Bac­teria in the capsule

The tar­geted delivery of living microor­gan­isms opens up a new class of ther­a­peu­tics. Seres Ther­a­peu­tics’ VOWST™ is the first FDA-approved, orally deliv­ered micro­biome product to treat recur­rent Clostridium dif­fi­cile infec­tions. Working closely with Harro Höfliger, a cus­tomized system was devel­oped for filling microbes into capsules.

Every human body is home to many tril­lions of microor­gan­isms, like fungi, viruses and bac­teria. Together they form the micro­biome whose com­po­si­tion is as indi­vidual as a fin­ger­print. But for all its unique­ness, every micro­biome has one thing in common: It plays an impor­tant role in health. Our intestinal bac­teria sup­port diges­tion and pro­tect against pathogens, for instance.

So the problem is all the more serious if this sen­si­tive ecosystem gets out of bal­ance. This could lead to a variety of health prob­lems – like diges­tive dis­or­ders and inflammation.

“Live bio­ther­a­peutic ­prod­ucts have the poten­tial to treat a wide range of dis­eases.”Michael Philbrook,
Senior Director of Formulations 
at Seres Therapeutics

Drugs with microorganisms

Live bio­ther­a­peutic prod­ucts – LBPs – are based on ­spe­cific strains of bac­teria or other microor­gan­isms. Their pur­pose is to restore bal­ance. The US biotech com­pany Seres Ther­a­peu­tics spe­cial­izes in such micro­biome ther­a­pies. Its new drug – VOWST™ – is used to combat rCDI, a serious gas­troin­testinal infec­tion. Michael Philbrook, Senior Director of For­mu­la­tions at Seres Ther­a­peu­tics, explains: “Recur­rent CDI can occur after taking cer­tain antibi­otics, because while they fight harmful bac­teria, ben­e­fi­cial bac­teria are also sig­nif­i­cantly impacted. In a dis­rupted micro­biome, the bac­terium C. dif­fi­cile can mul­tiply and pro­duce harmful toxins that cause severe inflam­ma­tion of the colon and debil­i­tating diarrhea.”

Although antibi­otics are nec­es­sary to kill the toxin pro­ducing C. dif­fi­cile bac­teria, they do not address the dis­rupted micro­biome, which may increase the risk of rein­fec­tion. That’s why Seres Ther­a­peu­tics devel­oped VOWST™ for such recur­rent forms of infec­tion: A cap­sule con­taining a mix­ture of dif­ferent live bac­te­rial strains which pro­duce metabo­lites that end the cycle of recur­rent C. difficile.

Cap­sule filling, a tricky business

The process for pro­ducing this promising drug is demanding. Michael Philbrook: “The bac­teria are obtained from a healthy donor’s stool sample which is then puri­fied, cleared of poten­tial pathogens, and for­mu­lated to a target con­cen­tra­tion. The process results in a stable bac­te­rial spore sus­pen­sion which is then filled into cap­sules.” These cap­sules are then over-encap­su­lated into a slightly larger size.

Harro Höfliger is the partner for all aspects of encap­su­la­tion. “This was based on our proven Modu‑C LS Con­tain­ment machine,” explains Daniel Müller, Sales Director in the Cap­sule Tech­nolo­gies divi­sion. This includes a trolley system. Which means: The dosing sys­tems are mounted on mobile car­riages, making them inter­change­able. This allows both processes to run on one machine.

Four steps to the per­fect product

Fill liquid into capsule

Close inner capsule

Fill cap­sule into capsule

Close outer capsule

Two new developments

The first dosing sta­tion is for filling the liquid into the smaller cap­sule. Müller: “We’ve devel­oped a dosing system that max­i­mizes the filling effi­ciency so none of the valu­able product is wasted.” Spe­cial­ists then inspect each cap­sule out­side the machine before over-encap­su­la­tion takes place again.

The Modu‑C LS Con­tain­ment is set up to pro­tect the oper­ator while han­dling living organisms.

The second dosing trolley is now used for this pur­pose. “This is also a cus­tomer-spe­cific devel­op­ment and an absolute nov­elty in the market,” says Daniel Müller. “So far, it was like this: When one cap­sule is filled into another, there was usu­ally a two cap­sule size dif­fer­ence, e.g. a size 1 cap­sule in a size 00 cap­sule. This buffer did not exist here, how­ever, because we are filling a 0 cap­sule into the next larger 00 cap­sule. In close coor­di­na­tion with Seres spe­cial­ists, our engi­neers devel­oped a per­fect solu­tion for this.”

High-tech cleaning

Han­dling living organ­isms requires spe­cial pro­tec­tion. Daniel Müller explains the back­ground: “Even the slightest amount of bac­teria left behind after one batch could con­t­a­m­i­nate the next one. Mea­sures to pre­vent this include dis­in­fecting with vapor­ized hydrogen per­oxide (VHP). During this process, you can run the machine slowly with the doors open – thus ensuring that the gas reaches into every corner of the machine. A scanner is also inte­grated to check the area in front of the Modu‑C for safety rea­sons. If it detects a person, the machine stops immediately.”

“In close coop­er­a­tion with Seres, we have devel­oped two spe­cial dosing sys­tems.”Daniel Müller,
Sales Director Cap­sule Technologies 
at Harro Höfliger

“The equip­ment is tailor-made and pre­cisely meets the excep­tional require­ments of this product,” Daniel Müller sum­ma­rizes. “The close part­ner­ship with Seres con­tributed to the suc­cess of this design. We are always inter­ested in exploring appli­ca­tions where new tech­nolo­gies must be found.”

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Photo: Helmar Lünig