1. Introduction
Good Manufacturing Practices (GMP) are not standards or guidelines in the same way as ISO standards. They are based on European Directives, such as Directive 2003/94/EC, which was transposed into Spanish law through Royal Decree 2183/2004.
Their introductory and concluding provisions are mandatory.
As directives, they allow a certain degree of interpretation, although this margin is gradually narrowing as a result of inspections, official observations and the growing body of industry literature. In the US, cGMP (current Good Manufacturing Practice) also helps to reduce this scope for interpretation.
By law, we are required to ensure the manufacture of products that are safe, high-quality and effective.
The different regulations and guidelines surrounding GMP provide guidance that helps reduce this margin for interpretation. This enables good practices to be implemented in both facility design and operation. The objective remains the same: to ensure the reliable manufacture of safe, effective and high-quality medicinal products, with consistent performance over time.
It is important to remember that a standard does not become legally mandatory unless this is established by legislation. GMP requirements refer to both ICH guidelines and ISO 14644. These supporting or mandatory standards have been developed to define sensitive processes and activities more precisely.
The wide variety of pharmaceutical manufacturing processes has led to the development of these standards, meaning that, except in the case of novel applications, the pathways to compliance are generally well established.
However, they do not provide definitive, specific answers for every individual case, as this would be impossible given the vast range of products involved. The manufacturer therefore retains ultimate responsibility for justifying the solutions implemented to comply with GMP requirements.
This is where one of the most widely discussed and documented tools comes into play: risk assessment. Generally applied to a process, risk assessment helps determine the preventive measures — including design and procedures — as well as the organisational and operational measures that should be implemented in each case.
In this article, we examine some of the specific considerations involved in applying regulatory requirements to medicinal cannabis, as well as the significant role played by GACP (Good Agricultural and Collection Practice).
2. Medicinal Cannabis
Cannabis represents a particular case within standard pharmaceutical manufacturing practices for several reasons:
- Although many medicinal products, APIs and supplements are derived from plants, they generally reach the end consumer or patient in the form of extracts.
- Unlike other products, cannabis can reach patients not only in conventional formats but also in its original form as a flower. This excludes traditional plant-based compounded preparations, which have gradually disappeared from pharmacopoeias and do not fall within the definition of medicinal products with a therapeutic effect.
- Cannabis is a highly potent API, with multiple combinations of components — including cannabinoids and terpenes — and a wide range of therapeutic applications, some of which may involve side effects or psychotropic effects, with the associated safety implications.
- The main characteristics of cannabis as an API are determined by its genetics, but the potency or concentration can vary considerably as the plant grows.
- Cannabis has also introduced a new professional profile into pharmaceutical manufacturing, involving specialists from outside the traditional pharmaceutical production sector. This has led to differing interpretations regarding the application of GMP requirements to the process.
3. Application of GMP Requirements
Based on our experience and our product and process risk assessments for cannabis, let us examine some of the specific considerations involved in applying GMP requirements to cannabis production.
Dried Cannabis Flower for Direct Use as a Medicinal Product
According to Table 1 on the application of the GMP Guide to the manufacture of active substances of plant origin, this would correspond to the third row.
Following the indications in the table, GMP requirements begin to apply at the physical processing and packaging stage, including drying and trimming, which are the final processing stages before the product is dispensed to patients.
Because GMP requirements apply only to the final processing stages, the application of GACP during cultivation becomes particularly important for the following reasons:
- The different active substances develop for more than 10 weeks in what, from a pharmaceutical perspective, is an uncontrolled environment. This is an unusual situation. If we compare it with the formulation of an API, GMP requirements normally apply from the point at which the active molecule appears. In this case, however, the active molecule appears and develops long before the process enters the GMP-controlled stage.
- Environmental conditions — temperature, humidity and light — as well as cultivation processes and strategies such as plant density, irrigation and fertilisation, can have a major influence on the composition of the different APIs and on crop yield.
- If any of these parameters fall outside their appropriate ranges, the entire product may be invalidated. Since GMP requirements are not mandatory during this stage, the application of GACP becomes even more important.
- Supplier assessment, personnel training and facility conditions require highly rigorous procedures, even though the process is not yet subject to GMP requirements.
Controlling the different parameters involved in the cultivation phase is essential to ensure crop quality, stability and yield.
At the same time, keeping these parameters under strict control involves greater investment and higher operating costs, making it necessary to find the right balance.
Dried Cannabis Flower for Direct Use as a Medicinal Product
When defining the classification of the controlled environment in which cannabis is processed, GMP requirements once again provide no clear-cut answer. Annex 7 simply states that specific measures should be implemented to prevent cross-contamination.
Chapter 1 of the revised Annex 1 indicates that its principles and guidance — including the Contamination Control Strategy (CCS), facility design, cleanroom classification, qualification, validation, monitoring and personnel gowning — may also be used to support the manufacture of certain non-sterile products where controlling and reducing microbial contamination is considered important.
We therefore consider ISO 8 to be an appropriate minimum precaution for addressing the characteristics of this product. But why not another classification?
There are several specific considerations:
- This is essentially single-product manufacturing, but because some process stages — such as drying and curing — take a considerable amount of time, different batches may be present within the manufacturing area simultaneously.
- Unlike other pharmaceutical products, the main cross-contamination risk does not arise from mixing active substances, even where different cannabis genetics are being processed.
- The greatest risk is biological contamination — fungi, bacteria and other microorganisms — originating either from the product itself or from external sources. Such biological contamination may be evident and detectable during the initial GMP stages and batch quality controls, or it may remain latent and develop during the first few days of drying, when environmental conditions may still favour the proliferation of fungi and bacteria.
- According to our analysis, the greatest risk of cross-contamination occurs in the wet-processing and drying rooms. For these areas, we recommend a containment pressure strategy together with rigorous procedures regarding PPE and corrective actions in the event that contamination is detected.
- It is important to note that during processing, the product remains exposed to the room environment for extended periods, potentially several days, with the room itself effectively acting as the container. Cleaning and disinfection procedures must therefore be extremely thorough. This brings us back to Annex 1 and the need to develop a detailed CCS (Contamination Control Strategy), supported by scientific risk assessment and adapted to the particular circumstance that, for much of the process, the room environment and its operators effectively form part of the product containment system until the packaging stage.
Batch Definition
GMP requirements consistently refer to a manufacturing batch, meaning a defined quantity of product produced under the same conditions and using the same process in order to ensure uniformity. This creates considerable complexity in medicinal cannabis production. Once GACP has ensured the highest possible level of uniformity within the limitations of the available cultivation facilities, the GMP process must ensure that this uniformity is maintained:
- Processes are slow — a batch may require between one and two working shifts to process — and the product remains exposed to an environment to which it is sensitive. This environment must therefore be appropriate and controlled to ensure that the first and last products processed have the same characteristics.
- During drying, there is a large volume of product consisting of “living” material that continues to evolve over several days. Facilities must therefore be optimally designed and properly validated, including temperature and humidity mapping, drying recipes and loading procedures.
- Many processes require human intervention. Examples include manual trimming and decisions relating to curing times and conditions, where judgement can be subjective.
- Finally, the size of each batch can vary considerably after a process lasting more than 100 days, from obtaining cuttings through to the finished product. Reconciling the number of plants, rejected material, waste and the final quantity of product obtained is highly complex and critical because cannabis is a controlled substance.
Cannabis Flower for Medicinal Cannabis Extracts
In this case, we would be referring to the first and second rows of the previously mentioned Table 1 on the application of the GMP Guide.
Based on our experience, where the product undergoes only a single extraction process, this extraction should be performed in a GMP environment. However, where extraction is followed by distillation or purification, the initial extraction could be performed in a non-GMP environment, provided that the subsequent stages are necessarily carried out under GMP conditions.
The more highly purified the final product is intended to be, the greater the acceptable variability of the starting material — the cannabis flower — although this variability can have a significant impact on process yield and therefore on costs. Greater variability in flower characteristics could allow for less specialised cultivation infrastructure, but it does not remove the need for strict compliance with GACP, since plant material that falls outside the required parameters cannot meet the standards required by the subsequent GMP process.
For full-spectrum extracts — following the first extraction stage — where the presence of other cannabinoids or terpenes is valued, highly specific genetics are used and may even form part of the description associated with the final product. The quality of the starting flower is therefore fundamental, fulfilling a role comparable to that of a reactor in the manufacture of chemical APIs. For this level of “GMP flower for extraction”, the person responsible for the medicinal product should be involved in defining the production process.
4. Conclusions
Understanding how GMP requirements should be applied to the production of medicinal cannabis requires detailed knowledge of both the product and the manufacturing process. Some of the answers must be drawn from the revised Annex 1, together with the development of a CCS based on a scientific risk-assessment approach.
Applying GMP requirements to the medicinal cannabis production process — certified by the AEMPS (Spanish Agency for Medicines and Health Products) — not only helps ensure product quality and stability, but also represents a fundamental and mandatory step towards recognising cannabis as a medicinal product and distancing it from negative perceptions within society.
5. References
- Good Manufacturing Practice for Medicinal Products: Directive 2003/94/EC; Commission Directive (EU) 2017/1572 for medicinal products for human use, particularly Annex 7 and Annex 1.
- ICH Q9: Quality Risk Management, 2005.
- ICH Q7A: GMP Active Pharmaceutical Ingredients.
- ICH Q10: Pharmaceutical Quality System.
- Pharmacopoea Helvetica 11.3 Ed-fr_2019: Cannabis Flower, CH211-S-263.
- Analytical Monograph Cannabis Flos – OMC / Farmalyse BV V7, 28 November 2014.
- Bundesinstitut für Arzneimittel und Medizinprodukte Bekanntmachung zum Deutschen Arzneibuch 2018, 9 April 2018.
- PIC/S Guide to Good Manufacturing Practice for Medicinal Products.