Method and system for microbial contamination reduction of herbal medicinal products

Abstract

The present invention refers to a method and a system for the microbial contamination reduction of herbal medicinal products. The method for microbial contamination reduction of herbal medicinal products comprises: filling an empty vessel (1) with a predetermined amount of an herbal medicinal product (5) to be treated and with a predetermined amount of decontamination agent in liquid state; closing the filled vessel and allowing the herbal medicinal product to be exposed to the decontamination agent vapors under controlled temperature for a programmed time period. The invention also refers to a system for carrying out the method for microbial contamination reduction of herbal medicinal products, which comprises: one or more liquid decontamination agent chamber (2); one or more vapor decontamination agent chamber (3); and one or more herbal medicinal product holding means (4) arranged inside the vapor decontamination agent chamber (3), for accommodating the herbal medicinal product (5).

Description

[0001] DESCRIPTION

[0002] " METHOD AND SYSTEM FOR MICROBIAL CONTAMINATION REDUCTION OF HERBAL MEDICINAL PRODUCTS"

[0003] FIELD OF THE INVENTION

[0004] The present invention relates to a method and a system for the microbial contamination reduction of herbal medicinal products using selected volatile decontamination agent (s).

[0005] BACKGROUND OF THE INVENTION

[0006] The human use of botanical products is ancestral and encompasses a multitude of industries, including biotechnology; construction; chemical; energy; food and drinks; forestry; pharmaceutical; pulp and paper; or textiles.

[0007] In specific, herbal medicinal products, have been progressively framed by evolving strict standards of pharmaceutical industry so that their widespread use for medical conditions can match the expected requisites of quality, safety, and efficacy. By the current European rules, the herbal medicinal products can be categorized as having 'well-established use' based on sufficient safety and efficacy data and or as 'traditional use' based on sufficient safety data and plausible efficacy.

[0008] Among the thorough mandatory quality requisites required for herbal medicines products one can find the microbiological state of these products. According to the European Pharmacopeia11.0 the acceptance criteria for microbiological quality is based on four types of indicators:

[0009] i) the total aerobic microbial count (TAMC);

[0010] ii) the total combined yeasts / moulds count (TYMC);

[0011] iii) content of the bile-tolerant gram-negative bacteria; iv) absence / presence of specific bacteria species.

[0012] These give rise to different quality categories. Three microbiological quality specifications are given in Table 1 for the case of herbal medicinal products for oral use and extracts used in their preparation (v. 04 / 2019:50108 ).

[0013] Table 1 - Microbiological quality specifications.

[0014] A. Herbal medicinal products containing hcrhai drugs,

[0015] with or without excipients, itsten ed for the preparation of itifii ioiss. and dec< K.ti<ms using boiling water (for example herbal teas, with or without added flavourings)

[0016] TAMO (26. f J) crU’Sfiof}: B)' C. FU.'g

[0017] Maxira«:iS3 5?) (W CRJ / g

[0018] TYMC (2.6.12) Acceptance criterion: 10⁵ CFU / g

[0019] Maximsnn actepUbie cosssm 5(S(S 8S»CFU / g

[0020] Esrfssfr ScsSi? rns; Acceptance criterion:! (Y -..n g

[0021]

[0022] (2.251} Absence (25 §)

[0023] B.. Herbal medicinal products coufoinmg, for example,

[0024] extracts and / or herbal drugs, with or without excipients, where the method of processing (for example, extraction} or, where appropriate, in the case of herbal drugs, of

[0025] pre- treatment reduces the levels of organisms to below

[0026] those stated for this category

[0027] TAMC (2. A 22) Acceptance criterion: CFU / g or CFUhnL

[0028] Mastimssn coant: 56 SiY) CFU'g

[0029] erCFU / asL

[0030] TYMC (2612; Acceptance criterion: 13‘ CFU / g or CPL’lmL

[0031] Maximm JKssptabte cosiit: 590 CFU / g

[0032] orCFUfml.

[0033] Siie-totemit

[0034] grain -negative Acceptance crilexiun: 10* C;’V;'g Ci;LYfs; I.

[0035] bscfefta;2.fi.?f)

[0036] (2.6.311 Absence (i g or i ml)

[0037]

[0038] & S»e8a (26,31; Absence > 25 g or 25 isd. ■Q. Herbal Bted inal produc ts containing, for example,

[0039] extracts au or herbal rugs, with or without excipients,

[0040] where it can be demonstrated that the method of processing

[0041] (for example, extraction with low-strength ethanol or water that is not boiling, or lo -temperature concentration)

[0042] or, in the case of herbal drugs, of pre- treatment, would

[0043] not redace the level of organisms sufficiently to reach the

[0044] criteria required under B

[0045] TAAiC (2. SJ3S Acceptance criterion: •, ft? CFU / g or CFU / ERL.

[0046] Maxbntun sccepahsa emsnh 58090S CFU / g

[0047] or CFU / mL

[0048] Acceptance crAertan; iff CFU / g or CFUtol

[0049] MextinatBAceeptaffe cout’L 58899<'FU: / g

[0050] w CFU / mt

[0051] Slfe-tuferanl

[0052] gram -negative Acceptance criterion; id CFUfgor CFU / asL

[0053] bacterta < AS)

[0054] Absents i 1 g iff i SKLJ

[0055] (2<6,.s / i

[0056]

[0057] SaA’jejsiAfe, y.sog Absence il5 g tsr 25 sub}

[0058] To exemplify, for TAMC the acceptance can range from 107to 104CFU / g, and for TYMC from 105to 102CFU / g. Other routes of administration have alternative criteria (see chapter 5.1.4 of the same pharmacopeia, v. 01 / 2021: 50104 ).

[0059] In this context, it is highly frequent that herbal medicinal products need to be submitted to unit operations devoted to their microbial contamination reduction and, ultimately, the compliance with the applicable microbiological quality specifications.

[0060] The existing methods for decontaminating herbal medicinal products include ionizing radiation (US11160891B2 ) such as gamma irradiation, beta irradiation, x-ray (US20230381354A1, WO2024044159A1 ), etc.; non-ionizing radiation such as ultraviolet (AU616998B2 ), infrared, microwave (WO2023233089A1, US4808782A), radio frequency (US2023355693A1 ), etc.; steam or air based-treatments combining pressure and temperatureconditions, such as autoclave steam processing, dry heating, or high pressure processing (US2021186062A1 ); cold plasma treatments involving air, inert or oxidant gases (EP3877008A1, US2016262410A1 ); or approaches relying on reactive / oxidant chemical agents such as ozone (EP4030916A1 ), hydrogen peroxide, or chlorine dioxide.

[0061] Each of the prior art options come with its own problematic cons, namely:

[0062] i) The usage of beta irradiation as a source of ionizing radiation, although very effective for microbial contamination reduction and of widespread use in the pharma industry, can pose difficulties for industrial manufacturers due to the lack of authorization to implement and operate the method inhouse, forcing a disconnection of the internal value chain and creating a permanent dependence from third parties. This raises significantly the production costs due to extra logistics, bureaucratic work, and processing fees. What is more, an important European market such as Germany requires a specific approval for the marketing of medicinal products treated with any type of ionizing radiation (Ordinance on Medicinal Products Treated with Radioactive or Ionising Radiation, AMRadV), which is itself costly, time consuming, and creates uncertainty over new economic deals.

[0063] ii) The use of microwaves or radiofrequency is limited to non-dry materials and typically creates uneven spots of high temperature that can damage or modify the composition of the herbal medicinal products (s). The fact its efficacy is tied to higher degrees of humidity is itself a risk because bioburden tends to aggravate under higher wateractivity levels. Furthermore, the drying of herbal medicinal products typically occurs right after harvesting these natural products to contain bioburden expansion, but microbial contamination reduction is safer to accomplish closer to the final packaging stage, where the herbal product moisture is already very reduced (e. g. below 10 % wt. ).

[0064] iii) As for the usage of thermal-based treatments, they often cause thermal degradation of herbal medicinal products, particularly when sensitive parts like fruits, leaves, flowers are involved; and they can also cause the accidental loss of the most volatile product constituents, particularly those that are relevant for the organoleptics and / or the medicinal effects. They can also dry the products unintendedly.

[0065] iv) Approaches using sub-atmospheric pressure ( i. e.

[0066] vacuum) can likewise lead to unintended losses of the most volatile product constituents and / or unintended drying of the product (s) even if conjugated with low temperatures. In fact, sub-atmospheric pressure is an ancillary feature, as it is not self-sufficient to attain contamination reduction. For this reason, it is many times combined with thermal, ionizing, non-ionizing and / or chemical methods, incorporating the cons of these approaches;

[0067] v) With regard to cold plasma treatments - being them of arc discharge, corona or other type - to our knowledge, these treatments are limited on the maximum logarithmic reduction they can attain, because long exposure time or higher system power induce irreversible surface damages on the product (s). If coupled to sub-atmospheric pressure, theyinherit the cons of the latter. If coupled to reactive gases as medias idem.

[0068] vi) Treatments with reactive / oxidant chemical agents pose risks regarding the accidental contamination of the product with chemical entities that typically are not Generally Recognized as Safe (GRAS). In addition, they may modify the chemical composition of the product due to unintended side reactions and, consequently, they may induce irreversible modifications of the aspect and organoleptic profile of the product ( s ).

[0069] For the exposed reasons a need exists in the field to ensure microbial contamination reduction of herbal medicinal products in a way that:

[0070] i) avoids the economic, legal and bureaucratic obstacles of ionizing radiation;

[0071] ii) is feasible to install and couple to existing or new industrial processes devoted to processing herbal medicinal products;

[0072] iii) is tunable and versatile to address alterable microbial contamination reduction targets;

[0073] iv) is technically reliable even for the most exigent contamination reduction targets;

[0074] v) does not detract irreversibly the product quality (textural, mechanical, chemical composition, organoleptic, etc. );

[0075] vi) does not require the product to be wet to be effective;

[0076] vii) does not dry the product as a side effect; and viii) is cost competitive in relation to benchmarked solutions.BRIEF DESCRIPTION OF THE FIGURES

[0077] Without intent to limit the disclosure herein, the present invention will be further described in greater detail based upon preferred embodiments and respective Figures attached hereto, for an easier understanding.

[0078] Figure 1 depicts a conceptual scheme of the system for the microbial contamination reduction of herbal medicinal products.

[0079] Figure 2 depicts the saturation concentration of two decontamination agents - ethanol and isopropyl alcohol - in gas phase for temperatures between 1 °C and 30 °C.

[0080] Figure 3 is a schematic representation of an embodiment of the system for the microbial contamination reduction of herbal products.

[0081] SUMMARY OF THE INVENTION

[0082] The present invention is directed to a method for microbial contamination reduction of herbal medicinal products comprising the following steps:

[0083] a) filling one or more parts of an empty vessel with a predetermined amount of an herbal medicinal product to be treated;

[0084] b) filling one or more parts of the referred vessel with a predetermined amount of decontamination agent in liquid state;c) closing the filled vessel in a way to ensure sealed conditions;

[0085] d) allowing the herbal medicinal product to be exposed to the decontamination agent vapors under controlled temperature for a programmed time period; and

[0086] e) retrieving the treated herbal medicinal product from the vessel.

[0087] In an embodiment, the step b) precedes step a).

[0088] In another embodiment, the method further comprises the following steps between the steps d) and e):

[0089] i) removing the decontamination agent liquid from the vessel; and

[0090] ii) removing the decontamination agent vapors from the vessel.

[0091] In a further embodiment, step b) comprises a continuous or discontinuous inlet of a gas stream enriched in the decontamination agent.

[0092] In another embodiment, step i) comprises a continuous or discontinuous outlet of a gas stream.

[0093] In other embodiment, the herbal medicinal product is any vegetal material selected from the group of leaves, fruits, inflorescences, flowers, stems, roots or their mixtures.

[0094] In a further embodiment, the herbal medicinal product is medicinal cannabis, preferably, cannabis inflorescences.In another embodiment, the decontamination agent is selected from the alcohol group compounds from the C2-C15 class or their mixtures, the alcohol group compounds from the C2-C7 class or their mixtures or the alcohol group compounds from the C2-C3 class or their mixtures.

[0095] In a preferred embodiment, the decontamination agent is ethanol or isopropyl alcohol or their mixtures.

[0096] In other embodiment, step d) is performed at a temperature in the range of 1 °C to 30 °C, preferably 5 °C to 10 °C, more preferably 6 °C.

[0097] In another embodiment, step d) is performed during a time period in the range of 3 h to 69 h, preferably 12 h to 48 h, more preferably 24 h.

[0098] The invention also relates to a system for carrying out the method of the invention, the system comprising a sealed vessel ( 1 ) wherein it comprises:

[0099] • one or more liquid decontamination agent chamber (2); • one or more vapor decontamination agent chamber (3); • one or more herbal medicinal product holding means (4) arranged inside the chamber (3), for accommodating the herbal medicinal product.

[0100] In an embodiment, the herbal medicinal product holding means (4) is selected from tray, basket, mesh bag or similar.DETAILED DESCRIPTION OF THE INVENTION

[0101] The present disclosure provides a method and a system for the microbial contamination reduction of herbal medicinal products using selected volatile decontamination agent (s). The invention applies to herbal medicinal products regardless of the biological species; variety; morphological parts; dryness; preceding process stages; and regardless of being mixtures or not.

[0102] The method and the system of the present invention allow a microbial contamination reduction of herbal medicinal products as well as avoidance of irreversible degradation of the other quality parameters of the herbal medicinal products, such as texture, size, color, and organoleptics, as well as of the chemical composition of either the active substance (s) or of complementary constituents playing a role on the herbal product effects.

[0103] More specifically, the invention comprises a method and a system of herbal medicinal products impregnation with vapors of selected volatile decontamination agent (s) through the creation of an atmosphere rich in the same agent (s) inside a sealed vessel.

[0104] As used in this description and the appended claims, the singular forms "a, " "an, " and "the" include plural referents unless the context clearly indicates otherwise.The term "and / or" as used herein means that the listed items are present, or used, individually or in combination. In effect, this term means that "at least one of' or "one or more" of the listed items is present or used.

[0105] In the context of the present description, the terms "comprising" (and any form thereof, such as "comprise" and "comprises"), "having" (and any form thereof, such as "have" and "has"), "including" (and any form thereof, such as "include" and "includes") or "containing" (and any form thereof, such as "contain" and "contains"), are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. As such, said terms should not be interpreted as "consisting only of".

[0106] In the following detailed description, preferred embodiments of the invention are described to enable practice of the invention. Although specific terms are used to describe and illustrate the preferred embodiments, such terms are not intended as limitations on practice of the invention. Moreover, although the invention is described with reference to preferred embodiments, numerous variations and modifications of the invention will be apparent to those of skill in the art upon consideration of the foregoing together with the following detailed description.

[0107] In the context of the present invention, the terms "decontamination" and "decontaminate" refer to a logarithmic reduction of microbial loads in the herbal medicinal product (s), and comprises aerobic bacteria, yeasts, and moulds.Also, in the context of the present invention the term "decontamination agent" refers to a chemical substance or mixture of substances that is able to induce a microbial decontamination effect of any type and under any mechanism when held in contact with herbal medicinal product.

[0108] The term "sealed vessel" as used herein refers to a vessel of undeformable shape and dimensions, forming a constant internal volume, and being spacious enough to accommodate inside other components.

[0109] The term "holder means" as used herein refers to physical means that allow the accommodation of an herbal medicinal product and prevention of accidental falls or movement of the herbal medicinal product before, during, or after the treatment.

[0110] The term "chamber" as used herein refers to an identifiable location or position inside the treatment vessel, having independent structure or not, that plays a distinct role in the method.

[0111] The terms "herbal products", "herbal medicinal products" or "vegetal material" as used herein refers to any plant with savoury or aromatic properties that is used for flavouring and garnishing food, for medicinal purposes, or for fragrances. An example of a "herbal product", "herbal medicinal product" or "vegetal material" is cannabis.

[0112] The method of the present invention for reduction of the microbial contamination of herbal medicinal products comprises the following steps:a) filling one or more parts of an empty vessel ( 1 ) with a predetermined amount of an herbal medicinal product to be treated, supporting it with a holder means (4 );

[0113] b) filling one or more parts of the referred vessel ( 1 ) with a predetermined amount of decontamination agent in liquid state;

[0114] c) closing the filled vessel ( 1 ) in a way to ensure sealed conditions;

[0115] d) allowing the herbal medicinal product to be exposed to the decontamination agent vapors under controlled temperature for a programmed time period; and

[0116] e) retrieving the treated herbal medicinal product from the vessel ( 1 ), with or without the respective holder means (4 ).

[0117] In an embodiment of the method, steps a) and b) can be inverted, i. e. step b) - filling one or more parts of the referred vessel ( 1 ) with a predetermined amount of decontamination agent (s) in liquid state - precedes step a) filling one or more parts of an empty vessel ( 1 ) with a predetermined amount of an herbal medicinal product to be treated, supporting it with a holder means (4 ).

[0118] In another embodiment of the method, between the steps d) and e) it comprises the following two steps:

[0119] i) removing the decontamination agent liquid from the vessel ( 1 ); and

[0120] ii) removing the decontamination agent vapors from the vessel ( 1 ).In other embodiment of the method, step b) comprises a continuous or discontinuous inlet of a gas stream enriched in the selected decontamination agent (s) and step ii) comprises a continuous or discontinuous outlet of a gas stream from the vessel ( 1 ), which could be a gas stream enriched in the selected decontamination agent (s).

[0121] The holder means (4 ) is selected from the group comprising tray, basket, mesh bag and similar means.

[0122] The decontamination agent used in the present invention is any chemical compound with a bioburden reduction potential and comprising the following features:

[0123] (i) having competitive prices and availability for industrial scale utilization;

[0124] (ii) being liquid at 1 atm in the 1°C to 30 °C temperature window;

[0125] (iii) being classified as volatile by comprising a boiling point range from 50-100 °C to 240-260 °C;

[0126] (iv) being classified as Generally Recognized as Safe ( GRAS );

[0127] (v) exhibiting chemical affinity for natural absorption by lignocellulosic matrices; and

[0128] (vi) exhibiting antibacterial and / or antifungal activity.

[0129] Among other possible compounds, alcohol group compounds from a C2 to C15 class or mixtures involving them can match with the listed criteria; preferably from C2-C7 class, and most preferably being from the C2-C3 class. Examples of such compounds are ethanol or isopropyl alcohol.The method and system of this invention is directed to herbal medicinal products, for instance medicinal cannabis and preferably cannabis inflorescences, but can be applied to any individual or combined vegetal material (s), regardless of the morphological parts (e. g., leaves, fruits, inflorescences, flowers, stems, and roots), and of pretreatments, such as drying, cutting, washing, or others.

[0130] Considering the preferred decontamination agent (s) for this invention exhibit volatility, upon exposure conclusion to the agent (s) enriched atmosphere, the product (s) will naturally start to lose the impregnated agent (s) to the surrounding atmosphere as long as the latter is of null or very low concentration of the same agent (s). To speed up the disimpregnation process the product (s) may benefit from a storage at equal or higher temperature than those of the treatment; from being submitted to natural or forced convection flush with air or inert gases of none or reduced humidity level; and / or from a modification of system pressure towards sub-atmospheric conditions to favor evaporation. Alternatively, the treated herbal medicinal products can be downstream processed with a typical drying stage such as tray drying with forced convection; freeze drying, or other technical approach intended to reduce moisture from a vegetal material in a timely way.

[0131] The invention also relates to a system for microbial decontamination of herbal medicinal products comprising a sealed vessel ( 1 ) wherein it comprises the following components (Figure 1 and 3):

[0132] - one or more liquid decontamination agent chamber (2 ) inside the sealed vessel ( 1 ), to hold a selected amountof decontamination agent (s) in liquid state, creating with it a permanent section area for natural evaporation; and

[0133] - one or more vapor decontamination agent chamber (3) inside the sealed vessel ( 1 ), to allow the formed vapor (s) of the decontamination agent (s) to be accumulated and to diffuse to the surface of the herbal medicinal product (5);

[0134] - one or more herbal medicinal product holding means (4 ) devoted to accommodating the herbal medicinal product (5) in chamber (3), and to prevent from accidental falls of the herbal medicinal products to chamber (s) (2 ) or from any other unintended movement of the latter before, during, or after the treatment.

[0135] Surprisingly, it was observed that the operation of the method and the system of the invention, if components ( 1 ), (2 ), (3) and (4 ) are correctly designed, and if conjugated with suitable temperature and decontamination agent (s), can attain equal or best decontamination results for aerobic bacteria, yeasts, and / or moulds than the state-of-the-art options for the same purpose. Also, the product quality is not irreversibly detracted.

[0136] In the present invention, it was found with surprise that the formation of an enriched atmosphere in the selected decontamination agent (s) under lower temperatures - where saturation concentration is deemed to be unfavorable for natural evaporation - enables a fine tunability of the impregnation phenomenon that correlates with the degree logarithmic reduction of the bioburden loads, regardless of their type. The microbialcontaminants covered by the invention include naturally occurring aerobic bacteria (including bile-tolerant gramnegative bacteria), yeasts and moulds.

[0137] The saturation concentration of a given decontamination agent in gas phase is a substance-specific property and can be controlled imposing a working temperature to the system. For instance, for ethanol and isopropyl alcohol, Figure 2 provides data of the saturation concentration in gas phase for different temperatures. Accordingly, the increment of temperature from 1 °C to 30 °C boosts 5. 6 times the ethanol concentration in gas phase, and 6.5 times for the case of isopropyl alcohol. Equivalent trends can be anticipated for other agent (s).

[0138] Despite higher temperatures favor the formation of more concentrated atmospheres and, consequently, more powerful means for microbial contamination reduction, they may also imply:

[0139] - higher consumption of decontamination agent per treatment cycle; and

[0140] - increased difficulties to control the treatment progress, particularly when subtle impregnation increments are targeted and / or when the process kinetics needs to be compatible with operational pauses for manual preparation (e. g., product (s) loading to treatment vessel (s) ) or conclusion (e. g. product (s) unloading from treatment vessel (s) ) of large industrial lots.

[0141] Surprisingly, we found that setting the working temperature between 5 and 10 °C was preferable and most effective than working at higher temperatures. This is counter-intuitive given the exigent microbial specifications of Table 1 and attending tothe very low saturation concentration enabled by the referred range of temperatures.

[0142] In the research tests carried out to develop the invention, we found the impregnation of herbal medicinal products with the selected volatile decontamination agent above a certain threshold impregnation point caused the product (s) to be decontaminated down the minimum quantification level available, which by default was to 100 CFU / g for both TAMC and TYMC indicators (or, very exceptionally, 10 CFU / g). Whenever the threshold impregnation point was not reached, proportional degrees of logarithmic microbial reduction were obtained. The said proportionality was different for TAMC or TYMC responses, but the trend was that contamination decreased when an increase of the impregnation level was achieved.

[0143] Within the carried-out research tests, we noticed that above certain maximum level of impregnation, the treated vegetal material (s) started to exhibit irreversible aggressions on the surface, depreciating irreversible its quality. Hence, the system and method of this invention requires a correct design, working temperature, and an appropriate control to prevent excessive impregnation of the herbal medicinal products.

[0144] In the present invention, the creation of an enriched atmosphere in the decontamination agents is preferably approached from a supply of a selected amount of such agent (s) in liquid state, under a selected temperature before the beginning of the treatment. Thus, the driving force ruling the formation of the treatment atmosphere relies on the evaporation rate and on the thermally- imposed saturation concentration ingas phase. The evaporation rate is also a function of the section area, imposed by the geometry of the individual or multiple parts of the chamber (2 ), namely at the interface (s) of chamber (2 ) with chamber (3). It is also a function of the agent concentration in chamber (3), where vapors are accumulated and exposed to the herbal product (s). Saturation concentration may or may not be reached during the treatment because the herbal products will be absorbing (i. e. subtracting) the agent from the gas phase of chamber (3) concurrently with the evaporation process from chamber (2 ).

[0145] Within the carried-out research tests, we also found that direct spraying the volatile decontamination agent (s) liquid to the herbal medicinal products towards a target impregnation level caused irreversible aggressions on the surface due to the uneven quantities being administered to the products surface, creating a too high concentration of decontamination agents at the product (s) surface, and therefore causing an irreversible quality depreciation.

[0146] Surprisingly, we found that the absorption of the volatile decontamination agent (s) by means of natural evaporation, natural diffusion, and natural absorption by the vegetal material (s) sufficed to attain logarithm reductions of the product (s) bioburden while not causing irreversible depreciation of the product. This was true as long as the process was interrupted before reaching a threshold impregnation level that triggered the irreversible quality depreciation.

[0147] The preferred mode of operation relies on a self-regulation mechanism for the decontamination agent (s) vapor concentrationin the gas phase. In fact, the rate of vapors absorption by the herbal medicinal products depends on intrinsic botanical features as well as on the chemical affinity with the decontamination agent. As the herbal medicinal products being treated consume decontamination agent vapors from the gas phase through absorption, it decreases the concentration of the said agent in that phase, thus rising the driving force for evaporation from the individual or multiple parts of chamber (3). This is the basis for classifying it a self-regulating method.

[0148] To emphasize the importance of a precise design of the system, its loads and selected operating conditions, it should be emphasized that the method loses its effectiveness and / or controllability if:

[0149] • the feed of decontamination agent liquid inside the sealed vessel is insufficient, resulting in impossibility to reach the desired impregnation level and / or to enrich / maintain the gas phase with an agent (s) concentration high enough to allow the absorption by the herbal medicinal product until the desired target and / or in a timely manner. The optimal feed of decontamination agent inside the sealed vessel is 8-12 % of the total internal volume of sealed vessel;

[0150] • the section area for evaporation is too small in relation to the load of liquid that needs to be supplied, resulting in an insufficient enrichment of the gas phase due to low rate of evaporation; turning the impregnation phenomenon to be discontinuous and / or slow. The optimal section area for evaporation is 0.05-0.09 m2 / L of decontamination agent;

[0151] • the temperature is too high, resulting in an excessive concentration of vapors in the gas phase, and / or animpregnation that occurs too fast; and / or a process controllability problem for industrial scale operation;

[0152] • the temperature is too low, resulting in an impregnation process to last an uncompetitive time and / or to become discontinuous due to absence or low concentration of agent (s) vapor (s) to be absorbed by the herbal medicinal product;

[0153] • the gas phase volume is not enough to buffer a sufficiently high concentration of decontamination agent (s) and let the natural absorption by the herbal medicinal product to be the limiting step, resulting in an uncompetitive time to reach the target impregnation level. The optimal gas phase volume is 50-60 % of the total internal volume of sealed vessel;

[0154] • the vessel is not sealed and the gas phase atmosphere and / or the liquid phase suffer losses from during the treatment period, resulting in deficits of decontamination agent (s) either in liquid or vapor state to reach the target decontamination level, and / or accidental disimpregnation of agent (s) due to its dilution in the gas phase;

[0155] • the holding means of the herbal medicinal product is badly designed (e. g., prone to dead volumes, and / or imposing excessive and / or non-homogeneous mean distances of the product pieces to the free gas) thus creating a physical blockage / resistance to the natural diffusion of the decontamination agent (s) vapors, resulting in an uncompetitive time to reach the target impregnation level and / or too heterogeneous results;

[0156] the load of herbal medicinal products inside the vessel is excessive in relation to the gas phase volume andattainable concentration through natural evaporation, resulting in an uncompetitive time to reach the target impregnation level or discontinuous process due to unavailability or low concentration of agent (s) vapor to impregnate the product. The optimal load of herbal medicinal product is 0.040-0.070 kg of product per L of gas phase.

[0157] Globally, it is very surprising that the method and system of this invention can achieve bioburden reduction of herbal medicinal products for aerobic bacteria, moulds and / or yeasts combining all the following features:

[0158] • the targeted product (s) contamination reduction can be achieved using a single step;

[0159] • the decontamination is based on the sequence of three thermally dependent phenomena: evaporation > diffusion in gas phase > solid absorption;

[0160] • the decontamination progress is based on a self-regulation mechanism for the decontamination agent vapor concentration, balancing the evaporation rate (to the gas phase) with the impregnation rate (to the herbal medicinal product);

[0161] • the method and the system are preferably operated under thermal conditions requiring refrigeration, preferably between 5 and 10 °C;

[0162] • the resulting logarithmic microbial contamination reduction is tunable upon the control of the attained impregnation extent;

[0163] a fine kinetic control of the impregnation process can be ensured through a proper design of four parameters: (i)solid to liquid to gas proportion; (ii) total treatment time; (iii) system temperature; (iv) decontamination agent (s) section area for evaporation.

[0164] • the method exhibits a capacity to reduce bacterial, fungal or yeast contaminations of herbal medicinal products at least down to 100 CFU / g;

[0165] • for its effective operation there is no need to couple any mechanical means for mixing, recycling, regeneration, and / or pressure change; and

[0166] • the decontamination is effective under isobaric and isothermal conditions.

[0167] EXAMPLES

[0168] A number of experiments were carried out based on the microbial contamination reduction method of the invention and using a prototype of the described preferred system of the invention.

[0169] EXAMPLE 1

[0170] It was used a vessel of cylindrical shape with an widthheight ratio of 1 to 1. 6; the herbal medicinal product was cannabis inflorescences (particle size of < 1.25 cm); the humidity of product was 11 wt. %; the decontamination agent was ethanol 96 % v / v; the holder means were a single non-perf orated tray; the section area for evaporation was 0.085 m2per L of decontamination liquid; the treatment time was 24 h; and the product to decontamination liquid to gas phase proportions of the system were 1 kg to 5.2 L to 44.8 L, respectively. Table 1 presents impregnation results of this arrangement for different temperatures.Table 2

[0171] Resulting average Irreversible product Temperature

[0172] impregnation quality depreciation 6 °C 8.3 % (n= 1 ) No

[0173] 14 °C 10. 6 % (n= 1 ) Yes

[0174] 22 ° C 17.7 % (n= 1 ) Yes

[0175] 30 °C 22.0 % (n= 1 ) Yes

[0176]

[0177] EXAMPLE 2

[0178] It was used a different vessel of cylindrical shape with a width-height ratio of 1 to 1.7; the herbal medicinal product was cannabis inflorescences (particle size >1.25 cm); the humidity of product was 12 wt. %; the decontamination agent was ethanol 96 % v / v; the holder means comprised eight polymeric mesh bags; the section area for evaporation was 0.089 m2per L of decontamination liquid; the temperature was 6 °C; and the product to decontamination liquid to gas phase proportions of the system were 1 kg to 4.0 L to 24.9 L, respectively. Table 2 presents impregnation results of this arrangement for different treatment times.

[0179] Table 3

[0180] Treatment Resulting average

[0181] time impregnation (% wt. )

[0182] 24 h 1.7 ± 0.2 (n= 5)

[0183] 48 h 2.5 ± 0.3 (n= 5)

[0184] 69 h 3.8 ± 0.9 (n= 5)

[0185]

[0186] EXAMPLE 3

[0187] It was used a vessel of cylindrical shape with a widthheight ratio of 1 to 1.7; the herbal medicinal product was cannabis inflorescences (particle size >1.25 cm), the humidity of product was 12 wt. %; the decontamination agent was ethanol 96 % v / v; the holder means comprised a basket with cylindrical ring shape; the section area for evaporation was 0.059 m2per L of decontamination liquid; the temperature was 6 °C; and the product to decontamination liquid to gas phase proportions of the system were 1 kg to 4.0 L to 14.3 L, respectively. Table 3 presents impregnation results of this arrangement.

[0188] Table 4

[0189] Treatment Resulting average

[0190] time impregnation (% wt. )

[0191] 24 h 4.1 ± 0.2 (n= 2 )

[0192]

[0193] EXAMPLE 4

[0194] It was used a vessel of cylindrical shape with a widthheight ratio of 1 to 1. 6; the herbal medicinal product was cannabis inflorescences with particle size >1.25 cm; the humidity of product was 12 wt. %; the decontamination agent was isopropyl alcohol with 99.5 % purity; the holder means comprised a single basket with cylindrical ring shape; the section area for evaporation was 0.085 m2per L of decontamination liquid; the temperature was 6 °C; and the product to decontamination liquid to gas phase proportions of the system were 1 kg to 3.8 L to 25.7 L, respectively. Table 4 presents impregnation results of this arrangement for different treatment times.Table 5

[0195] Treatment Resulting average

[0196] time impregnation (% wt. )

[0197] 3 h 1.9 (n= 1 )

[0198] 6 h 2.2 (n= 2 )

[0199] 23 h 4.8 (n= 1 )

[0200]

[0201] EXAMPLE 5

[0202] To illustrate the correlation of the logarithmic reduction of the bioburden of herbal medicinal products with the progressive impregnation of the latter, we found with surprise that it can be tuned as function of the average impregnation degree. Table 5 shows the progressivity of the decontamination as function of average impregnation with ethanol 96 % v / v, where the herbal medicinal product is cannabis inflorescences.

[0203] Table 6

[0204] Average impregnation (% TAMC (log TYMC (log

[0205] wt. ) reduction) reduction) 2. 5 0. 5 0. 8

[0206] 3. 0 1. 6 1. 5

[0207] 5.2 2.7* 2.7*

[0208] 5.8 2. 8* 3.2*

[0209] 6.7 2.4* 3. 5*

[0210] 6.8 3.7** 2. 8*

[0211]

[0212] *Reached a minimum quantification level of 100 CFU / g.

[0213] ** Reached a minimum quantification level of 10 CFU / g.Table 6 shows the progressivity of the decontamination as function of average impregnation with isopropyl alcohol 99.5 %, where the herbal medicinal product is cannabis inflorescences.

[0214] Table 7

[0215] Average impregnation TAMC (log TYMC (log

[0216] (% wt. ) reduction) reduction)

[0217] 1. 8 0. 4 0. 4

[0218] 4. 8 1. 1 1.2

[0219]

[0220] EXAMPLE 6

[0221] In the case of herbal medicinal products, a critical requirement of the decontamination method comprises the nondegradation of the active substance (s). For the illustrative case of medical cannabis inflorescences, three important cannabinoid classes can be monitored, being them Total THC; Total CBD; and Total CBN. Table 7 reports the content of the cannabinoid classes for cannabis inflorescences treated with the method of this invention, where the decontamination agent is ethanol 96 % v / v. No depreciation was noticed on cannabinoids content of the treated product in comparison to the control sample.

[0222] Table 8

[0223] Average Total Total Total CBN impregnation THC (%) CBD (%)

[0224] Control 27.2 0. 1 0. 3

[0225] 6.1 % (wt. ) 28. 6 0. 1 0. 3

[0226]

[0227] The description herein should be construed as non-limitative of the scope thereof which is defined only by the independent claim. The dependent claims define particular embodiments of the invention.

Claims

CLAIMS1. A method for microbial contamination reduction of herbal medicinal products comprising the following steps:a) filling one or more parts of an empty vessel with a predetermined amount of an herbal medicinal product to be treated;b) filling one or more parts of the referred vessel with a predetermined amount of decontamination agent in liquid state;c) closing the filled vessel in a way to ensure sealed conditions;d) allowing the herbal medicinal product to be exposed to the decontamination agent vapors under controlled temperature for a programmed time period; ande) retrieving the treated herbal medicinal product from the vessel.

2. The method according to claim 1, wherein the step b) precedes step a).

3. The method according to claim 1, further comprising the following steps between the steps d) and e):i) removing the decontamination agent liquid from the vessel; andii) removing the decontamination agent vapors from the vessel.

4. The method according to claim 1, wherein step b) comprises a continuous or discontinuous inlet of a gas stream enriched in the decontamination agent.

5. The method according to claim 1, wherein step i) comprises a continuous or discontinuous outlet of a gas stream.

6. The method according to claim 1, wherein the medicinal herbal product is any vegetal material selected from the group of leaves, fruits, inflorescences, flowers, stems, roots or their mixtures.

7. The method according to claims 1 and 6, wherein the herbal medicinal product is medicinal cannabis, preferably cannabis inflorescences.

8. The method according to claim 1, wherein the decontamination agent is selected from the alcohol group compounds from the C2 to C15 class or their mixtures, the alcohol group compounds from the C2-C7 class or their mixtures or the alcohol group compounds from the C2-C3 class or their mixtures.

9. The method according to claims 1 and 8, wherein the decontamination agent is ethanol or isopropyl alcohol or their mixtures.

10. The method according to claim 1, wherein step d) is performed at a temperature in the range of 1 °C to 30 °C, preferably 5 °C to 10 °C, more preferably 6 °C.

11. The method according to claim 1, wherein step d) is performed during a time period in the range of 3 h to 69 h, preferably 12 h to 48 h, more preferably 24 h.

12. A system for carrying out the method according to any one of claims 1 to 11, the system comprising a sealed vessel (1) wherein it comprises:• one or more liquid decontamination agent chamber (2); • one or more vapor decontamination agent chamber (3); • one or more herbal medicinal product holding means (4) arranged inside the chamber (3), for accommodating the herbal medicinal product.

13. The system according to claim 12, wherein the herbal medicinal product holding means (4) is selected from tray, basket, mesh bag or similar.

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