The European Union Good Manufacturing Practices for the Cannabis Industry
Every industry is expected to have its own unique set of rules and laws. The cannabis industry is no exception either. Behind the GMP sign on the CBD oil label hides the assurance of its quality, safety, and effectiveness. Hence, cannabis companies who are eager to earn a spotlight in the cannabis world would often have their facilities GMP-certified.
In this article, we'll consider what challenges and opportunities may occur on the way to receive this certification.
What is GMP?
Good Manufacturing Practices (GMP) are the minimum requirements a manufacturer must meet to ensure that products are consistent, high quality, and safe for their intended use. GMP certifications may also apply to a single stage or the entire production process. Such practises are involved in various markets, including food and beverages, cosmetics, pharmaceutical products, dietary supplements, and medical devices.
The basic principle of GMP is that quality control should be integrated into each batch of product at all stages of the manufacturing process. These practices are the basis of regulation for industries. Specifically, consistency is important for:
- Physicians and patients – to validate the product composition and dosage
- Researchers – to compare results from clinical trials and studies
- The cannabis industry – to obtain GMP-certified active pharmaceutical ingredient (API), and provide seamless GMP manufacturing that speeds up the production timeline and diminishes risks from manufacturing activities.
It is important to note that the GMPs are guidelines, not fixed steps. Furthermore, all international and national standards include a few basic similar principles of GMP:
- Manufacturing processes are clean, controlled, auditable and repeatable. Any changes must be documented
- Products are manufactured in a suitable facility, with the use of appropriate and regularly maintained equipment
- Hygiene processes are in effect to prevent further contamination
- Employees are healthy and are certified and trained to perform their tasks
- Accurate record-keeping, documentation and accounting are carried out, including batch history from manufacturing to the distribution to the end user
- Repeatable audits and inspection of production stations by certified bodies are performed
- Recall and withdrawal procedures must be in effect, and complaints on the products must be checked
In general, GMP-certified products must:
- Suit the intended use
- Come from the licensed supply chain
- Be of consistently high quality, including consistency in storage, transportation and handling
- Comply with the requirements of the marketing authorisation or product specification
GMP in the cannabis industry
Global regulations on cannabis are changing as more and more countries legalise it. Many countries, such as the United Kingdom, Germany, Canada, the USA, Greece, Australia and many more have legalised cannabis for medical purposes. With such speed, Europe is expected to become the world's largest legal cannabis market, whereby it is estimated to be worth up to €123b by 2028.
Fewer countries have legalised cannabis for recreational use, including Canada, Uruguay, Georgia, South Africa, along with 11 states, two territories, and the District of Columbia in the USA and the Australian Capital Territory in Australia. Some other countries have begun to decriminalise or de-penalise cannabis use. The markets, such as the Netherlands and Spain, have loosen the controls and penalties related to cannabis. This presents great news as decriminalisation and depenalisation are the first steps towards a more tolerant attitude to cannabis legalisation.
The European Union (EU)
EU authorities classified medical cannabis as a medical product and therefore apply an established standard, known as EudraLex Volume 4 of "the rules governing medicinal products in the European Union" ("EU-GMP"). European pharmaceutical companies follow this standard, and medicinal products are sold in Europe under EU-GMP.
The EU-GMP guidelines include key requirements for:
- The quality system and quality control
- Facility and equipment
- Documentation (including records keeping and data integrity)
- Validation of manufacturing, computer system, and other
- Qualified person batch release
- Outsourced activities, including audits
- Complaints and product recall
- In-house inspection
Before entering the market, all medical cannabis sold in Europe needs to be manufactured and tested under European GMP, along with Good Distribution Practices (GDP) certification for distribution and warehousing. All European cosmetics and medications that contain CBD should be GMP-certified and listed in the Eudra Database. That is the Union database maintained and operated by the EMA (European Medicines Agency) that lists products with GMP certificates and import authorisations. Other authorisations mean compliance with Directive 2001/83/EC, that approves cannabis production as an active pharmaceutical ingredient (API) and Directive 2003/94/EC, which outlines principles and guidelines of GMP related to medicinal products and investigational medicinal products for human use. EU-GMP certification evaluates the quality system and quality control, personnel, facility, equipment, documentation, manufacturing, complaint and recall processes.
The UK followed the EU regulations. As of 1 February 2020, the UK left the EU, though the EU law still applies to the country during the transition period. GMP certification is necessary for cannabis-based medications. Not to mention, some CBD products are considered to be food supplements instead of a type of medication. Hence, these CBD products undergo fewer production controls when compared to medicines. Nonetheless, it is still highly likely that GMP standards still apply.
In Canada, cannabis is legal for medicinal and recreational purposes. Medical cannabis is regulated under the conditions of the Access to Cannabis for Medical Purposes Regulations, whereas recreational cannabis is regulated under the Cannabis Act. Moreover, Canada created unique standards known as GPP (Good Production Practices) for medicinal cannabis that outline the requirements for cannabis cultivation and processing facilities. GPP standards evaluate facilities and equipment, quality assurance and quality control, sanitation, documentation, and security.
The peculiarity of GPP is in a combination of principles of medical and consumer product regulation. It should be noted that there are significant differences between the GMP and GPP. The EU-GMP guidelines are more detailed and have established specific requirements and principles on what must be included in the quality control measures. In contrast, the GPP standards are less detailed and more open to interpretation. These differences make it difficult to compare the two standards. Hence, GPP-compliant Canadian companies have to apply for the EU-Good Manufacturing Practices (EU-GMP) certification if they intend to export cannabis products to European markets.
In the United States, the Food and Drug Administration (FDA) sets the guidelines for food, dietary supplements, drugs and cosmetics manufacturers. These are current Good Manufacturing Practice (cGMP), where "c" means the facility's responsibility to ensure compliance with the FDA's most current guidelines, which changes often. However, because cannabis remains illegal at the federal level, there are no uniform Good Manufacturing Practice guidelines for the cannabis industry. The FDA sets cGMPs guidelines in the Code of Federal Regulations. However, the FDA has yet to establish regulations on CBD, and it's the responsibility of the manufacturer to follow GMP guidelines and undergo inspection voluntarily.
Mutual Recognition Agreement (MRA) agreements
The EU, United States, and Canada regulate drugs independently, which leads to different regulations and information from regulatory bodies, thereby creating trade barriers. As a result, the major markets created a Mutual Recognition Agreement (MRA) for GMP across different markets.
Since 2003, the MRA has been set between Canada and the EU, which helped to reduce many barriers and paved the way for a more homogeneous market for its players. Unfortunately, those agreements may not cover medical cannabis, which is why many Canadian companies joined the EU-GMP certification race. For example, MRA agreements between some EU countries and Australia include medical cannabis, if it is regulated as a medication in the other country. Therefore, an Australian medical cannabis company with GMP certification from the Australian Therapeutic Goods Administration has the right to export medicinal cannabis to the EU without having a separate EU-GMP certification.
What is the difference between cannabis GMP and GPP?
In comparison to GMP, receiving the Good Production Practices (GPP) certification is a less detailed and lengthy process. The GPP covers information on a cannabis product label, including its cannabinoids content, though its regulations do not require a batch-to-batch consistency. On the other hand, the GMP covers many additional quality aspects, such as manufacturing process, raw material control, in-process testing, storage, distribution, validation and final product quality, including the accuracy of cannabinoids content and batch-to-batch consistency.
For example, if the manufacturer produces a million CBD products, they might test just a fraction of them. If GMP standards are not followed, and there is no consistency in the safety of production; some of these products may be safe for consumption, while others may not. This may lead to product recalls or withdrawals, damage to brand reputation, and further lawsuits.
Why apply for GMP certification in the cannabis industry?
Here are the main reasons why GMP compliance may bring benefits to cannabis businesses:
- GMP certification helps to align international market participants to a well-known and accepted standard. However, the implementation of GMP guidelines alone will not remove the need for international inspections until cannabis is properly regulated and considered in mutual agreements
- GMP manufacturing ensures that the production and products comply with the highest quality standards
- Having a GMP certification means that cannabis products are safe, which gives companies a reputational advantage
- A GMP certification allows companies to expand businesses to international markets
GMP compliance and certification are not widely required. However, it may become the standard as the industry matures and overlaps with more established ones such as food and pharmaceuticals. By complying with GMP standards, businesses gain access to wider international opportunities and reduce further business risks due to the high level of manufacturing processes, quality testing, product stability and distribution.
What is the GMP certification process?
The EU-GMP certification process may include the following steps:
Setting a target
There may be different reasons for one to apply for a EU-GMP certification, ranging from hoping to enter overseas markets to marketing purposes. Establishing a clear objective helps one to define the appropriate GMP certification to obtain. There may be other GMP's, such as cGMP in the US, EU-GMP in EU and Guide-104 GMP in Canada. These certifications are similar, though they are generally applicable for companies for the jurisdictions where they are certified. For example, if a Canadian company plans to produce cannabis-based medications or active pharmaceutical ingredients in Canada, it will have to apply for Guide-104 GMP. However, if the company plans to sell these medications in the European Union, it requires the EU-GMP certification.
At this stage, the company evaluates the infrastructure and its compliance with GMP requirements. EU-GMP requirements differ from GPP as it covers wider areas, such as production and storage. This evaluation detects the gaps in infrastructure requirements, measures their ability to fix them and potential costs. If the company accepts the EU-GMP infrastructure requirements, it must implement and minimise these gaps in a way that is acceptable under GMP guidelines.
Quality management systems assessment
This stage is a gap analysis between the existing quality management system and the one that complies with EU-GMP. A good example is a gap assessment between GPP and EU-GMP quality management systems. Things are complicated, as there are no specific requirements in GPP, and a GPP compliance does not provide a shortcut to a GMP certification. On the other hand, some GPP requirements may be similar to GMP. Therefore, a GPP-compliant company is likely to meet some Quality Management System (QMS) requirements. If necessary, the QMS of a GPP compliant company can be audited and updated to conform to GMP.
Many businesses don't have high-level documentation, such as a master validation plan or a quality manual. These documents describe how the company operates. At this stage, the company needs to create these documents for further submission to the relevant authorities, including the Federal Institute for Drugs and Medical Devices in Germany.
Standard operating procedures update
A standard operating procedure (SOP) includes a company's instructions, which help employees to carry out complex routine tasks. Manufacturers can have up to several hundreds of SOP's. These instructions need to be updated for GMP compliance, including the update of the regulatory references within operating procedures.
If the company reaches this stage, it goes through a validation and stability programme. The validation stage helps to update documentation, standardised operating procedures, and add missing programs. Validation can show that the facility can manufacture products of consistently high quality and in compliance with standards. However, many cannabis processes don't require full validation, just validation for separate processes. Validation is a long process that can take up to a year.
The stability stage is necessary as it helps to establish a shelf life for the product. Stability isn't required under GPP regulations. Therefore GPP-compliant companies are likely to undergo the GMP compliance from the very beginning due to the lack of data. That is a time-consuming process. For example, if a company performs a stability program and plans to establish a one-year expiry, they would need to test the products every few months within a year. Stability stages should be designed according to international standards, such as ICH Q1 or BfArM.
After GMP implementation, it is time to run with new systems for a number of months to show that the company is functioning under the GMP standards.
This stage is not necessary but highly recommended. Mock inspection is performed by a third party and helps to identify any potential issues regarding EU-GMP compliance. A mock inspection is conducted in the same way as a real inspection and may include reviewing records, interviewing employees, discussing the logistics of the inspection and touring the facility. This stage helps to prepare for future inspection and be more confident that the company will pass.
An audit is an outer, outsourced procedure. It is performed by the importer's Qualified Person (QP) for an audit or a third-party auditor. For example, the auditor of supply chain logistics ensures that the quality and integrity of products during transportation, warehousing, handling, testing and distribution is maintained through the whole way from the supplier to the customer.
In Europe, GMP standards compliance is verified by the European Medicines Agency (EMA). It coordinates inspections to examine the quality of products and their relevance to the intended use. Once the EMA, FDA, or another certifying body has received an application for GMP certification, they will arrange the inspections and confirm the company's compliance to standards.
EU-GMP applications are submitted via EudraGMDP. This is long and costly, which is why smaller producers may lack the means to become GMP certified, despite full compliance with GMP standards. The EU-GMP inspectors will issue EU-GMP certificates or manufacturing and import licences. The applicant will have to complete a GMP compliance report before an inspection. The inspection team will interview relevant personnel, review documentation and visit the facility. During the site visits, the inspectors may check manufacturing areas, quality control laboratories, stock and storage areas, temperature control, returns areas, purchasing and sales functions, and transportation arrangements. Overseas manufacturing sites will also be inspected. Further periodical inspections are also performed based on risk assessments. During the COVID-19 pandemic licences and certificates will be issued as an electronic PDF copy.
Why is GMP important for CBD products?
Over the last years, CBD became a wellness trend and one of the buzziest products, known for its benefits for wellbeing. However, CBD's popularity was exploited by some manufacturers. In addition, authorities can't always keep up with the speed at which the CBD industry grows. The CBD hype has also exposed many consumers to fake products that were not created under quality standards, including GMP regulations.
According to a 2019 investigative report by Ellipse Analytics and CBS Austin, up to 70% of the 240 bestselling hemp CBD products available online or from non-dispensary retailers might contain heavy metals, chemical pesticides, toxic mould, and other harmful impurities. The results of independent lab tests emphasise why it's important to make sure that CBD products are GMP certified and have quality certificates.
Is GMP for cannabis products necessary?
GMP certification is necessary for cannabis-based medications. As for CBD products, it's highly likely a necessity, but it still remains at the manufacturer's discretion. Unfortunately, not all CBD products are GMP-certified. Therefore, the lack of a GMP certification makes it difficult for consumers to know if they're buying a safe and pure product.
Most reputable companies undergo GMP certification to ensure that their CBD products are genuine and do not have harmful ingredients. Considering the lack of regulations and excess of unregulated supplements, GMP certification is a chance to make those products safe. GMP certification is likely to become a requirement despite the significant costs of compliance and certification, as the cannabis industry grows and matures and demand from other industries increases.
A GMP certification is applicable at a jurisdiction level, which means that to work as a GMP-compliant company in the EU, a CBD manufacturer in the US or Canada will need to apply for GMP-EU certification.
Why is GMP certification a must in the cannabis industry?
Both local cannabis products and the ones exported outside the country should have an appropriate and consistent quality. To reach the desired quality and safety of cannabis products, the manufacturers should adopt quality standards and employ best practices in all processes ranging from cultivation and production to distribution and documentation. The main goal of the GMP certification in the cannabis industry is to create a "pharma-grade" cannabis product.
As for the end-users, GMP certification promotes more informed decisions and ensures that cannabis products are effective, do not contain contaminants nor pose any risk to our health. People, using cannabis, would like to get relief and improve their wellbeing but not to suffer from side effects due to the poor quality of cannabis products. For the end-user, the manufacturer's GMP certification along with a clean certificate of analysis is the way to ensure the safety of a CBD product. Using a GMP-certified CBD oil or tincture means the origin of the CBD product and its quality are known. That ensures the CBD product has been processed, extracted, packaged, and distributed in sterile conditions and has undergone GMP requirements.
Considering the lack of regulations on the cannabis market, customers would want to make sure they buy the products of good quality. By purchasing from a company that tests its products by third-party labs, obtains and publishes its Certificates of Analysis, and is GMP-compliant, this means that the customer can have full confidence that their product is pure and of high-quality.
What may happen without GMP certification in the cannabis industry?
Although GMP standards are not commonly applied and required in the cannabis industry, cannabis regulations are expected to become necessary in the near future.
The failure to conform to GMP standards in the cultivation, production, packaging and distribution of cannabis products, can lead to them becoming restricted goods. Such products may lack the declared active material content and contain heavy metals, toxins and contaminants. As a result, manufacturers may lose sales opportunities in international markets due to the missing GMP certification.
Furthermore, GMP certification may win the trust of patients and customers for cannabis manufacturers, whereby they would consider their cannabis products to be equivalent to a “pharmaceutical-grade”.
How did COVID-19 affect GMP certification?
This halt can challenge or suspend the receipt of GMP certification and exports to the EU market. The companies that didn't undergo an audit before the COVID-19 pandemic will have to wait until EU inspectors can travel overseas. The Medicines and Healthcare Products Regulatory Agency in the UK has decided to limit the inspections only to the essential businesses for an unknown period. Nonetheless, audits remain necessary for the EU-GMP certification and exports to EU markets.
The good thing is that some local producers in the EU, such as Denmark, can be certified by domestic health agencies. In this case, EU companies can sell medical cannabis throughout the European Union, replacing more expensive foreign products.
The bottom line
The main goal of GMP certification, whether it is a GMP or EU-GMP is always to provide markets with safe products and prevent customers from potential harm. EU-GMP certification is a costly, time-consuming, and data-driven process. Sometimes, it requires the insight of consultants, experienced in GMP certifications or additional mock inspections.
Even with all these challenges, GMP has many potential advantages:
- GMP certification creates an even playing field for all market participants and helps to bring their operational processes and products to an established and accepted standard
- GMP ensures that cannabis and CBD products are produced under the highest quality standards
- The GMP sign on the label means that cannabis and CBD products are safe and effective
- GMP certification contributes to the company's reputational advantage
- GMP allows companies to export products to international markets
In any case, GMP certification helps companies to reach the gold standard for international quality compliance and ensure the safety, quality, and efficacy of cannabis. However, the certification process requires funds, time, and a thorough and well-designed strategy.