Goldilocks And GMP

Posted August 7th, 2019 by Aoife Brennan, in External R&D, From The Trenches, Science & Medicine, Translational research

This blog was written by Aoife Brennan, CEO of Synlogic Therapeutics, as part of the From The Trenches feature of LifeSciVC.

New therapeutic platforms, like those based on cell and gene therapy, provide potential to address diseases in new ways and hold tremendous promise for alleviating human suffering.  Despite this, progress often reaches a critical juncture when attempts are made to scale manufacturing from research to late-stage clinical trials and commercialization.

The Synlogic platform is based on applying the tools and principles of synthetic biology to rationally engineer non-pathogenic bacteria to perform a therapeutic function that may be missing or impaired due to disease. All of our programs to date have used the same ‘starter strain’ or chassis, a well-studied probiotic called E coli Nissle or EcN. Being an E. coli, EcN grows rapidly in a fermenter and has been manufactured as a probiotic for commercial use which provides great advantages out of the gate.  Despite these starting advantages, identifying a contract manufacturing organization (CMO) that could meet the needs of our pipeline programs was a challenge for a number of reasons;

  1. Many CMOs will not work with live bacteria
  2. CMOs who have experience of manufacturing bacteria often lack mature quality control and infrastructure
  3. We required co-location of fermentation, downstream processing and lyophilization
  4. While fermenting bacteria for protein production is common, expertise in maintaining viability is critical for our living medicine application and uncommon

Like other companies in this space, Synlogic was faced with a difficult decision; tie up capital building our own facility (too hot), continue to rely on contract manufacturing infrastructure (too cold) or find something that was just right (a hybrid approach).

This issue came to a head in the fall of 2018 as we searched for a CMO to manufacture our oncology candidate, SYNB1891. In addition to the complexities above, this product is intended for administration via intra-tumoral administration and required sterile fill infrastructure. The quoted timelines and costs from the single vendor who was willing to take on the project made this CEO want to cry.

I tend to be an early bird in the office and was complaining to my fellow early birds as I waited for coffee one morning. I joked to our Head of Quality that we would go into business as a CMO when he replied, no joke, “I think I know a way.” We proceeded to reach out to Azzur, a pharmaceutical consulting group who lease clean room space to companies. As it happened, they had availability in their facility in Waltham, a couple of miles west of our office and lab space in Cambridge.

The beauty of the Azzur model is that the physical cleanroom also comes with a menu of wrap-around services for organizations like ours who do not want to build out full capabilities in inventory control, warehousing and environmental monitoring etc. We were able to equip the cleanroom to meet the needs of our process and move our own staff (who were trained in GMP and had developed the process in our labs) into the suite to run the campaign. Of course, we needed to establish some documentation and quality infrastructure at Synlogic, and there was some heroism required, but within three months, we had manufactured our first lot of clinical trial material. Expanding the relationship was the next step and, based on our successful pilot, we executed a four-year lease and services agreement to custom build a suite at the Waltham facility that our manufacturing team now call home.

If finding the correct balance between contract and owning is Goldilocks, then getting the correct team and setting the right tone is Goldilocks’ twin sister. Balancing a healthy respect for GMP and process with a can-do attitude is critical to our success. Fear and paralysis can easily set in when the stakes are high and one is doing something for the first time. Here, hiring a few key team members who had GMP experience and providing training to others, allows us to be agile in responding to the needs in the clinic.

While we are out of the woods for now, other challenges are sure to arise as we develop our pipeline of synthetic biotics for patients. When they do, we plan to continue to follow the lead of a girl who eats a microbiome-healthy meal of luke-warm porridge for breakfast.

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