GMP Drug Substance Part 1: Scope

15 April 2021

The first step in process development for live biotherapeutic product manufacturing is to identify the microbe that will be used in the drug product and assess the conditions it needs to grow. There are several parameters that must be taken into account, as different bacteria will require different approaches.

  • Aerobic & anaerobic bacteria

The correct environment must be created to grow the bacterial candidate being manufactured. If the microbial candidate is an obligate aerobe, it needs oxygen to grow. In a process known as cellular respiration, these organisms use oxygen to oxidize substrates (for example, sugars and fats) and generate energy, and this requirement must be incorporated into the manufacturing process. Facultative anaerobes, on the other hand, use oxygen if it is available, but also have anaerobic methods of energy production. Aerotolerant anaerobes do not use oxygen but are not harmed by it. The most challenging, however, are usually the microbes that must be manufactured in the absence of oxygen. Microaerophiles require oxygen for energy production but are harmed by atmospheric concentrations of oxygen (around 21% O2), and obligate anaerobes are microorganisms killed by normal atmospheric concentrations of oxygen.

  • Single strains, multiple strains & consortia

Single strain products are normally the most straightforward, since the requirements of only one bacterial strain must be met. For multi-strain products or consortia, Biose Industrie scientists strategize about whether the strains are best grown together or separately. In certain situations, the team may be able to co-culture several bacteria that are part of a live biotherapeutic product. This is complex to develop and is not guaranteed to work, but it can be very rewarding in the cases where it can be achieved successfully. More often, however, each strain in a multi-strain product undergoes separate fermentation and freeze-drying processes before the different strains are brought together in the finished product.

  • Commensal and GMO

Generally live biotherapeutic products use commensal bacteria, which naturally occur in the human gut(or skin, vagina etc) and are isolated for therapeutic use. These bacteria, adapted to living harmoniously with us, tend to have established ways of acting in concert with the host’s immune system to induce protective responses.

Genetically modified organisms (GMOs) are microorganisms whose genetic material has been altered using genetic engineering techniques such as gene delivery, (2) recombinant DNA or (3) Genome editing using TALEN or CRISPR. These GMOs are created to have specific functions and do not occur in nature. Compared to the bacteria from which they are derived, GMO bacteria may have peculiarities in how they grow that must be taken into account in manufacturing.