that serves the training, application, marketing, and writing needs of the trace element user community. He has worked in the field of atomic and mass spectroscopy for more than 45 years, including 24 years for a manufacturer of atomic spectroscopic instrumentation. He has served on the American Chemical Society (ACS) Committee on Analytical Reagents (CAR) for the past 19 years as leader of the plasma spectrochemistry, heavy metals task force, where he has worked very closely with the United States Pharmacopeia (USP) to align ACS heavy metal testing procedures with pharmaceutical guidelines. Rob has written almost 100 technical publications including five textbooks on the fundamental principles and applications of ICP-MS.

 is a Senior Applications Scientist with SPEX CertiPrep and a member of both the AOAC and ASTM committees for cannabis.

Navigating the Lab

This article takes a look at the major atomic spectroscopy techniques and compares their performance characteristics and in particular examines the limits of quantitation for the four heavy metals (Pb, As, Cd, and Hg) currently being regulated in cannabis and hemp by most states in the US.

Measuring Heavy Metals in Cannabis: What Atomic Spectroscopic Technique Is Right for Your Laboratory?

Good agricultural and collecting practice (GACP) guidelines and good manufacturing practice (GMP) guidelines each have the simple goals of protecting patients and ensuring that product quality is not compromised through the imposition of standardized practices and procedures in production processes. No business should risk jeopardizing product standards or the well-being of downstream consumers, and compliance with GACP and GMP can assist in avoiding such situations.

The use and application of GACP or GMP guidelines can differ depending on the intended use of the product in question and how each manufacturer defines its production processes. However, in relation to practical application and in terms of the requirements that each set of guidelines impose, there seem to be no substantive differences between the two regimes, other than the stage of the production process to which they are applied.

This article intends to clarify the main goals of each set of guidelines, to identify differences between the two, and also to explore why it is important, when operating within the medicinal cannabis sector, that these two guidelines are complied with and their standards achieved.

Good agricultural and collecting practices (GACP) guidelines were developed to create a single supranational framework to ensure appropriate and consistent quality in the cultivation and production of medicinal plant and herbal substances. They were developed by the World Health Organization (WHO) in 2003 with the aim of improving the quality of medicinal plants being used in herbal medicines in the commercial market.

Interest in herbal medicines has increased over recent decades and therefore the global market for medicinal herbs has grown rapidly. Consequently, the safety and quality of herbal medicines have become ever more important for both health authorities and consumers.

Production and primary processing of medicinal plants and herbal substances have a direct influence on the final quality of active pharmaceutical ingredients (APIs) produced and such production and primary processing actions can constitute the first step in the quality assurance process, which is central to compliance with the GACP guidelines. To achieve consistently reproduceable “starting materials of herbal origin” of an appropriate standard, an adequate quality assurance system for the collection or cultivation, harvest, and primary processing is required. The GACP guidelines provide a basis for homogenized national or regional standards for the cultivation and collection of medicinal plants and should therefore be viewed as an effective “working tool” whose benefits are to reduce waste, ensure quality of raw material, and gain market credibility.

GACP guidelines should always be read in connection with good manufacturing practice (GMP) guidelines for APIs. In addition, the basic principles of GMP such as the statement that “quality cannot be simply tested into a batch of product but must be built into each batch of product during all stages of manufacturing process” should be then extended to the GACP requirements (2). This interrelation is confirmed in the GACP statement (2): "The Guideline on good agricultural and collection practice does not fall directly under GMP guidelines in the traditional sense. However, these considerations should be used as a basis for the establishment of such an appropriate quality assurance system

 The combination of both requirements plays a huge role in achieving the right quality fit.

 (1) is the collection of rules and regulations governing medicinal products in the European Union and contains guidance for the interpretation of the principles and guidelines of good manufacturing practices for medicinal products for human and veterinary use. Part II of 

 sets out the basic requirements for “active substances used as starting materials.”

The goal of the GMP guide is to “provide guidance regarding (GMP) for the manufacture of active substances under an appropriate system for managing quality. It is also intended to help ensure that active substances meet the requirements for quality and purity that they purport or are represented to possess” (1). The guidelines do not apply to bulk-packaged medicinal products, but only to all other active starting materials that enter in downstream processing. As such these guidelines are applicable to medicinal cannabis operations that intend to produce APIs for sale to pharmaceutical companies.

All GMP recommendations are expected to be applied (unless shown to be inapplicable); this means that they are flexible in the way they are implemented if an equivalent level of quality assurance is ensured in relation to the operations carried out. The guidelines can therefore be adapted and customized, allowing for different types of models to be implemented to best fit the business in question, provided that all applicable chapters are addressed. The guidelines are not applicable to registration commitments nor intended to define registration or pharmacopeial requirements. 

 sets basic requirements for medicinal products; these apply to herbal products such as medicinal cannabis because of their often complex and variable nature, which requires a tight control of starting materials (1). Herbal substances that are destined to be used in pharmaceutical products must be of suitable quality and supporting data needs to be maintained to document satisfaction of the requisite quality standards. Ensuring consistent quality of herbal substances can require detailed information on its agricultural production and, therefore, the selection and source of seeds, cultivation process details, and harvesting conditions are important areas to cover and as stated in 

 of GMPs (Manufacture of Herbal Medicinal Products). “Recommendations on an appropriate quality assurance system for good agricultural and collection practice are provided in the HMPC [European Medicines Agency Committee on Herbal Medicinal Products] guidance document: Guideline on Good Agricultural and Collection Practice for starting materials of herbal origin;” in this way the GMP guidelines emphasize the utmost importance of GACP and recommend its use as a reference to build a proper quality system (1). This highlights the importance of GACPs and GMPs being implemented side-by-side in relation to medicinal cannabis production processes.

Application of GACP and GMP to Medicinal Cannabis Production

The pharmaceutical industry is one of the most demanding industries in the world in terms of compliance requirements and the production of medicinal cannabis is inextricably linked to such standards. To ensure downstream patient safety, all operators must work within good practice frameworks at all stages of their operations to ensure that the output is a high-quality, safe, reliable, and effective product. The consequences of failure are severe and regulators have the power to impose fines, close facilities, or even suspend licences in such circumstances. As such, it is imperative that a responsible producer in the medicinal cannabis industry complies with the applicable rules and standards in their operations.

 can have a broad range of meanings and connotations including being considered a drug substance of herbal origin, a drug product, an herbal medicinal product, a controlled drug substance, a controlled drug product, or a "raw material" from which medicinal products are prepared. Products containing cannabis can also range from medicines to therapeutic goods and food products.

Depending on how products will be used, different production standards can apply and in different jurisdictions, different legal regimes may apply (which can lead to inconsistent understanding and practices among drug regulators in different countries). Additionally, production standards should always be designed to take into consideration clients and final consumers' requirements and expectations for high quality products.

The usage and applicability of GACP and GMP guidelines may also change depending on the nature of the production process and the intended product use. As such, proper contextualization is very important when discussing production of cannabis products for medicinal purposes and the inter-relation with GACP and GMP guidelines.

In any case, where products are to be delivered into the medicinal market (whether as an active substance, an intermediate, or a finished product), GMP standards are mandatory and should be strictly followed; it is the manufacturer´s responsibility to ensure that the appropriate GMP classification is applied. The major objective for a manufacturer in applying GMP standards is to make sure that safety, quality, and efficacy of the product are not compromised, whilst also minimizing business risk.

Part II, “Basic Requirements for Active Substances used as Starting Materials

” of Volume 4 of the GMP guidelines was published (according to Article 46 (f) of Directive 2001/83/EC and Article 50 (f) of Directive 2001/82/EC; as amended by Directives 2004/27/EC and 2004/28/EC, respectively) new obligations were placed on authorized manufacturers to use only active substances that have been manufactured in accordance with GMP for starting materials (1). As a consequence, in the context of medicinal cannabis production, GMP guidelines and requirements will begin to apply at the initial extraction stage (that is, following harvest), until such time as the physical processing of the cannabis material and packaging, including labelling of the APIs is fully completed.

Depending on the manufacturer determination of a product´s intended usage and classification, a GACP product can be inserted in a GMP supply chain. In the context of medicinal cannabis production, this means that all stages in the cultivation process up to initial extraction will be subject to GACP guidelines (as illustrated in Figure 1). In practical terms, the manufacturer must nominate and document the rationale for the point at which production of the active substance begins and GMP requirements begin to apply. For extraction processes, this rationale should be established on a case-by-case basis since it is dependent on the type of manufacturing or process being used.

When considering cultivation and harvest processes—where human intervention is needed and manual operations often prevail—the risk of contamination is increased and in such circumstances, the choice to apply GMP standards before they become mandatory (that is, during the wet trimming and drying steps) can benefit manufacturers by separating operations into different risk classes and smoothing the transition from GACP regime to the GMP regime within the same facility. In practical terms this can be achieved by sectional separation inside the facility; one area can be fully dedicated to cultivation and harvesting of material and be subject only to the GACP requirements and a different area can be dedicated to primary processing and obtaining of APIs, subject to GMP requirements (regulated by Part II of the GMP guide). A third area for finished product manufacturing (regulated by Part I of the GMP guide) can also be created during the facility layout process. By creating physical separation and different zones, clarity is added to the type of operations being undertaken in each zone and the regulations that apply within each one.

As operations approach physical processing and packaging, which is the final step of active substance manufacturing, the stringency of GMP requirements in relation to the active substance manufacturing increase. The GMP regulations and requirements increase as the product gets closer to its final form because risks increase during this time. Compliance with these increasing requirements both protect patients from harm and can also be relied upon by manufacturers as a compliance “shield.”

In relation to the production of medicinal cannabis products, compliance with the requirements of GACP and GMP is mandatory. Whilst this is not an easy task, successfully achieving compliance will distinguish a manufacturer from competitors. Designing and implementing a competent quality assurance (QA) system will be vital in this regard.

The key aspects for an effective QA system include, amongst others, well-written standard operating procedures (SOPs), well informed personnel, and a clear understanding of roles and responsibilities of the personnel involved. The development of a culture that achieves high quality and standards throughout is also important. Quality will only be ensured when all business units work in cooperation, keeping product quality and patient safety as their primary goals.

Although we have seen that the different requirements apply at different stages in the production process, it is legitimate to query and endeavor to understand if there are any differences to distinguish GACP requirements from GMP requirements and whether one is more demanding than the other.

The simple answer to the first question is that no, there are not any significant differences. The concepts and controls within both regimes are intended to be the same. While GACP requirements are applied to cultivation and collective practices (outside of the pharmaceutical industry), GMP requirements encompass primary processing of cannabis material to transform raw materials into APIs and transform APIs into pharmaceutical products.

Both regimes have a goal of ensuring consumer safety by establishing appropriate quality standards for medicinal plants and herbal substances; each set of regulations addresses the same topics and disciplines (such as quality assurance, quality control, personnel, calibration, validation, and storage). It is fair to say that GMP standards do incorporate more detail on every topic than GACP standards, but in both cases the requirements are not overly prescriptive, but rather require interpretation.

The practice of incorporating herbal products into manufacturing within the pharmaceutical industry is not new, but in fact it is where the pharmaceutical industry took its first steps (botanical drugs such as 

 having been prevalent in pharmaceuticals for generations). Thus, the combination and inter-relation of the two different areas of agricultural cultivation and pharmaceutical production is unsurprising in relation to medicinal cannabis production processes, nor is the interplay and subtle shifts between the imposition of GACP and GMP rules, respectively.

Below is a brief comparison of aspects of GACP and GMP.

GMP and GACP guidelines set out similar requirements in relation to processing instructions for an herbal substance and require the process to be described in relation to each operation carried out upon the herbal substance (for example, GMP requires that drying time, temperatures, and all methods involved to control cut size or particle size should be described; the GACP requirements state that “all processes and procedures that could affect the quality of the product must be documented”). All processing steps must therefore be documented to ensure compliance from both GACP and GMP perspectives.

This article intends to clarify the main goals of GACP and GMP guidelines, identify differences between the two, and also explore why it is important, when operating within the medicinal cannabis sector, that these two guidelines are complied with and their standards achieved.

November/December 2020

The FDA is Coming…Will the Cannabis Industry Be Ready? Part II: In-House Testing for Extractors

Methods and Advancements in Wax Fractionation from Cannabis Extract

Resource Benchmarking for Competitive and Efficient Cannabis Cultivation and Production Processes

Measuring Heavy Metals in Cannabis: What Atomic Spectroscopic Technique Is Right for Your Laboratory?

GACP and GMP in the Medicinal Cannabis Industry—Is There a Clear Difference?

What the Hellth?! Research Project Shows How Grant Funding Has Focused on Cannabis Harms