For two to three years, the cannabis manufacturing industry has been experiencing a new hype - the prospect of medical use, especially of products containing THC. The positive effect of cannabis and the products derived from it in medicine is undisputed; whether as a painkiller, in epilepsy or other disease-related convulsive conditions. But also with regard to addiction treatment, the legalization of cannabis is on the rise worldwide. This opens up completely new opportunities for manufacturers, especially in the segment of high-quality medicinal products, which could counteract the current drop in prices in the CBD products segment.
At the same time, however, new challenges stand in the way of the positive outlook. The manufacture of a medicinal product and the associated active substance is subject to strict legal regulations; in particular quality requirements for product, process and processing, which are commonly summarized under the term "Good Manufacturing Practice" (GMP - Good Manufacturing Practice). This is not something to be implemented “simple and voluntarily”. quality assurance system.
Rather, it is about a wealth of detailed requirements that address issues such as personnel, hygiene, raw materials, technical facilities, documentation, processes, analyzes and much more. In the case of production in Switzerland, these requirements are stipulated in both the European and the PIC/S guidelines. There are additional GMP guidelines to be observed if you want to export your products to countries that are outside the scope of the EU and PIC/S.
If the production is geared towards medical cannabis, you have to deal with this topic very early on. One of the most common mistakes is that the first facilities, the construction and expansion of production facilities, are started quickly without having created the special planning documents required in the GMP-regulated environment. However, this can end up jeopardizing the entire project when it comes to official inspection and certification.
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At the beginning there is the product idea and of course the business plan - both of which initially appear to have no connection to GMP. But far from it! The considerations regarding the product portfolio, the sources of supply (e.g. biomass or flowers) and the planned markets essentially determine the regulatory and GMP requirements. It is about questions of import, export and GMP compliance of possible foreign suppliers. All of this must be carefully considered and defined in the strategy.
At the very beginning, it must be clarified what is really feasible and what is not – in this regulatory environment that is still very uncertain. Some have already stumbled over the fact that their business partner in Canada was not EU GMP-compliant or that the Macedonian manufacturer did not have permission to supply the German market from a regulatory point of view. A GMP compliance check of potential partners is required at a very early stage.
Figure 1 shows a very simplified scheme of the most important steps in the sequentially prescribed process. Only those who consistently follow these steps have a chance of obtaining the necessary certification at the end.
A document that is important in the GMP environment and also required by the authorities are the User Requirement Specifications (URS) – in short: the user requirements. The results of the business strategy (but without the economic aspects) are laid down in this document. In particular, the basic GMP requirements that follow from the strategy and are to be observed are fixed therein. This document is the basis for all further actions and is kept up to date throughout the life cycle of the project. It is a formal document that must be officially released with date and signature.
Once the regulatory boundary conditions have been set, the basic structural concept can be started – usually with the first layout plans. Here, however, it is important to look at these plans for the first time from a GMP point of view, to carry out so-called design reviews. It is about the establishment of hygiene zones prescribed by GMP, the definition of clearly defined personnel and material flow plans, the definition of functional rooms according to the logical production process, air flow and air quality strategies and much more. In addition to the basic "construction plan", a "GMP zone plan" is also required, which represents an important basis for the first plan review by the authorities. The plan review meeting is a project milestone that should not be underestimated. Only after this can the further construction progress be recommended.
In the implementation phase - construction or conversion of the production facility - the cannabis manufacturer is confronted with a new GMP-typical requirement, the qualification. This corresponds to a very in-depth, detailed and systematic technical check, which, however, must be planned in advance and documented in detail. All documents must be created in a specific order and signed and released by the later manufacturer and a quality person assigned to him. Here, too, not adhering to a given order can jeopardize the entire project.
It is important to create a URS for each individual technical system and to subject the system to a risk assessment. Furthermore, test documents for the installation, functional and performance test (IQ, OQ, PQ – Installation, Operational, Performance Qualification) must be created, the tests carried out and concluded with an evaluation report. Only when all these tests have been carried out and an error-free report is available can the manufacturing activities begin - with one restriction: validation. Because similar to the technical system, the manufacturing process itself is also subject to intensive tests, which must be formally described and processed to the same extent.
Once the system is up and running, the next important step is to set up a GMP-compliant quality assurance system. GMP strives for a high level of product safety and therefore requires that all processes and work steps must be documented in an instruction. This should help that different people always carry out the same work processes, that errors are avoided and that tried and tested processes are fixed and not forgotten. But not only the instructions for the processes have to be created. It is expected that every procedure will be accurately recorded, that errors will be recorded and evaluated and that changes will only be made with prior approval. In addition to the instructions, there are also a lot of logs to be generated to record the processes. Some people sometimes translate GMP with “a whole lot of paper”. 60 and more instructions and many other documents and protocols are no exception.
The last and certainly the most difficult step is to implement everything that has been described in the documents. And here the focus is on the person, the staff. Here, too, the old adage applies that a system is only as good as it is understood, accepted and ultimately implemented. And that is a big challenge in practice. Many a GMP candidate failed in the end because the hired personnel did not understand many points and therefore did not implement them or did so incorrectly, i. H. poorly documented. With such a project, it is never too early to start hiring the planned personnel, integrating them directly into the project process and providing them with ongoing training. It is certainly not presumptuous to say that, based on our own experience, another one to two years after the construction of a system must be reckoned with until everything runs largely without complaint and error-free.
Last but not least, GMP compliance - the agreement with the GMP requirements - is then put to the test when it comes to the formal, official acceptance, the inspection. Not only the system, the defined zones and the technical designs are checked here. The quality assurance system, qualification, validation and behavior of the staff (the documents kept by the staff) are also examined very closely. Now you can see whether the topic of GMP was taken seriously, whether it started on time and whether the given order was followed. If you have taken all this too lightly, it will become clear at this point at the latest what the meaning of GMP is.
Finally, the importance of GMP
Many incidents in the past in which people were harmed or even killed by medicinal products of poor quality have led to the development of the GMP regulations. In the end it's about protecting people; here specifically of a sick person who trusts in medicine. This does not allow any leeway with regard to a qualitatively flawless production. For this reason, GMP focuses on at least the following three essential aspects:
Avoidance of any kind of contamination of the product (physical, chemical and microbial) or other qualitative impairments (e.g. wrong or missing effect). Processes that are as reproducible as possible, which show that the process is mastered and under control. Detailed and complete documentation that supports the consistent processes and, in the event of an error, enables tracing and troubleshooting at any time.
About the author Ralf Gengenbach
Ralf Gengenbach, chemical engineer (TU Karlsruhe), founded gempex GmbH in 2002, an international GMP service company. Before that, he was active as an internal GMP consultant at BASF in numerous technical committees (DIN, VCI, DECHEMA) and was involved early on in the drafting and commenting of the PIC7S document PI006 (validation) and the ICH Q7 GMP guideline. In addition to numerous publications, lectures and lectures, Ralf Gengenbach has written down his accumulated knowledge in the book "GMP, Qualification and Validation of Active Ingredient Plants" (published by Wiley Verlag).
This content was originally published here.
