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This article intends to clarify the main goals of GACP and GMP guidelines, identify differences between the two, and also explore why it is important, when operating within the medicinal cannabis sector, that these two guidelines are complied with and their standards achieved.
Good agricultural and collecting practice (GACP) guidelines and good manufacturing practice (GMP) guidelines each have the simple goals of protecting patients and ensuring that product quality is not compromised through the imposition of standardized practices and procedures in production processes. No business should risk jeopardizing product standards or the well-being of downstream consumers, and compliance with GACP and GMP can assist in avoiding such situations.
The use and application of GACP or GMP guidelines can differ depending on the intended use of the product in question and how each manufacturer defines its production processes. However, in relation to practical application and in terms of the requirements that each set of guidelines impose, there seem to be no substantive differences between the two regimes, other than the stage of the production process to which they are applied.
This article intends to clarify the main goals of each set of guidelines, to identify differences between the two, and also to explore why it is important, when operating within the medicinal cannabis sector, that these two guidelines are complied with and their standards achieved.
Good agricultural and collecting practices (GACP) guidelines were developed to create a single supranational framework to ensure appropriate and consistent quality in the cultivation and production of medicinal plant and herbal substances. They were developed by the World Health Organization (WHO) in 2003 with the aim of improving the quality of medicinal plants being used in herbal medicines in the commercial market.
Interest in herbal medicines has increased over recent decades and therefore the global market for medicinal herbs has grown rapidly. Consequently, the safety and quality of herbal medicines have become ever more important for both health authorities and consumers.
Production and primary processing of medicinal plants and herbal substances have a direct influence on the final quality of active pharmaceutical ingredients (APIs) produced and such production and primary processing actions can constitute the first step in the quality assurance process, which is central to compliance with the GACP guidelines. To achieve consistently reproduceable “starting materials of herbal origin” of an appropriate standard, an adequate quality assurance system for the collection or cultivation, harvest, and primary processing is required. The GACP guidelines provide a basis for homogenized national or regional standards for the cultivation and collection of medicinal plants and should therefore be viewed as an effective “working tool” whose benefits are to reduce waste, ensure quality of raw material, and gain market credibility.
GACP guidelines should always be read in connection with good manufacturing practice (GMP) guidelines for APIs. In addition, the basic principles of GMP such as the statement that “quality cannot be simply tested into a batch of product but must be built into each batch of product during all stages of manufacturing process” should be then extended to the GACP requirements (2). This interrelation is confirmed in the GACP statement (2): "The Guideline on good agricultural and collection practice does not fall directly under GMP guidelines in the traditional sense. However, these considerations should be used as a basis for the establishment of such an appropriate quality assurance system.” The combination of both requirements plays a huge role in achieving the right quality fit.
Eudralex Volume 4 (1) is the collection of rules and regulations governing medicinal products in the European Union and contains guidance for the interpretation of the principles and guidelines of good manufacturing practices for medicinal products for human and veterinary use. Part II of Eudralex Volume 4 sets out the basic requirements for “active substances used as starting materials.”
The goal of the GMP guide is to “provide guidance regarding (GMP) for the manufacture of active substances under an appropriate system for managing quality. It is also intended to help ensure that active substances meet the requirements for quality and purity that they purport or are represented to possess” (1). The guidelines do not apply to bulk-packaged medicinal products, but only to all other active starting materials that enter in downstream processing. As such these guidelines are applicable to medicinal cannabis operations that intend to produce APIs for sale to pharmaceutical companies.
All GMP recommendations are expected to be applied (unless shown to be inapplicable); this means that they are flexible in the way they are implemented if an equivalent level of quality assurance is ensured in relation to the operations carried out. The guidelines can therefore be adapted and customized, allowing for different types of models to be implemented to best fit the business in question, provided that all applicable chapters are addressed. The guidelines are not applicable to registration commitments nor intended to define registration or pharmacopeial requirements.
Annex 7 of GMPs - Part I sets basic requirements for medicinal products; these apply to herbal products such as medicinal cannabis because of their often complex and variable nature, which requires a tight control of starting materials (1). Herbal substances that are destined to be used in pharmaceutical products must be of suitable quality and supporting data needs to be maintained to document satisfaction of the requisite quality standards. Ensuring consistent quality of herbal substances can require detailed information on its agricultural production and, therefore, the selection and source of seeds, cultivation process details, and harvesting conditions are important areas to cover and as stated in Annex 7 of Eudralex - Volume 4 of GMPs (Manufacture of Herbal Medicinal Products). “Recommendations on an appropriate quality assurance system for good agricultural and collection practice are provided in the HMPC [European Medicines Agency Committee on Herbal Medicinal Products] guidance document: Guideline on Good Agricultural and Collection Practice for starting materials of herbal origin;” in this way the GMP guidelines emphasize the utmost importance of GACP and recommend its use as a reference to build a proper quality system (1). This highlights the importance of GACPs and GMPs being implemented side-by-side in relation to medicinal cannabis production processes.
The pharmaceutical industry is one of the most demanding industries in the world in terms of compliance requirements and the production of medicinal cannabis is inextricably linked to such standards. To ensure downstream patient safety, all operators must work within good practice frameworks at all stages of their operations to ensure that the output is a high-quality, safe, reliable, and effective product. The consequences of failure are severe and regulators have the power to impose fines, close facilities, or even suspend licences in such circumstances. As such, it is imperative that a responsible producer in the medicinal cannabis industry complies with the applicable rules and standards in their operations.
The term cannabis can have a broad range of meanings and connotations including being considered a drug substance of herbal origin, a drug product, an herbal medicinal product, a controlled drug substance, a controlled drug product, or a "raw material" from which medicinal products are prepared. Products containing cannabis can also range from medicines to therapeutic goods and food products.
Depending on how products will be used, different production standards can apply and in different jurisdictions, different legal regimes may apply (which can lead to inconsistent understanding and practices among drug regulators in different countries). Additionally, production standards should always be designed to take into consideration clients and final consumers' requirements and expectations for high quality products.
The usage and applicability of GACP and GMP guidelines may also change depending on the nature of the production process and the intended product use. As such, proper contextualization is very important when discussing production of cannabis products for medicinal purposes and the inter-relation with GACP and GMP guidelines.
In any case, where products are to be delivered into the medicinal market (whether as an active substance, an intermediate, or a finished product), GMP standards are mandatory and should be strictly followed; it is the manufacturer´s responsibility to ensure that the appropriate GMP classification is applied. The major objective for a manufacturer in applying GMP standards is to make sure that safety, quality, and efficacy of the product are not compromised, whilst also minimizing business risk.
Since Part II, “Basic Requirements for Active Substances used as Starting Materials” of Volume 4 of the GMP guidelines was published (according to Article 46 (f) of Directive 2001/83/EC and Article 50 (f) of Directive 2001/82/EC; as amended by Directives 2004/27/EC and 2004/28/EC, respectively) new obligations were placed on authorized manufacturers to use only active substances that have been manufactured in accordance with GMP for starting materials (1). As a consequence, in the context of medicinal cannabis production, GMP guidelines and requirements will begin to apply at the initial extraction stage (that is, following harvest), until such time as the physical processing of the cannabis material and packaging, including labelling of the APIs is fully completed.
Depending on the manufacturer determination of a product´s intended usage and classification, a GACP product can be inserted in a GMP supply chain. In the context of medicinal cannabis production, this means that all stages in the cultivation process up to initial extraction will be subject to GACP guidelines (as illustrated in Figure 1). In practical terms, the manufacturer must nominate and document the rationale for the point at which production of the active substance begins and GMP requirements begin to apply. For extraction processes, this rationale should be established on a case-by-case basis since it is dependent on the type of manufacturing or process being used.
When considering cultivation and harvest processes—where human intervention is needed and manual operations often prevail—the risk of contamination is increased and in such circumstances, the choice to apply GMP standards before they become mandatory (that is, during the wet trimming and drying steps) can benefit manufacturers by separating operations into different risk classes and smoothing the transition from GACP regime to the GMP regime within the same facility. In practical terms this can be achieved by sectional separation inside the facility; one area can be fully dedicated to cultivation and harvesting of material and be subject only to the GACP requirements and a different area can be dedicated to primary processing and obtaining of APIs, subject to GMP requirements (regulated by Part II of the GMP guide). A third area for finished product manufacturing (regulated by Part I of the GMP guide) can also be created during the facility layout process. By creating physical separation and different zones, clarity is added to the type of operations being undertaken in each zone and the regulations that apply within each one.
As operations approach physical processing and packaging, which is the final step of active substance manufacturing, the stringency of GMP requirements in relation to the active substance manufacturing increase. The GMP regulations and requirements increase as the product gets closer to its final form because risks increase during this time. Compliance with these increasing requirements both protect patients from harm and can also be relied upon by manufacturers as a compliance “shield.”
In relation to the production of medicinal cannabis products, compliance with the requirements of GACP and GMP is mandatory. Whilst this is not an easy task, successfully achieving compliance will distinguish a manufacturer from competitors. Designing and implementing a competent quality assurance (QA) system will be vital in this regard.
The key aspects for an effective QA system include, amongst others, well-written standard operating procedures (SOPs), well informed personnel, and a clear understanding of roles and responsibilities of the personnel involved. The development of a culture that achieves high quality and standards throughout is also important. Quality will only be ensured when all business units work in cooperation, keeping product quality and patient safety as their primary goals.
Although we have seen that the different requirements apply at different stages in the production process, it is legitimate to query and endeavor to understand if there are any differences to distinguish GACP requirements from GMP requirements and whether one is more demanding than the other.
The simple answer to the first question is that no, there are not any significant differences. The concepts and controls within both regimes are intended to be the same. While GACP requirements are applied to cultivation and collective practices (outside of the pharmaceutical industry), GMP requirements encompass primary processing of cannabis material to transform raw materials into APIs and transform APIs into pharmaceutical products.
Both regimes have a goal of ensuring consumer safety by establishing appropriate quality standards for medicinal plants and herbal substances; each set of regulations addresses the same topics and disciplines (such as quality assurance, quality control, personnel, calibration, validation, and storage). It is fair to say that GMP standards do incorporate more detail on every topic than GACP standards, but in both cases the requirements are not overly prescriptive, but rather require interpretation.
The practice of incorporating herbal products into manufacturing within the pharmaceutical industry is not new, but in fact it is where the pharmaceutical industry took its first steps (botanical drugs such as morphine and quinine having been prevalent in pharmaceuticals for generations). Thus, the combination and inter-relation of the two different areas of agricultural cultivation and pharmaceutical production is unsurprising in relation to medicinal cannabis production processes, nor is the interplay and subtle shifts between the imposition of GACP and GMP rules, respectively.
Below is a brief comparison of aspects of GACP and GMP.
Description of Processing Instructions
GMP and GACP guidelines set out similar requirements in relation to processing instructions for an herbal substance and require the process to be described in relation to each operation carried out upon the herbal substance (for example, GMP requires that drying time, temperatures, and all methods involved to control cut size or particle size should be described; the GACP requirements state that “all processes and procedures that could affect the quality of the product must be documented”). All processing steps must therefore be documented to ensure compliance from both GACP and GMP perspectives.
Regarding traceability, both guidelines require unambiguous and unmistakable traceability from the beginning to the end of the process. Labeling and batch assignment take an important part of the process and should be taken as early as possible in the process chain. GACP collected and cultivated medicinal plants should carry different batch numbers and (as also mentioned in Annex 7 of GMP guide and chapter 4 of Basic requirements for medicinal products [Part I]) the scientific name of the plant and all relevant information that allows one to characterize and describe the material and herbal plant should be included.
Treatments to Reduce Fungal and Microbial Contamination
In relation to treatments needed to reduce fungal and microbial contamination, both guides effectively require the processes to be documented (despite expressing this in different ways). The proper level of documentation, specifications, and procedures implemented and updated, including proper level of detail, tests performed afterwards, specification, and limit of residues must be retained to comply with either regime (also applicable for fumigation procedures). The use of substances such as fertilizers, pesticides, herbicides, or any growth promoters must be limited to those in the list of approved materials for production, in conjunction with applicable legislation.
Audits and self-inspections are important under both regimes. Any comprehensive documentation on audits of the herbal starting material suppliers carried out should always be made available. According to Annex 7 of Part I of the GMP, it is the manufacturer´s responsibility to assure that suppliers of the herbal substance preparation follow GACPs. GACP requirements prescribe that the results of any audits and inspection should be documented in an audit report and be stored for a minimum of 10 years.
Both guidelines contain the same requirements in relation to training; there should be specific training on matters such as on personal hygiene responsibilities and adequate botanical training before performing tasks requiring specific knowledge as well as records documenting the training performed. Specific training on good documentation practices must be also included on the training package.
For the reasons explored above, we can conclude that there is a difference between GACP and GMP guidelines in relation to the stage of production at which they should be applied. However, from a holistic perspective they are very similar in their goals and objectives and they are also similar in the fact that they require interpretation and application on a case-by-case basis.
For cultivation, collection and manufacturing practices in relation to production of medicinal cannabis, GACP and GMP guidelines must be complied with at different production stages to ensure that the outcome of the cultivation and manufacture process is a compliant product that can be sold into the market. On top of these guidelines, additional requirements may also be prescribed by different local regulators.
The challenge facing all participants in the industry is to find a common understanding and interpretation of the GACP and GMP guidelines, given the fact that the guidelines are not simply prescriptive, but require analysis and consideration by qualified professionals, and individual application to each set of circumstances.
To achieve success in compliance with GACP and GMP requirements as they apply throughout the cultivation and production process, a robust risk management and quality assessment program must be implemented. This will facilitate the performance of requisite, ongoing risk assessments and risk analyses to properly map and understand the production process, identify any potential risks (for product quality and consumer and patient safety), and provide solutions to address such risks, while promoting cost saving (from reduction in defects and poor quality to greater likelihood of passing regulatory inspections).
The goal is always the same when it comes to performing such assessments or analyses: identify, eliminate, and exclude risks, so as to achieve a consistent product quality based in defined criteria and specifications. Risk assessments or analyses are also a good tool to increase the awareness perception by staff of risk concepts, leading to better compliance with GACP, GMP, and product safety, quality, and efficacy.
MIGUEL FAGUNDES is a pharmacist by training, and a specialist in the pharmaceutical industry by the Portuguese Pharmaceutical Society, able to act as a Qualified Person. He completed a Leading Pharma program for Pharmaceutical Industry at Católica Lisbon School of Business & Economics and has a comprehensive expertise in drug development, quality assurance, and manufacturing process validation gained throughout his diversified experience; his expertise lies in successfully managing teams, processes and programs contributing to continuous improvement and overall performance excellence and also ensure compliance with local and international regulations (such as the EMA and FDA). He is the Head Pharmacist and Qualified Person (QP) at EuroCan (a Botanical Holdings company) in Mação, Portugal. Direct correspondence to: firstname.lastname@example.org
M. Fagundes, Cannabis Science and Technology 3(9), 33-38 (2020).