The new Medical Device Regulation (MDR) have been approved on May 2017 and the date for its implementation was May 2020, but recently its implementation was postponed due to the Corona pandemic and currently the target date is May 2021.
In this Newsletter, I will briefly highlight the changes in the new regulation related to clinical data collection.Beyond the many changes in aspects such as: new classifications, risk levels, Notified Bodies, certification processes and more, clinical evaluation requirements have been updated as well. The new regulation requires now a constant “live” connection between the risk management and the Clinical Evaluation and requires adjustment of the risk management processes and interphase with the clinical evaluation.
The sponsor is essentially required to assess each risk through clinical investigations, clinical evaluations, and of course through post-market clinical follow-up. Overall, referring to risk management, the MDR is in alignment with EN ISO 14971:2019 and EN ISO 13485:2016. While developing or amending the clinical plan, it should be taken into account that any change derived from the new regulation may also have implications on the clinical program. I.e. the question of medical device classification can have such implications and it is therefore advisable to characterize these implications before establishing the clinical program.
The transition from MDD (Medical Device Directive) to MDR has resulted in significant additional information in aspects of clinical data collection which is manifested in 20 new articles (articles 62-82). For Europe these are a fundamental changes and alignment with norms that are accepted worldwide in the medical device arena. The additional articles specify in fact requirements that have been relatively ambiguous so far, among other things, they specify requirements regarding:
●the responsibility of the sponsor;
●ethical considerations;
●subject consent process;
●reference to vulnerable populations;
●safety information reports;
●insurance etc.
In addition to these articles Annex XV, which extend the MDD Annex X, explains what information is required to appear in various core documents such as:
●Clinical investigation report,
●Investigator`s Brochure,
●Clinical Investigation plan and others.
In terms of definitions, the MDR defined “Clinical Evidence”, extend the equivalence requirements to be more stringent and increased oversight of PMS (Post Marketing Surveillance) data. Despite the considerable extensions, more detailed standards and requirements will be found in the ISO 14155 and of course in ICH GCP.
Article 61 provides a concrete requirement for the need to conduct clinical trials with reference to implants or Class III For the other classifications, the requirement for conducting clinical trials is derived from the level of clinical information collected by the sponsor throughout the life cycle of the product. It is the responsibility of the sponsor to characterize the Clinical Evidence required for the product according to its characteristics and intended use. Given that the clinical information is limited, additional data, based on clinical investigation conducted in accordance with the GCP Guidelines, ISO 14155: 2011 and the Declaration of Helsinki would be required to complete gaps.
Article 62 indicates potential purposes for the clinical trial, these operations should be performed under the product design, the “normal” conditions of its intended use, including manufacturing and packaging. The clinical operations may be carried out to characterize the performance, benefits of its use as well as its safety implications. The structure of the trial and its design will be derived from the concrete need. Those operations may be:
relatively small in scope and their purpose will be to continue learning and improving aspects of product performance (Pilot studies) or, alternatively,
more extensive operations designed to present device performance under the conditions and constraints required to its function in the intended environment (Pivotal Study). Pivotal studies will most often be performed when the product is mature and expected to function as required and present its intended performance in accordance with the Claims.
The responsibility for maintaining clinical knowledge about the product on its variety of models and versions is the sole responsibility of the sponsor. When existing clinical knowledge changes or loses its validity as a result of changes in the product, adaptation of the clinical data collection plan should be considered. That process should use existing knowledge to establish updated conclusions and characterize the gap, and clinical investigation may be executed in order to complete the gap. Usually, a solution will be found that combines these two approaches.
In conclusion, for any product intended to be marketed in Europe, a continuous clinical information collection process is required throughout the product life cycle. The aforementioned sources of information include: literature and scientific publications, clinical operations, and information gathering from marketed products. The nature of the information collected and its purpose will be defined and adjusted to the product requirements and to the risk’s assessments. This process importance is further elaborated under the new regulation and plays a critical role in the dynamic assessment of the benefits and risks of using the medical device.
In a nutshell, changes in clinical requirements under the MDR:
The International Medical Device Regulators Forum (IMDRF) recognizes that a global approach to auditing and monitoring medical device developers and manufacturers could improve the devices’ safety and the regulators’ oversight on an international scale. Back in 2012, the IMDRF identified a work group to develop specific documents for advancing a Medical Device Single Audit Program (MDSAP).
The MDSAP Program allows an MDSAP recognized Auditing Organization to conduct a single regulatory audit of a medical device manufacturer that satisfies the relevant requirements of the regulatory authorities participating in the program.
Gsap has led MDSAP readiness activities with its Medical Device customers. We have a professional and knowledgeable team to support you in defining and aligning your business regulatory and quality strategy in accordance with the new approach of the MDSAP.
International partners that are participating in the MDSAP:
• Australia’s Therapeutic Goods Administration (TGA) • Brazil’s Agência Nacional de Vigilância Sanitária (ANVISA) • Health Canada – Santé Canada – MDSAP is mandatory from January 2019 • Japan’s Ministry of Health, Labour and Welfare (MHLW) • USA – Food and Drug Administration (FDA)
MDSAP in General
• MDSAP covers regulatory aspects as well as: o Registration o Licensing o Adverse event reporting • MDSAP participating countries have direct access to the audit reports • Audit is focused on requirements of ISO 13485:2016 and the regulatory requirements of the applicable jurisdictions (A manufacturer may exclude the requirements of a jurisdiction where the organization does not intend to supply medical devices) • Audits conducted by approved Auditing Organizations (AO; Updated, official list is available at FDA site)
Preparation for the MDSAP
• Perform gap assessment for all procedures and processes • Develop and implement risk assessment program • Reach out to approved Auditing Organizations (AO) • Fill AO’s questionnaire (to be used for additional assessment) • Get a quote for services • List products, registrations and licenses for applicable markets • List types of products under the scope of the company • Schedule an audit • Be prepared for audits – # of days based on # of tasks to be audited
Gsap will be happy to support you in getting ready for the MDSAP requirements!
For more information visit Medical device Industry page
Who isn’t talking about the EU MDR and the new challenges ahead? At Gsap we want to do as well as talk. Gsap has led MDR readiness activities with its Medical Device customers. We have a professional and knowledgeable team to support you in defining the business and regulatory strategy in light of the new landscape.
Medical Device Regulation (MDR) requires stringent standards of quality and safety for medical devices which will lead to a higher level of protection for patients and users. It seeks to increase premarket control (especially for high-risk devices), smooth communication between the different EU markets, increase surveillance at the post-market phase, and enhance traceability (UDI) and transparency (EUDAMED).
EU MDR for whom?
For beginners in the Medical Device industry, meeting MDR requirements is mandatory for those wishing to sell their products in Europe. Since one of the main changes is the inclusion of devices without a medical purpose (such as esthetic products), there are new players in the Medical Device Landscape.
EU MDR by when?
By May 26th, 2020. No grandfathering, all existing devices must comply with new requirements by this deadline or when the NB certificate runs out (not later than May 26th, 2024).
EU MDR by whom?
Currently there 2 notified bodies approved for MDR audits TUV SUD and BSI. BSI’s future is questionable with the Brexit, making TUV SUD the only feasible player on the field.
How can you get ready now for the EU MDR?
Determine the intended purpose of the device for Declaration of conformity including technical documentation by:
Medical Device classification (CLASS I \ CLASS IIa \ CLASS IIb \ CLASS III)
GSPS (General Safety and Performance Requirements replaces ‘essential requirements’).
Traceability by UDI & EUDAMED registration
PMS activities
Biocompatibility changes
Main changes vs MDD
Wider coverage of devices without a medical purpose
New obligations for authorised representatives, distributors and importers
New European database (EUDAMED)
Unique Device Identification (UDI)
PRRC – appointment of Person responsible for regulatory compliance
Stricter requirements on:
Risk management as a continuous iterative process throughout entire lifecycle of a device
Pre-market controls of high-risk devices
Clinical evaluation and investigation
Use of hazardous substances
Gsap will be happy to help you get ready for the MDR storm!
As time passes, keeping track of all the changes in the Global Medical Cannabis market is becoming more and more challenging. The current newsletter will provide clarity where possible, regarding the design and implementation of Clinical Trials. Valid Clinical Trials are necessary for the expansion of labeling in the US. In Europe in general, and in Germany in particular, labeling requirements are less precise and the authorities allow for physicians’ discretion in prescribing Cannabis.
Currently, Israel is known worldwide as a pioneer in Medical Cannabis research and Clinical trials. More than 50 Israeli startups are developing Medical Cannabis products. Most Israeli start-ups are gradually maturing and progressing to clinical trials, mainly for PK, Phase 1, and Phase 2. Since 2011, over 45 clinical trials have been conducted in the field of Cannabis worldwide, with most of these studies being preliminary studies, about 5 phase 3 studies (including GW Pharmaceuticals and Takeda studies), and about 10 phases 2 studies.
The main research question investigated usually is the efficacy of the research product, but most studies also explore safety aspects where the most popular indications are central nervous system disease, Inflammation, and cancer. The quality of the results and the scientific value of these studies are “varied”; therefore, practitioners should develop the ability to monitor the quality of execution and planning of clinical trials. As a result of what we have learned and observed, we believe that proper planning and execution of a Clinical Trial is critical to achieving regulatory approval in a timely manner. We wish everyone a fruitful and prosperous year, and of course, may it be the year of Cannabis.
Designing medical Cannabis clinical trials
Clinical studies are a significant and necessary portion of the process of developing and approving medical products. Cannabis-based medical products also require clinical trials and the submission of detailed clinical study reports of the clinical trials in order to be included in the Registration file that will be submitted to the authorities. This review will address two key aspects: • Basic principles in clinical trials design • Guiding considerations in the design of medical Cannabis clinical trials
Clinical trials should be designed and conducted according to three general principles:
1. Protection of Clinical Study Subject This principle provides guidance for planning and execution in a way that ensures the patient’s well-being and rights while emphasizing special populations in a way that requires compliance with the ICH E6 Good Clinical Practice requirements and ISO 14155 when the clinical investigation involves medical devices.
2. Scientific Approach in Clinical Study Design Conduct and Analysis This principle requires a scientific approach in designing the research objectives, executing, collecting the results, and analyzing them, to ensure obtaining reliable data and the required answers for the intended questions.
3. Patient Input into Study Design Aimed at integrating, receiving feedback, and involvement of patients and patient organizations in the design and implementation of the study. This is done in order to plan and conduct a feasibility study that addresses the real needs of patients. The characteristics of clinical research in Cannabis, as well as preclinical steps in product development, are derived from the regulatory submission path and therefore great importance should be given to determining the correct regulatory strategy for each product and at the earliest stage. Although clinical trials are sometimes not mandatory, clinical trials are almost always performed. These clinical trials will be performed for the purpose of accumulating safety and efficacy information, for marketing needs, financial needs, and or needs to confirm assumptions about the efficacy of the product under different indications, different administration routes, combined with other treatments, etc. This review focuses on the design and conduct of the clinical trials in accordance with the regulatory requirements of a nonherbal pharmaceutical product, these requirements are the most rigorous and demanding and ensure as much as possible the reliability of the scientific insights that can be derived from the research.
Cannabis research requires special attention to these requirements because prior information on cannabinoids / Cannabis use in medical products is limited. This is due to, among other things, a lack of reliable scientific and clinical information in the field of Cannabis research and is the result of conducting studies that are lacking in their design and without the use of common methods to reduce BIAS. Once the indication has been thoroughly studied and the relevant literature reviewed, the research rationale and assumptions sought by the research can be formulated. In each case, the research and its objectives will be planned with reference to, and in connection with, the broader clinical program and the stages of the project or product.
The research design should focus on the guidelines outlined below at both the planning and execution levels:
1. Study Population The characteristics of the study target population are derived first from the target product population, the study as a whole will characterize the effect of the investigated product on a particular population and the conclusions, in principle, will be relevant to that population. Later on, the criteria for inclusion and exclusion will also include considerations related to safety, ethics, DDI (Drug-Drug Interaction), background and medical history, etc.
Cannabis studies should also take into account, the extent to which patients have been exposed to Cannabis use in the past, the psychoactive consequences of THC, and the patients’ ability to consume the product as required. In general, the characteristic of the study population can be said to be a delicate balance between reducing the variability between patients in order to increase the chances of demonstrating the therapeutic effect on the one hand, and the implications of these decisions on the ability to recruit patients for research and approve treatment based on research in a population characterized by limited variability on the other hand.
2. Intervention The dosage, treatment duration, route of administration, and a number of treatments have a major impact on “Product Success / Research”. Dosage, treatment regimen, and administration have a direct effect on product usability, the absorption of active ingredients, their effectiveness, as well on their safety, and economics. Cannabis studies show a wide variety of forms of administration, ranging from topical ointment form through to nasal and oral vaporizers, sub-lingual, and even rectal administration. Each of the forms of administration has pros and cons. For example, using a vaporizer significantly reduces smoking damage and allows for an “ Entourage Effect” and has close proximity to the traditional Cannabis consumption, but requires patients to be supplied with a vaporizer which significantly increases the operative and regulatory requirements both during and after the study. Oral administration is relatively simple to use and operate but is characterized by a slower and less effective absorption of the active ingredients. Apart from these, the “intervention” consideration also corresponds to the indication itself and the target patient population, which dictates restrictions on how the patient consumes the product being tested.
3. Control Group The requirement for controlled research is a “gold standard” in clinical studies design and usually, research cannot be carried out with good reliability without a control arm. The need for a control arm/ group results from a phenomenon that has been documented since the 1930s and is called the “Hawthorne effect.” In general, this effect shows that solely just the participation of the subject in the clinical trial results in a change not related to the medication. The purpose of the control group and its value derived from the fact that it allows us to analyze the effects of the treatment only regardless of the effect of other external factors not related to the medication/treatment. There are different types of controls, for example; a Comparison of the research drug or treatment with another drug or other conventional treatment as well as a placebo. This aspect is particularly challenging in Cannabis trials as it is difficult to create a “placebo” in Cannabis products especially when the tested product is consumed via inhalation and/or contains a THC component that gives a unique feeling and allows for easy differentiation of treatment arms by the patient. Due to this reason, cross-over and double-dummy studies for example are more relevant in the cannabis territory.
4. Response Variables Endpoints are derived directly from the study objectives and are used to assess and characterize the treatment effects. The endpoints selection has a critical impact on the success of the study and is the result of a complex set of considerations. The endpoints are first and foremost intersected with the indication, regulatory requirements, and statistical considerations, but also take into account broader elements of the clinical development program such as follow-up and future planned studies, patient needs and limitations, competitors and competition, etc. Early studies will usually use measures related to safety and tolerability as a Primary endpoint, while efficacy questions can be also expressed in Secondary endpoints. In the more advanced stages of product development, the priority is changed and the main objective will focus on the question of effectiveness while safety information collection continues throughout the life cycle of the product in order to produce safety knowledge at different levels of product exposure.
5. Reduce or Assess Bias Bias is an accumulation of factors that can compromise the reliability of clinical trial results. The bias is derived from the unique research structure and needs to be addressed to reduce it as much as possible. The two most powerful tools for reducing bias are “RANDOMIZATION” and “BLIND”.
Randomization means randomly assigning patients to the treatment arms. This randomization is expressed as an equal probability for each patient to be included in each arm, thus avoiding the conscious and unconscious bias of patient allocation and balancing the baseline characteristics of the treatment groups (The larger the group in the trial, the value of the randomness set increases).
BLIND or MASKING, however, requires that the patient or the research team (SINGLE BLIND \ DOUBLE) do not know to which treatment arm the patient is assigned. Creating a proper blind study creates operative challenges that need to be addressed in order to avoid psychosomatic effects and biases.
Apart from this, every procedure in the study that can influence the results of the study should be considered to ensure that its application is not affected by bias.
6. Statistical Analysis When the structure of the trial and the selected endpoints are determined, a suitable statistical model should be formulated to analyze the results of the study and a preliminary plan for the analysis of the results should be formulated. It is difficult to overstate the importance of bio-statistician involvement in model selection, sample size, decision making during the study, and of course in analyzing the results and presenting them. As mentioned before, these aspects have great importance in the planning phase and any changes may affect other aspects. Apart from this, during the Study Execution, the Sponsor is expected to ensure that the study conduct is done according to the approved plan and in compliance with the study protocol. In Cannabis trials this challenge is particularly tangible as these are studies with relatively high operative and regulatory complexity. In cases where the design and conduct are properly performed, authentic results are guaranteed which reflect product performance appropriately.
1.The GMP requirements for Post-Harvest in Europe:
1.1 Medical cannabis manufacturers aiming to sell their products in Europe and specifically in the German market must meet several requirements:
• Compliance with the Herbal Medicinal Products Committee (HPMC) requirements of the European Medicines Agency (EMEA) and Good Agricultural and Collection Practice (GACP) Guidelines for Plant-Derived Starting Materials.
• Compliance with European GMP requirements, EudraLex – Volume 4 – Annex 7, Manufacture of Herbal Medicinal Products. Annex 7 (to EU GMP) presents the requirements for facility, equipment, documentation, and process control for the production of herbal products. In the Annex, the referencing matrix is presented – for each stage of inflorescence processing, to the relevant quality requirements.
Figure No. 1: Application of Good Practices to the manufacture of herbal medicinal products:
1.2 The GMP classification depends on the stage of the inflorescence processing – raw material, intermediate material, or finished product, and the possible impact on the finished product. It is the responsibility of the medical cannabis product manufacturer to ensure that the processing and production processes comply with the relevant GMP requirements.
1.3 Propagation, cultivation, and harvesting of cannabis inflorescence are subject to the GACP guidelines. The GACP guidelines do not directly fall within the GMP guidelines in the traditional sense. However, these guidelines should be the basis for establishing a proper quality assurance system.
1.4 Post Harvesting processes such as Trimming, Drying, Curing, and Hand trimming are considered as a starting material for a medical product and therefore may also be subject to EudraLex part I or part II quality requirements in addition to being subject to the GACP guidelines. Parts I and II of EudraLex Vol. 4 are intended to provide GMP guidelines to the manufacture of medicinal products and active ingredients used as raw materials, respectively. This is to ensure that they meet the quality requirements stated by them.
2.Submissions of Medical Cannabis Products in Europe
2.1 Generally, there is not a single route for Medical Cannabis approval across Europe. Each country has established its own regulations regarding Cannabis.
2.2 Cannabis is legally authorized in the Netherlands and is decriminalized for use in Germany, Portugal, the United Kingdom, the Czech Republic, Spain, and Estonia.
2.3 In countries such as France, Italy, Poland, Bulgaria, Cyprus, Denmark, Croatia, Finland, Luxembourg, Malta, Romania, Sweden, Austria, Latvia, Slovakia, Slovenia, Lithuania, Belgium, and Hungary Cannabis is still illegal.
2.4 The use of Cannabis-based medications is possible by means of three pathways (in some European countries): • Cannabis preparations to improve wellbeing – not defined as medicine and without any specific therapeutic indication (wellness). • A medicinal product – intended for the treatment of a labeled disease, requires clinical trials and in most cases also intended for marketing (e.g. paracetamol – analgesics). • Medical Cannabis Path for Personal Care – For a specific patient, for certain illnesses accompanied by a doctor. This course is possible in some European countries.
2.4.1 Path No. 1: The cannabis preparations path does not require marketing authorization (MA). Cannabis preparation is originated from the Cannabis plant raw material – for example, inflorescence, oil extraction, and concentrated extraction. Cannabis preparations contain a low amount of THC (the approved level 0.3%, 0.2%) or without THC, thereby eliminating the psychoactive effect. Some countries allow the distribution without medical approval – in such countries where the sale of Cannabis is legal, or in countries where the personal use of Cannabis is decriminalized.
2.4.2 Path No. 2: Medical Cannabis for Personal Care. This pathway allows a specific patient to receive special approval for an unapproved drug, usually under a physician’s supervision for the treatment of serious illnesses, illnesses that have not responded to other medications, or as a compassionate treatment (chronic pain, terminal cancer, or degenerative neurological disease). The doctor who provides the prescription is required to monitor and report the results of the treatment as well as any side effects or adverse events. Medical Cannabis is supplied by pharmacies and requires EU GMP approval and a valid agreement with a local distributor. (see section 2.6).
2.4.3 Path No. 3 Cannabis-based Medicinal Products Medicinal Product – A substance or combination of substances used to cure or diagnose a disease, or to restore, repair, or alter physiological functions by activating pharmacological, immunological, or metabolic activities. This pathway requires MA for medicinal products. The MA is obtained after submission of a registration file to the health authorities, which includes clinical trials demonstrating effectiveness, efficiency, safety.
2.5 The source of the medicinal product may be synthetic or herbal:
2.5.1 A non-herbal source medicinal product route (e.g. synthetic origin). This path is a regular medicinal product route, manufactured in the pharmaceutical factories (such as paracetamol), and requires all tests to be approved (Clinical and Preclinical Trials).
2.5.4 Herbal-based medicinal product (similar to Sativex®): A medicinal product containing one or more active substances from a plant source or an herbal preparation or a combination of the two. Data should be presented that the herbal material has well-established pharmaceutical use, with over 15 years in the European community, a recognized efficacy, and an acceptable level of safety. In addition, it is necessary to demonstrate the quality and consistency of the drug manufactured in order to ensure that the patient receives the same product every time and is free of contaminants. A long tradition of using herbal medical products enables the reduction of clinical trials to prove the safety of the medicinal product. The need for pre-clinical examinations seems unnecessary, as long as the medical history of the drug and its long-standing traditional use have not caused any harm. However, the competent authorities are entitled to request, where necessary, the data for the safety assessment. In terms of the quality aspects of the medicinal product, the product must be analyzed for physical\chemical, biological, and microbiological tests and to comply with the relevant quality standards in Europe: Pharmacopeial monograph, HPMC guidelines, and relevant directives (2004/24 / EC & 2001/83 / EC).
2.6 Obtaining a permit to import Medical Cannabis into Germany
2.6.1 Germany only imports medical Cannabis from farms and facilities operating under the 1961 Convention of Narcotic Drugs.
2.6.2 In order to import Medical Cannabis to Germany, a EUGMP certificate from the EU member state is required.
2.6.3 Manufacturers wishing to distribute Medical Cannabis products in Germany must be in agreement with or be the owner of a domestic importer. The domestic importer will have: • Registered business. • Wholesale distributor drug license, applied at a regional level. • Federal-level Narcotics handling license.
2.6.4 In order to obtain the necessary licenses, importers should meet the local and federal requirements, such as: employing at least one employee responsible for narcotics, applying extensive security measures, etc.
2.6.5 Regional German inspectors have granted GMP certificates to foreign manufacturers and provided import permits to Germany.
2.6.6 The type of approval depends on the activity planned by the importer: • Production and import authorization. • Compliance with EU-GMP requirements. • Approval of wholesaler-distributors. • Compliance with Good Distribution Practice (GDP) requirements.
2.6.7 In order to obtain EU-GMP approval, an on-site audit and document set must be submitted in accordance with the requirements of the Authority.
2.6.8 The issues with the approval of Medical Cannabis as an herbal medicine in Europe are due to: • Medical Cannabis is still included in the narcotic drug regulation in some countries. • The difficulty in characterizing the full spectrum of the plant’s cannabinoids. • To demonstrate product stability and purity in terms of microbiological contamination, heavy metals, and pesticides residues.
2.6.8Table No. 1 lists the requirements for personal care in some European countries. Changes in the legal status of Medical Cannabis use through Europe and the growing demand for approval of medical Cannabis make it difficult to predict the approach to Medical Cannabis in the near future. At any rate, it is advisable to consult with the local health authorities of the country in question in order to assess if it is feasible both financially and logistically.
Table No. 1: Requirements for Personal Care Pathway in some European countries:
3.1 Similarly, to medicinal products, test methods, and specifications have been defined in some countries. The set of methods and specifications for raw material or medicinal is defined as a monograph.
3.2 In several countries where medical Cannabis products were approved, such as in the Netherlands and in Germany, local monographs for medical Cannabis were defined. We will review the defined requirements in Israel, The Netherlands, and Germany.
3.3 Israel:
3.3.1 The Medical Cannabis unit (IMC) in the Israel Ministry of Health, has issued several guidelines related to the supply chain of Medical Cannabis. SOP 152, “IMC-GMP Quality Requirements for Manufacturing Medical Cannabis Products”, defines the set of tests and specifications required for Medical Cannabis products marketed in Israel. The tests requirements described in SOP 152 are based on the requirements of the European Pharmacopoeia (Ph. Eur.) General Monograph for Herbal Drugs (Ph. Eur., 1433, Herbal Drugs).
3.3.2 According to SOP 152 and the January 2019 notification, there are four main approved medical Cannabis products groups – inflorescences, cigarettes, oils, and cookies.
3.3.3 For inflorescences (flowers or grind flowers): 12 different products are defined, which differ in the concentration of active ingredients, and for THC products also in the source (sativa / Indica);
3.3.4 For oils: 9 different products are defined, which differ in the concentration of active ingredients.
3.4 The Netherlands:
3.4.1 The Office of Medical Cannabis (OMC) has defined specifications for 5 different inflorescences varieties that differ in the concentration of active ingredients (as of January Bedrocan (Sativa), THC concentration ~ 22%; CBD concentration <1.0% • Bedrobinol (sativa), THC concentration ~ 13.5%; CBD concentration <1.0% • Bediol (sativa), THC concentration ~ 6.3%; CBD concentration ~ 8% • Bedica (indica), THC concentration ~ 14%; CBD concentration <1.0% • Bedrolite (sativa), THC concentration <1.0%; CBD concentration ~ 9.0%
3.4.2 The Office of Medical Cannabis is also responsible for final batch release to the market.
3.5 Germany:
3.5.1 Germany has two local pharmacopoeia DAB (Deutsches Arzneibuch) and DAC (Deutscher Arzneimittel Codex). DAB has published a monograph for Cannabis inflorescence (flowers) of the female plants of Cannabis Sativa L. The requirement for Assay shall meet 90.0-110.0% of the labeled amount (calculated on a dries basis). Inflorescence storage conditions according to the monograph: tightly closed container, stored below 25°C. The monograph indicates that inflorescence products are divided into three groups: THC >> CBD, THC = CBD, THC << CBD.
3.5.2 In June 2019 a draft monograph of Cannabis oil (extract) monograph was published in DAB and it is planned to become effective during 2020. According to the draft monograph (which is still under review), the Cannabis oil should be prepared by extracting whole or grinded inflorescences of the female plants of Cannabis sativa L. The active ingredient content: THC is in the range of 1-25% and for CBD the range is NMT 10% (m/m). The active substance content shall be within the range of 90.0-110.0% of the labeled amount. The monograph includes applicable manufacturing processes: extraction (such April as ethanol or CO2), dilution of the crude extract with oil (MCT, grapes) in order to reach the target concentration. The material must undergo de-carboxylation where applicable in the process. The storage conditions according to the monograph: tightly closed container, protected from light and refrigerated (2-8 °C) – this probably will be changed in the official monograph. It should be noted that the tests specified in the German Pharmacopoeia (DAB) monographs are in addition to the requirements for Herbal Drugs (Ph. Eur.\ HPMC guidelines).
3.5.3 Table 2 includes a comparison between the specification requirements in the different countries stated above for inflorescences (flowers).
Table 3 includes a comparison for Medical cannabis oils. The tables do not include references to the active ingredient content mentioned above. Also, keep in mind that there may be differences in the test procedures between the different monographs.
Table No. 2: Medical Cannabis Inflorescence
As the world moves to implement Good Manufacturing Practices for the Medical Cannabis industry, the need for standardization is also increased. More and more countries, in Europe and in the rest of the world, are starting to initiate regulation regarding Medical Cannabis. Outside of Europe, we can find Australia, New Zealand, Brazil, and more.
