Botox and the logic of regulation

Botox and the logic of regulation
11 May 2020

Westport is a small, beautiful town in Ireland which is home to around 6000 people. It would be completely unremarkable (save, perhaps, as one of the nicer places in the world to live and for its proximity to the pilgrimage site on Croagh Patrick), were it not for the fact that it is the source of one hundred percent of the world’s authentic Botox™. Here, in an Allergan facility with layers of security (against physical and, more importantly, biological threats), workers wearing specialised protective equipment carefully dilute, formulate, dispense, preserve and package botulinum toxin before shipping it to distribution hubs around the world. Eventually, the products of this one plant will find their way into hundreds of millions of syringes wielded by medical practitioners to smooth wrinkles and still spasming muscles.

The input for the plant in Westport comes from a facility somewhere in Irvine, California, where the spore-forming bacterium Clostridium botulinum is grown under anaerobic conditions in suitable culture media. There, under an equally-impressive blanket of security (this time including careful controls on access to prevent prying eyes from seeing trade secrets) the bacterial soup is carefully filtered, processed and tested to produce the bulk toxin used in Westport. The two facilities are linked by secretive cargo flights, where security teams are reputed to guard the shipments in flight. This is less elaborate than it seems, however, the total yearly output of pure botulinum toxin from both of these facilities amounts to around a gram, and the consignments can be carried in a suitcase.

The sales of Botox amount to a bit over two billion dollars a year. This makes botulinum toxin one of the most expensive substances on earth, gram for gram, and a prime component of Allergan’s commercial empire. Which leads to a question: why isn’t everyone making the stuff?

Part of the answer lies in the sheer, hellish lethality of the toxin itself. The fatal inhaled dose of pure botulinum toxin is in the order of ten nanograms per kilogram of body mass, meaning that the single tablet’s worth of powder which intermittently flies out of California to Westport is enough to kill over a million people if dispersed in the breeze. This explains the plants’ fanatical approach to security on all fronts, as well as the armed guards.

This also comes as part and parcel of the manufacturing process itself. Even at the initial fermentation stage there is a risk of disaster – inadvertent botulinum production in, say, badly-manufactured canned goods, results in botulism and its attendant ills. So even the gasses produced by the fermenter in which the bacteria are growing must be carefully filtered to prevent the escape of bacteria and spores. At each step of the purification process both the purity and the danger grow. The result is what has been described as an onion of security – layers inside layers, with the purest toxin sitting at the centre.

The second issue is that the production of Botox is as much art as it is science. The process for carrying out this precipitation is a closely-guarded secret, with the most reliable information dating back to the early 1990s when Schantz and Johnson published the process that was used to produce the trial batches used to test and launch Botox onto the world stage. Since then the process has been refined and improved, but remains a trade secret. Here, a lot of quality of the finished product comes from the exact conditions of fermentation, which are of course highly secret. The sole clue available to the public is a patent family dating back to 2003, which describes the use of culture media which are substantially free of animal products. The proof of all of this is in the pudding; although competitor products exist, none of them have quite the same dose response, efficacy and safety as the original.

The final issue is one of regulation. Allergan put an enormous effort into developing their elaborate system of manufacture, with the result being a product that is safe and consistent batch to batch. This product was then exhaustively trialled before acceptance, with the drug going through the regulatory apparatus of multiple countries. If would-be competitors cannot produce the same product (and it seems that they cannot), then it stands to reason that their version of Botox cannot also be accepted for use without underdoing a similar level of scrutiny.

Here we reach the stark underlying logic of regulation. Botox is a biological compound, produced by a common bacterium which can be found nearly everywhere. Its products are perfectly natural, and incredibly lethal. In turning that product into injections, the smallest slip could prove fatal. So, the gravest oversight must be given to ensure that the product is as it is claimed to be.

Thankfully, the Botox story is something of an outlier: most substances won’t kill in homeopathic doses except by being ineffective. But it illustrates the underlying logic impelling regulators and producers. The fundamental answer to the question of why such an expensive substance isn’t being exploited by all and sundry lies in the difficulty of safely and effectively getting it from the bacterium to the needle.

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(This article is provided for informational purposes only and not for the purpose of providing legal advice. For more information on the topic, please contact the author/s or the relevant provider.)
Izaan Kuschke
Izaan Kuschke

Izaan Kuschke is an associate at Kisch IP's patent department. She is an Assistant for the University of Pretoria’s Centre for Intellectual Property Law. Her technical areas of expertise include:...

Thomas Schmidt
Thomas Schmidt

Thomas Gerard Schmidt has experience in plant and crop biotechnology with a focus towards molecular biology, genetics, plant pathogens and genetically-modified crop research.

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