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ABSTRACT
Many European Union (EU) countries have legalized or decriminalized the medical use of cannabis to some degree. The advent of broad acceptance of medical cannabis as public opinion shifts in the EU is driving the need for the cannabis industry to implement strict regulatory controls on the production of cannabis products. There is therefore a shift to implementation of GMP (Good Manufacturing Practices) in the cannabis space, most notably in Canada, where medical cannabis production has been legal since 2001 but regulated to a lesser extent than the GMP standard. Due to the lack of regulatory harmonization in the US, this shift to GMP standards for production is expected to impact the US market when medical cannabis laws become regulated federally. The interfaces of medical cannabis markets at the regulatory level is the subject of this article, as well as how GMP is being implemented in cannabis firms. The desire for global trade in cannabis will drive the regulatory compliance alignment to GMP in the future.
INTRODUCTION
Cannabis has been known by many names in society – marihuana, weed, ganja, grass, and others. Cannabis has a long history, having been used as far back as 8,000 BC1 to produce hemp fiber which was a burgeoning industry. Cannabis then went into a period of prohibition in most countries where it was classified as a controlled substance making growth, harvest, and use of the plant heavily restricted and criminal in most of the world. See below for a list of basic definitions related to cannabis.
Cannabis is simply a plant – it has a stiff upright stem known for the fiber, divided serrated leaves in the distinct 3, 5 or 7 leaf pattern, and glandular hairs containing trichomes. These trichomes are most concentrated on the flowers and are what give rise to cannabinoids. The two most recognized cannabinoids being THC (tetrahydrocannabinol) and CBD (cannabidiol), although there are over 113 recognized cannabinoids in the cannabis plant.
THC, being psychoactive, is what gave rise to the control over Cannabis. As society realized the psychoactive effects of this plant by smoking or ingesting THC, it increased popularity for recreational purposes which led to strict controls on cannabis. The percentage of THC is also how the distinction between Cannabis and hemp came to be, allowing the emergence of a hemp industry in some countries to take advantage of the industrial uses for the cannabis plant.
Both THC and CBD have numerous medical uses which have relatively recently been realized and continue to be studied. The discovery of the endocannabinoid system in 19883 is what launched the advent of research and later fueled the evidence-based push towards deregulation of the cannabis plant. This has opened some countries to recognizing the medical benefits of cannabis thus resulting in a change to the regulatory environment.
Cannabis Products Manufacturing Life Cycle
Medical cannabis can take on several forms, but all production starts with the cultivation of the plant. Figure 1 depicts a high-level process flow for growing and processing cannabis products. For medical cannabis this is typically done in indoor facilities that can be either retrofitted buildings, new indoor builds, or greenhouse-style grow areas. Some jurisdictions do allow outdoor grow; however, the use of outdoor grow will vary by country and climate. Countries, such as Columbia and Jamaica, already have a head start in the implementation of outdoor grow due to their optimal climate conditions allowing for successful crop cycles.
The cultivation, harvest, drying, and curing process can range from 4-6 months depending on the cultivar and growing methodology. Harvesting, drying, and curing are standard steps in the initial process, but the greatest variability is seen during processing. In Canada, processing can range from a simple product such as dried flower in a primary packaging container, to an extracted oil, to future products that include extracts, and to edible cannabis products that are food formulations4. The processing steps can add days or months to the product manufacturing process.
At each stage of the manufacturing process flow, regulations of the country dictate what controls must be put in place adding variability to the practices implemented for the production process. Each regulatory body must determine the method for regulation of production from cultivation through to processing. In addition, each regulatory body determines which products are allowed in their jurisdiction for medical/recreational use as well as for export.
The divergence of these regulatory regimes, product types, and need for international trade will require regimes to unite. The result is a compelling force for the industry to implement EU-GMP, particularly in Canada. At this moment, there is no such push in the US since no federal legislation exists for medical cannabis, however in the future the same forces will drive alignment.
The Regulatory Environment for Cannabis
The world regulatory status of cannabis is transforming, and the year 2018 was a great example of the emerging change. Several countries, including United Kingdom, Malta, and New Zealand, joined Germany, Canada, Greece and Australia in medical cannabis legalization. Europe is expected to continue the shift and to become the world’s largest legal cannabis market – projected to be worth up to €123b by 2028.5
Only a handful of countries/jurisdictions have legalized cannabis for recreational use: Uruguay in 2013, Canada in 2018 and ten US states. Luxembourg is projected to do so by 2023. Other jurisdictions have begun to shift their approach to cannabis by either decriminalizing (the offence is non-criminal) or de-penalizing (the offense is criminal but is not punishable) cannabis offenses. These markets have existed for some time, such as in the Netherlands and Spain, and more countries will continue to loosen the controls and penalties associated with cannabis. Decriminalization and depenalization are the starting point towards more lenient attitudes surrounding the legalization of cannabis.
While the world changes their legislative control on cannabis, we see the development of different regulatory regimes in these markets paralleling that which occurred with the evolution of regulatory standards for drug products. As Canada, US, and EU all independently regulated the drug supply chain, the results became a patchwork of regulations, and creation of trade barriers. The creation of the regulatory barriers in a global supply chain not only restricted cross-border movement of drugs, but also silos of information from regulatory inspections that were not shared between inspectorates resulting in inefficiencies. This led to a long period of time where the major markets worked towards a Mutual Recognition Agreement (MRA) for GMP across markets. The MRA has been operationally in effect since 2003 between Canada and the EU member states and has reduced many of those barriers and paved the way for a more cohesive market in participating countries.
For the cannabis industry, the same barriers are being created now. The implementation of GMP will become paramount in this industry to align international market participants to a known and accepted standard for medicinal products. Implementation of GMP alone will not solve the need for cross border inspections until cannabis is included in the scope of the MRA, and recreational products are addressed in international regulation.
DISCUSSION
Current regulatory regime: EU and the application of GMP
Medical cannabis is currently permitted in select EU jurisdictions, and those which have not yet legalized are likely to start with medical only. The regulatory approach has been led by several of the larger and first to legalize countries (such as Germany) and as such, pharmaceutical grade controls in production were an established requirement from the onset of medical cannabis legalization.
EU jurisdictions classified the product as medical and therefore looked to an already established standard – EudraLex The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use (“EU-GMP”).6 The EU-GMP standard provides guidance for the interpretation of the principles and guidelines of good manufacturing practices (GMP) for all medicinal products.
The choice of EU-GMP is particularly convenient because of the existence within EU-GMP of Annex 7 – Manufacture of Herbal Medicinal Products. This section of EU-GMP provides guidelines for the application of Good Agricultural and Collection Practices (GACP) versus the traditional application of GMP principles as applied to APIs and drug products derived from plant substances. This is precisely the category that cannabis fits into as the EU countries did not create a new standard when legalizing medicinal cannabis.
Figure 2 is an excerpt from Annex 7 of EU-GMP showing how conformance of the standard is applied to the manufacturing production process.
Major requirements of EU-GMP include Quality System Requirements, Personnel, Premises and Equipment, Documentation, Production, Quality Control, Outsourced Activities, Complaint/ Defect/ Recall and Self Inspection. These are the systems that must be considered and fully implemented in a cannabis production facility.
Current Regulatory Regime: Canada Implements GPP and GMP to Drive Trade
In Canada, cannabis is regulated by the Cannabis Legalization and Regulation Branch within Health Canada. Medicinal use of cannabis has been legal since 2001, whereas recreational use only since October 17, 2018. Canada initially created a construct referred to as GPP (Good Production Practices) for cultivation of medicinal cannabis. The standard evolved over time, and upon the legalization of recreational cannabis the same standard was applied. Today, the GPP framework governs the cultivation and processing of all cannabis products for both medicinal and recreational use.
Cultivation Facilities at Tantalus Labs
The Cannabis Regulations7 define the licence holder requirements for cannabis cultivation and processing facilities – those being Part 4 for Physical Security Measures and Part 5 for GPP. The major components of GPP include facilities and equipment, sanitation, quality assurance, quality control, record keeping, and security requirements.
The framework for GPP combines principles behind the regulation of a medical product with the regulation of a consumer good – which is unique in the world. There are no other jurisdictions that follow GPP. This uniqueness means that by following GPP alone, a Canadian cannabis firm is not able to compete in the cannabis world market because the regulations are at a mis-match to every other jurisdiction. This is the driving force for GPP Canadian facilities to implement a global standard, and with the emerging EU cannabis market, the logical step for Canadian firms is choosing to implement the EU-GMP standard.
Current Regulatory Regime: United States – No Standardization of Regulatory Requirements
While Canada and Europe have declared regulatory constructs for the domestic production of medical cannabis, the US has not yet done so at the federal level. Each state that does legalize is doing so on their own local requirements. For example, Nevada follows Nevada State Department of Taxation Regulation for Marijuana, whereas California follows the California Code of Regulations. All states do, however, follow the FDA Controlled Substances Act, and most have been incorporating GMP principles from the Code of Federal Regulations (CFR) into their regulations. Yet, there is no interstate alignment for regulatory standards.
If the US does move towards a federal legalization, there will be many hurdles to align regulations, both at the state level and internationally to compete with the world’s cannabis market. The US has yet to fully harmonize or share in the Mutual Recognition Agreement (MRA)8 with the EU for drug products, and if they choose the US CGMP as a federal standard for cannabis (i.e.:, 21 CFR Parts 210 and 211 – Current Good Manufacturing, Processing, Packing or Holding of Drugs; General and Current Good Manufacturing Practice For Finished Pharmaceuticals), further alignment for world trade will still be required.
IMPLEMENTATION OF GMP IN CANNABIS IN PRACTICE
Implementing EU-GMP in any facility requires deep knowledge of the multifaceted requirements that need to be put in place, as well as how to demonstrate compliance during an inspection. The inclusion of GACP means that the commercial horticultural practices along with the quality principles of the drug industry, will need to be combined requiring the skillsets from multiple disciplines.
The typical process for an implementation program includes:
- Confirming infrastructure meets the standard
- Define where in the operation GPP (if applicable) vs GACP vs GMP applies
- Quality Management System (QMS) updates
- Implementation of quality programs.
Confirming Infrastructure Meets the Standards
The implementation of GMP requires the site to accept the infrastructure requirements of EU-GMP which are much more prescriptive than GPP, and most other standards set by Annex 7 contains requirements for production areas, storage areas, and QC areas that are absent in GPP. If the facility is pre-existing, the ability of a site to address serious gaps in infrastructure requirements are limited from an engineering and cost perspective.
One example frequently observed, is the requirements in Section 3.11 of EU-GMP: “Drains should be of adequate size and have trapped gullies. Open channels should be avoided where possible, but if necessary, they should be shallow to facilitate cleaning and disinfection”6. Trapped gullies are often not a consideration in the retrofit or even new construction of a cannabis processing facility, yet when implementing GMP it is a requirement; if trapped gullies are not present risk mitigation needs to be implemented such as via a cleaning program.
Reviewing EU-GMP in detail finds many of these infrastructure related gaps that the firm must be aware of, must implement, and/or risk mitigate in a manner acceptable to a GMP Inspector.
Defining Where in the Operation GPP (If Applicable) vs GACP vs GMP Applies
Figure 1 has already outlined what main processes need to occur in a cannabis facility. The regulatory environment will then dictate the standards to be applied. Therefore, one of the first steps in implementing GMP is to ensure your facility is segregated appropriately, and that the flow of your personnel, materials, equipment, and product is conducive to achieving a controlled facility.
For example, a typical GPP facility implementing EU-GMP would choose to classify their grow areas and supporting areas where “dirty” activities (such as handling of soil and nutrients) occur to be GACP. These areas are then segregated with a connecting hallway from the downstream processing activities. Personnel transitions such as airlocks need to be considered between these functionally different areas in order to avoid cross contamination. A full assessment of the floorplan flows, and potential areas of cross contamination risk need to be performed and are best done under risk management principles.
For an existing facility, areas of concern may be identified during this assessment, and the site is best to consider risk mitigation strategies. For example, a site where dirty and clean personnel cross paths would need to consider re-directing foot traffic or adding engineering controls (i.e.:, airlock) where re-direction is not an option. As a last resort a facility may add procedural controls along with a vigorous training program to reduce the risk of contamination.
Quality Management Systems (QMS) Updates
The implementation program hinges on performing a gap assessment between the existing quality management system (QMS) and the desired quality management system, EU-GMP. For demonstration purposes, a theoretical gap assessment is performed on Canadian GPP and EU-GMP quality management systems by performing a comparison of GPP to EU-GMP and identifying gaps between the two standards. The gaps are classified as either:
- Major: There is no specific provision in GPP. Therefore, a GPP compliant facility is less likely to have these requirements addressed in their QMS.
- Minor: There are provisions in GPP for similar/relevant topics however GMP contains detailed requirement beyond those in GPP. A GPP compliant facility is likely to meet or partially meet these requirements in their QMS.
Refer to Figure 3 for a high-level summary of the gaps identified between the regulatory requirements for GPP and EU-GMP.
| Section of EudraLex – Volume 4 |
Gap Identified Between EU-GMP and GPP | Major Gap | Minor Gap |
| Chapter 2 – Personnel |
High level QMS planning (i.e.: objectives, management review) | ✔ | |
| Organizational structure, job descriptions and head of production requirements | ✔ | ||
| Lack of specific requirements which are likely implemented in practice which should be assessed | ✔ | ||
| Chapter 3 – Premise and Equipment |
Monitoring of environmental conditions | ✔ | |
| Requirements for storage areas, production areas and laboratories | ✔ | ✔ | |
| Metrology program | ✔ | ||
| Use of solvents compatibility with equipment | ✔ | ||
| Stability program equipment | ✔ | ||
| Lack of specific requirements which are likely implemented in practice which should be assessed | ✔ | ||
| Chapter 4 – Documentation |
Document listing review | ✔ | |
| Control of documents | ✔ | ||
| Application of Good Documentation Principles | ✔ | ||
| Security of storage of retained documents | ✔ | ||
| Record keeping for all listed systems | ✔ | ||
| Chapter 5 – Production |
Receiving | ✔ | |
| Sampling testing and release | ✔ | ||
| Labelling and Identification | ✔ | ||
| Production operations including dispensing, and packaging operations | ✔ | ||
| Supplier evaluation and auditing | ✔ | ||
| Quality risk management process for product/materials evaluation | ✔ | ||
| Deviation handling as related to production operations (see also chapter 8 for general application of deviations) | ✔ | ||
| Reprocessing procedures | ✔ | ||
| Returns | ✔ | ||
| Chapter 6 – Quality Control |
Approval for sale procedures | ✔ | |
| Control of in-process checks (if applicable) | ✔ | ||
| Laboratory controls | ✔ | ||
| Reference standards and control system | ✔ | ✔ | |
| Stability program | ✔ | ||
| Investigation of Out of Specification results | ✔ | ||
| Chapter 8 – Complaints and Product Recall |
Complaints handling procedures | ✔ | |
| Deviations and Root Cause Analysis | ✔ | ||
| Recall including recalled product segregation | ✔ | ✔ | |
| Chapter 9 – Self-Inspection
|
Self-inspection program | ✔ | |
| Figure 3: High level gap assessment of EU- GMP compared to GPP. Note that Chapter 7 for Outsourced Activities was not assessed. | |||
The gap assessment concludes that the two standards have numerous areas that do not align. From a high level, the key difference between the two can be summarized as EU-GMP is very prescriptive on what must be included in the QMS to comply which leads to numerous “minor” gaps, while GPP has more flexibility.
The QMS of a GPP compliant facility can be audited and updated if necessary, to comply to GMP. Many of the requirements of GMP may also naturally arise in a GPP QMS as the result of continuous improvement, audits, and as input from industry practitioners’ knowledge of best practices is incorporated into the system. GPP systems would require verification/audit for each major system to claim conformance to GMP.
Implementation of Quality Programs
While there are many quality systems to be revised for the implementation of GMP, there are two major GMP programs that are worthy of mention in this article that need to be considered early on when planning to implement GMP in cannabis. Both are fundamental to implementation of a GMP program and the duration of time required to implement is often underestimated. If infrastructure is not rate limiting on a GMP implementation program, these programs will prove to be critical path items:
Validation Program. The implementation of the validation master plan, process, computer, equipment and facilities is a long lead time item in planning for GMP implementation and is critical to demonstrate that the cumulative efforts of the firm can consistently produce product according to the specification and standards. However, in many cannabis operations today, there is no requirement for full validation. Most jurisdictions require validated analytical test methods, but not a full validation program as required in GMP.
The evidence requirement to be amassed can take up to 12 months to demonstrate full validation and functional GMP operations. Just take the example of warehouse temperature mapping over four seasons – that isn’t something that can be achieved in short order. That, combined with the long lead time to grow, process, and produce a cannabis product, makes validation planning a critical path item requiring consideration early in the GMP implementation stage.
Stability Program. The stability program is used to establish a shelf life (also referred to as “use before date” or “expiry date”) for the product within a given packaging configuration. Stability is not a requirement under GPP, therefore many Canadian firms undergoing the compliance update to GMP will be “starting from scratch” in the implementation of a compliant stability program due the complete lack of data.
The program needs to be designed in accordance with an internationally recognized standard (such as ICH Q1) in order to be accepted by international regulators. As an example of an international requirement, when BfArM (Bundesinstitut f✔r Arzneimittel und Medizinprodukte – the German Regulator) put out a tender to supply the market with medical cannabis,9 they referred to the requirement for stability information from accelerated and long-term testing to be provided on at least two production scale batches manufactured with a minimum of 6 months duration. The lead time from start of cultivation to data generation, can be upwards of 12 months.
GMP DRIVERS
As can be seen from the gap assessment in Figure 3, at this point in the evolution of cannabis regulation, it would not be possible for a regulatory authority in the EU to accept a GPP compliant facility as meeting EU-GMP requirements. Hence, any company wishing to import Canadian product into the EU is required to do so from a facility that has demonstrated conformance to EU-GMP. Currently, the method to do so is to host an inspection from a Competent Authority from the EU. Unlike drug products, Health Canada will not inspect domestic cannabis production facilities to GMP, and therefore the cannabis industry cannot take advantage of the MRA to achieve GMP compliance.
However, Canadian companies have first mover advantage in legalization and are looking to grow and expand their product sales to international markets. Other domestic pressures include the recent release of product data from Health Canada indicating adequate supply of cannabis10 for the Canadian market, driving Canadian licence holders to seek international buyers.
If international sales strategy is in their business plan, then this logically requires GMP implementation. Countries such as Germany are currently dependent on medical cannabis imports until such time as a domestic production system is established, making Canadian to German product transactions more common and incentivizing Canadian companies to implement EU-GMP.
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FUTURE OF THE MEDICAL REGULATORY REGIMES
In the near term there will not be an alignment of regulations between jurisdictions. The independent evolution of the Canadian system, the state-mandated system within the US and the requirement for EU-GMP in the EU countries means that, much like GMP prior to the MRA, the international community will be left with regulatory barriers to trade and having to host multiple regulatory authority inspections for markets where they are able to participate.
On the international front from alignment of regulatory standards, there are efforts in place to work on international standards. However, the industry’s move to GMP may end up dominating the field and putting in place a practical means to move forward on harmonization – the MRA.
CONCLUSION
The driving forces behind the need for implementation of GMP are the separately evolving regulatory regimes of numerous countries and states and the drive to trade internationally in a jurisdiction with a higher standard. Since EU countries have set a stake in the ground and declared EU-GMP – a known standard – as the requirement for medicinal cannabis, all countries which come on board with legalization will be driven towards compliance with GMP if they want to partake in international trade of medicinal cannabis. As non-GMP companies strive to implement GMP, there will be numerous quality management system considerations to implement in order to conform to the GMP requirements.
REFERENCES
- Massachusetts Institute of Technology, The People’s History, Volume 13, Number 2: Sept./Oct., 2000 https://www.mit.edu/~thistle/v13/2/history.html (accessed March 23, 2019)
- Environment, Public Health and Food Safety, “Resolution on use of cannabis for medicinal purposes”, Legislative Observatory, European Parliament, 2018 (Brussels, Belgium). oeil.secure.europarl.europa.eu/oeil/popups/ficheprocedure.do?lang=en&reference=2018/2775 (RSP) (accessed February 18, 2019)
- M. Moore, Cannabis Sciences, “How the Endocannabinoid System was Discovered”, April 8, 2018. https://www.labroots.com/trending/cannabis-sciences/8456/endocannabinoid… (accessed March 23, 2019)
- Health Canada, “Health Canada launches public consultations on the strict regulation of additional cannabis products”, Government of Canada, December 20, 2018 (Ottawa, ON). www.canada.ca/en/health-canada/news/2018/12/health-canada-launches-publi… (accessed February 18, 2019)
- D. Attwood, A. Curley, E. Keenan, and S. Murphy, The European Cannabis Report, Prohibition Partners, 4th ed., 2019.
- Public Health and Risk Assessment, Pharmaceuticals, “The Rules Governing Medicinal Products in the European Union”, EudraLex Volume 4 – EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, European Commission Health and Consumers Directorate, December 2010 (Brussels, Belgium). ec.europa.eu/health/documents/eudralex/vol-4_en (accessed February 18, 2019)
- Justice Laws Website, “Cannabis Regulations SOR/2018-144”, Government of Canada, January 1st, 2019 (Ottawa, ON). laws-lois.justice.gc.ca/eng/regulations/SOR-2018-144/page-1.html#docCont (accessed February 18, 2019)
- European Medicines Agency, “Mutual recognition agreements (MRA)”, European Union, (London, UK). www.ema.europa.eu/en/human-regulatory/research-development/compliance/go… (accessed February 18, 2019)
- Tender process for cultivation, processing, storage, packaging and delivery of cannabis for medical purposes, Application conditions for binding bids”, Bundesinstitut f✔r Arzneimittel und Medizinprodukte, August 8, 2018 (Bonn, Germany). www.bfarm.de/DE/Home/home_node.html (accessed February 21, 2019)
- “Cannabis Demand and Supply – initial report”, Government of Canada, January 1st, 2019 (Ottawa, ON). www.canada.ca/en/health-canada/services/drugs-medication/cannabis/licens… (accessed February 21, 2019)
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