HAPILA overcomes supply bottlenecks to synthesize anti-TB API agent BTZ-043 for clinical trials

Gera, Germany: – High-potency active ingredient specialist CDMO HAPILA GmbH (HAPILA) has overcome global supply disruptions to complete its synthesis campaign to produce the required 150 kilos of its innovative anti-tuberculosis antibiotic candidate BTZ‑043.

This keeps the BTZ-043 program on track for its clinical trials, with the API produced in the quantities needed to support Clinical Phase IIb trials on dose-ranging, as well as for tox-studies.

Effective anti-TB agent

BTZ-043 is a small molecule API that has been identified as effective against highly resistant strains of tuberculosis, the most common cause of death worldwide caused by bacterial infections. It was named ‘Drug of the Year’ by the Leibniz Wirkstofftage, the Leibniz Research Network Bioactive Compounds at its 2023 conference in Braunschweig, Germany.

HAPILA has conducted its BTZ-043 development program in partnership with the Leibniz-HKI Jena (Leibniz Institute for Natural Product Research and Infection Biology), which first discovered BTZ‑043 at its Natural Product Research and Infection Biology laboratories. Research studies have also been supported by the consortium InfectControl 2020 and the German Center for Infection Research (DZIF), as well as the Thüringer Aufbaubank for API development effort.

A Phase I study conducted in Germany showed good tolerability of BTZ‑043. Proving BTZ‑043 to be safe and effective in the current study Phase IIb would be a major step towards market launch as a tuberculosis drug.

Overcoming supply challenges

The 150 kg of BTZ‑043 was the amount HAPILA was required to produce to support the clinical trials to meet its CDMO responsibilities.

Due to global supply difficulties, the biggest challenge for HAPILA has been to procure suitable starting materials in the required quantities for the GMP-synthesis.

HAPILA CEO, Dr. Uwe Müller commented: “We had the greatest problems with the supply of solvents in “Ph. Eur.” grade, which we must use for the API-synthesis. Therefore, we put a lot of work into finding and qualifying new suppliers. This was not only time consuming but also expensive, as the entire quantity of solvents had to be purchased in small parcels from several suppliers, which was tremendously more expensive than the usual purchasing model.”

“Overcoming all the difficulties was only possible thanks to the teamwork of all employees in the company, who put in a lot of work in researching and qualifying new suppliers. This included researching suppliers online, purchasing several batches of the required solvent and full analysis according to the Ph. Eur. monography to qualify the supplier. This was done for at least three different solvents. This was a particular challenge to accomplish, especially in view of the tight timeline,” said Dr. Müller.

Ongoing development

HAPILA has undertaken complete synthesis development for BTZ‑043 as a tested and usable API as well as cGMP manufacturing to comply with guidelines covering Part II – API (Manufacturing, Verification and Release).

“Since the API is currently undergoing clinical trials, the validation of the synthesis is still ongoing. In particular, the Quality by Design (QbD) approach to developing the drug substance and eventual drug product has meant that synthesis and control-strategies have needed to be constantly re-evaluated to gain sufficient process knowledge, reduce the risk of errors and to ensure constant compliance with the specifications of the API,” Dr. Müller explained.

Made in Germany

He said that overcoming the recent supply issues were both testimony to the efficiency of HAPILA processes and a spur to further development.

“We are confident that the synthesis we have developed is very efficient in yield and meeting the requirements of the authorities. Therefore, the synthesis is already resource efficient. Nevertheless, the lessons we learned during the last campaign will help us in the future,” said Dr. Müller.

“Clinical phase II is still running until the end of 2024 and Phase III will not begin before 2026/2027. In the meantime, we will use the free capacities and our QbD knowledge to improve the process and control-strategies according to the ICH-guideline to ensure BTZ‑043 meets our high quality ‘Made in Germany’ standards,” he concluded.

About HAPILA GmbH

HAPILA GmbH is a contract developer and manufacturer (CDMO) that provides high-value services to pharma, biotech and fine chemicals client companies in the development and cGMP manufacture of active pharmaceutical ingredients (APIs).

HAPILA is an independent company with particular experience in GMP-related development and GMP manufacturing, offering full regulated service for API (IMPD, ASMF) to very high scientific and quality assurance (QA) levels.

It supports the development and manufacture of drug products with patented processes and in-depth experience in the API value-creation chain from synthesis through purification to particle design.

The company’s mission is to supply exclusive products of highest quality, potency and safety in compliance with GMP and environmental protection guidelines. All HAPILA teamwork is focused on product quality and customer satisfaction.

All HAPILA chemical synthesis is carried out at in-house at its GMP certified laboratories at Gera, Thuringia, in east-central Germany.

When combined with purification and particle design, HAPILA’s chemical synthesis services cover the complete API value-creation chain, enabling it to be a highly efficient bridge-builder between API production and pharmaceutical end-use.

For more information, visit: www.hapila.de/ecom

Resources

Click on HAPILA’s co-developed anti-TB agent BTZ‑043 named ‘Drug of the Year’ to learn more.
Click on HAPILA commences cGMP pilot scale manufacture of anti-TB API BTZ‑043 for further information.