This blog post will describe how the rise in more complex generic structures to cover controlled compounds has led to an unprecedented rise in the number of structures now covered under the various international legislations, and how it is now virtually impossible to identify what is - and is not - controlled without the aid of dedicated software packages.

The global nature of life science research and development externalisation - including outsourcing and collaboration - is increasingly prevalent in today’s pharmaceutical industry.

Synthesis, compound management, and testing facilities are distributed globally, and are totally reliant on fast and efficient shipment of compounds across borders to the appropriate testing facilities. The compliance aspects associated with sample management are therefore becoming more critical as new legislation is developed around controlled compounds.

Companies must track and trace materials and data both internally and externally to ensure they are compliant with international controlled drug legislation requirements.

Companies need to know what can be transferred where, and in what quantities, so they can move samples across borders efficiently, ensuring timely delivery, and ensuring compliance with any restrictions. 

No Pharmaceutical company, academic institution or Contract Research Organization wants to be caught unknowingly breaking the law. 

With millions of compounds in a typical large pharmaceutical library and shipments, ranging from microtiter plates of small volumes at low concentrations, to manufacturing batches of many kilos, it is imperative that systems are in place to identify controlled substances held by a company.

Controlled drug legislation is enacted both locally and internationally. The role of a Compliance  Officer within a company is to ensure adherence and timely response to any changes in worldwide drug legislation. Law enforcement in the United States is governed by the Drug Enforcement Agency; in the UK by the UK Home Office under the Misuse of Drugs Act. Coupled with these are various other international as well as country specific regulations; European Medicines Agency for the EU; UN conventions; Chemical Weapons regulations, which all need to be taken into account.

In recent decades, drug markets have grown increasingly complex.

Traditional plant-based substances like cannabis, cocaine, and morphine are now accompanied by numerous synthetic drugs, many of which lack international regulation. Among these substances, narcotics, hallucinogens, stimulants, depressants, and anabolic steroids are the most common compound families. According to UN data (United Nations Office on Drugs and Crime - Current NPS Threats Volume VI 2023), approximately 500 new psychoactive substances (NPS) emerge in the national markets of Member States each year.

To mitigate the impact of this explosion and to end the game of cat and mouse whereby new NPS emerged faster than the authorities could ban them, certain countries have adopted a novel proactive legal strategy by expanding the scope of their existing drug legislation with generic definitions.

Generic definitions are comprehensive descriptions or classifications that encompass entire groups or classes of compounds based on their chemical structures, providing a flexible framework for regulating new or emerging substances that share similar chemical characteristics and effects.

The criticism of generic legislation in drug control lies in its potential complexity and difficulty in interpretation, particularly for those outside chemistry or pharmacology, like legal professionals tasked with enforcing drug laws and prosecuting offenders. Additionally, the broad scope of generic definitions may include substances with therapeutic value, potentially hindering pharmaceutical R&D efforts. On the other hand, generic control offers advantages such as summarizing groups of substances with concise structure-specific definitions and the ability to anticipate new substances not yet seen in illicit trade. For instance, the pioneering generic control for phenethylamines was introduced in the UK in 1977 (The Misuse of Drugs Act 1971 (Modification) Order 1977), capturing numerous phenethylamines that came to light in the following years, including MDMA (3,4-Methylenedioxymethamphetamine - ecstasy) which did not appear until a decade later.

'any compound (not being methoxyphenamine or a compound for the time being specified in sub-paragraph (a) above) structurally derived from phenethylamine an N -alkylphenethylamine, a-methylphenethylamine, an N -alkyl-a-methylphenethylamine,a-ethylphenethylamine, or an N -alkyl-a-ethylphenethylamine by substitution in the ring to any extent with alkyl, alkoxy, alkylenedioxy or halide substituents, whether or not further substituted in the ring by one or more other univalent substituents.'

This wording is sufficiently clear and straightforward to be easily interpreted and therefore adhered to. Currently around 22 countries have incorporated generic definitions into their legislative frameworks (https://www.unodc.org/LSS/Country/List).

The unintentional overreach of Generic Legislation

The appearance of a plethora of synthetic cannabinoid analogues in the 2000s, particularly in the latter half of the decade, led to profound transformation in generic definition with far-reaching consequences. Consequently, due to the frequency of these new compounds appearing on UK streets, a generic definition was created to cover this class of compounds (third generation of synthetic cannabinoids) and was set into law as The Misuse of Drugs (Amendment) (England, Wales, and Scotland) Regulations 2016 to the Misuse of Drugs Act (1971). 

The  third generation synthetic cannabinoids gave rise to a wide-reaching generic, worded as:

‘any compound (not being clonitazene, etonitazene, acemetacin, atorvastatin, bazedoxifene, indometacin, losartan, olmesartan, proglumetacin, telmisartan, viminol, zafirlukast or a compound for the time being specified in sub-paragraphs (h) to (lc) above) structurally related to 1-pentyl-3-(1-naphthoyl)indole (JWH-018),

in that the four substructures, that is to say the indole ring, the pentyl substituent, the methanone linking group and the naphthyl ring, are linked together in a similar manner, whether or not any of the sub-structures have been modified, and whether or not substituted in any of the linked substructures with one or more univalent substituents and, where any of the sub-structures have been modified, the modifications of the sub-structures are limited to any of the following, that is to say—

(i)replacement of the indole ring with indane, indene, indazole, pyrrole, pyrazole, imidazole, benzimidazole, pyrrolo[2,3-b]pyridine, pyrrolo[3,2c]pyridine or pyrazolo[3,4-b]pyridine;

(ii)replacement of the pentyl substituent with alkyl, alkenyl, benzyl, cycloalkylmethyl, cycloalkylethyl, (N-methylpiperidin-2-yl)methyl, 2-(4morpholinyl)ethyl or (tetrahydropyran-4-yl)methyl;

(iii)replacement of the methanone linking group with an ethanone, carboxamide, carboxylate, methylene bridge or methine group;

(iv)replacement of the 1-naphthyl ring with 2-naphthyl, phenyl, benzyl, adamantyl, cycloalkyl, cycloalkylmethyl, cycloalkylethyl, bicyclo[2.2.1]heptanyl, 1,2,3,4-tetrahydronaphthyl, quinolinyl, isoquinolinyl, 1-amino-1-oxopropan-2-yl, 1-hydroxy-1oxopropan-2-yl, piperidinyl, morpholinyl, pyrrolidinyl, tetrahydropyranyl or piperazinyl’

This paragraph belies, or maybe not, the sheer complexity and breadth of the new generic. Estimates suggested that around 10³³ structures could be caught under this description. 

So how did this affect not only the pharmaceutical industry but also Contract Research Organisations with business interests worldwide? 

An Unprecedented Change 

This led to an unprecedented change for anyone trying to understand and adhere to controlled drug legislation.

Listing substance on a name to structure basis changed to the need to interpret complex generic descriptions.

The clarity and manageability of associated licensing, storage and tracking processes were superseded with uncertainty of ‘hits’ and an unparalleled scale. It was found that within a standard pharmaceutical library of around 2 million compounds, following the implementation of the amendment, suddenly around 100 000 compounds were controlled.

The Future

The complexity of the legislation negates the interpretation by simply reading and applying, as could be achieved before. To correctly identify the controlled substances, commercial software packages need to be used.

(In the opinion of the author) It is virtually impossible for any group or any size, large Pharma, small Pharma, contract research organisations, academia, charitable research groups and even legislators to comprehend the scope of generic legislation on their workflows. This includes, storage, usage, synthesis (whether as part of a synthetic route or as final product) shipping in any quantities or concentration, whether around the UK or into or out of the world.

Digitalisation offers a viable solution to the challenge of differentiating controlled substances covered by generic definitions from unregulated ones, a process that can be time-consuming even for experts. Commercial software packages, such as Chemaxon’s Compliance Checker, a combination of a software system and a regularly updated content package reflecting new controlled legislation, are possibly the only guaranteed way of identifying these vast numbers of controlled compounds covered by generic legislation in libraries today.

The Third Generation Cannabinoid generic descriptions were converted into complex Markush structures for the Compliance Checker software package, which allowed the identification of newly controlled substances to be confirmed.

More importantly, it showed the overreach of the legislation as it covered thousands of compounds. The software was used to test revisions for synthetic cannabinoids generic definition which led to the Third Generation Synthetic Cannabinoid generic legislation being amended in 2019. The intention of reducing the scope, so allowing research and development to continue unhindered, whilst keeping the original aim of curtailing access to harmful compounds, was successfully achieved. 

Identifying controlled substances must be a priority for every laboratory to ensure compliance with world wide legislation. The rise of generic descriptions within regulations means that it is no longer viable to check compound structures by looking them up on a list of controlled substances, it is much more complicated. They need a system that contains the difficult wording of regulations converted into structural representations that can be used to automatically identify controlled substances. That system also needs to include a technology that is able to reliably match the input structures even against the most complex Markush structures, and do it in a reasonable time even for millions of compounds. So a software package like Compliance Checker is needed to ensure controlled substance compliance, otherwise laboratories are open to unintentionally breaking the local and international laws. 

Companies need to be held accountable for ensuring their actions with respect to the storage and handling of compounds are in compliance with both local and international legislations. The surge in generic legislation, coupled with the general increase in laws around controlled substances, makes it imperative that a package that can quickly and easily identify controlled substances is implemented.