Good Manufacturing Practices (GMPs) are not standards and guidelines, as ISO can be, but they are European Directives (2003/94/CE), which were transposed into Spanish law by Royal Decree 2183/2004.
In introduction and conclusion, which are mandatory.
Their "directive" aspect leaves a certain level of interpretation, which is reduced day by day by the outcome of inspections, official deviations, and supported by literature. In the US, the cGMP (c=current) help to reduce this margin of interpretation,
By "law" we are obliged to ensure the production of "safe, quality and efficient" products.
The different regulations surrounding GMPs offer guidelines to reduce this margin of interpretation. This allows us to implement these good practices in the design and operation of the facilities. The objective remains the same: to ensure a safe, efficient, reliable and stable drug production result within the set time frame.
It is important to remember that a regulation is not mandatory until it is dictated by a decree of law.
It should then be noted that the GMPs mention the ICH and ISO 14644.
These satellite or mandatory standards have been developed to further define "sensitive" processes and activities.
The large number of manufacturing processes for pharmaceuticals has led to the creation of these standards, so that, with the exception of novel cases, the pathways end up being quite clear.
But neither do they offer definitive and concrete answers for each case, which would be impossible with the infinite number of products, but leave it up to the manufacturer to justify the solutions implemented to comply with the GMP.
This leads to one of the most talked about tools, with the most literature, "risk analysis" (generally on a process), which guides in each case on the preventive (design, procedures), organisational and operational actions to be implemented.
In this article we address some particularities of the application of standards in medical cannabis, as well as the great importance of the implementation of the GACP (Good Agricultural and Collection Practices) standards
Cannabis is a special case within standard medicine manufacturing practices for the following reasons:
Let's look at some particularities of the application of these GMP regulations in Cannabis production, based on our experience and our product and process risk analyses for cannabis.
According to table 1 of the application of the GMP regulations to the manufacture of active substances of plant origin, we would be placed in the third row:
Following the indications in the table, GMP regulations will start to be applied at the time of physical processing and packaging including drying and shaving (last processing steps before dispensing to patients).
As GMP regulations apply only to the final processing steps, the application of GACP regulations during the cultivation steps is of particular importance due to the following aspects:
It is essential to control the different parameters that make up the cultivation phase in order to ensure the quality, stability and yield of the crop.
At the same time, keeping the above parameters under control means higher investment and operating costs, so it is necessary to find a balance.
When it comes to defining the classification of the controlled environment for processing cannabis, we return to GMP and are left without a clear answer. In Annex 7, it simply tells us to implement particular measures to avoid cross-contamination.
From Chapter 1 of the new Annex 1 and its "principles and guidance, such as contamination control strategy, facility design, clean room classification, qualification, validation, monitoring and personnel clothing, can be used to support the manufacture of other products that are not intended to be sterile, such as certain liquids, creams, ointments and biological intermediates with low microbial load, but where the control and reduction of microbial contamination is considered important".
We are left with the choice of going to ISO 8, as a minimum precaution to respond to the characteristics of this product. But why not another classification?
Let's take a look at some particularities:
In GMP, reference is always made to the manufacturing batch, i.e. a fixed quantity of product obtained under the same conditions and process to ensure uniformity. This implies a great deal of complexity in medical cannabis. Once the application of GACP ensures maximum uniformity, within the possibilities of the cultivation facilities available, the GMP process ensures that this uniformity is maintained:
At this point, we would be in the first and second row of table 1 above (application of GMP Guide).
In our experience in the case of a product where only one extraction is performed, this must be done in a GMP environment. On the other hand, if extraction plus distillation or purification takes place, extraction could be performed in a NON-GMP environment, as long as the following steps necessarily take place in a GMP environment.
The more purified the product to be obtained, the more variability the starting material (flower) can have, although we will have an important impact on the yield (costs) of our process. This variability in flower characteristics would allow for a less specialised cultivation infrastructure but does not exempt from strict compliance with GACP standards, as an out-of-parameter plant source does not allow for compliance with GMP process standards.
For full spectrum extractions (first extraction) where the presence of other cannabinoids or terpenes is assessed, the starting point is very specific genetics that are even associated with the description that accompanies the final product. The quality of the starting flower is crucial (it would correspond to the function of a reactor for chemical APIs). For this "GMP flower for extraction" quality, it is necessary that the person responsible for the medicinal product is involved in the definition of the procurement process.
We see that shedding light on how to apply GMP regulations in the production of this particular medicine requires detailed knowledge of the product and the process. We have to go and look for part of the answers in the new Annex 1, and force ourselves to develop a CCS, with a scientific basis of risk analysis.
This GMP approach to the production process (certified by the AEMPS), in addition to ensuring the quality and stability of the products, is the basic and mandatory step to consider cannabis as a medicine and will keep it away from negative perceptions by society.
Author:
Eudald Bogatell
Collaborators:
Lidia Campillo
Frederic Pascuar