Understanding How Production Processes Impact Drug Quality

Making medicines is a stressful business, literally. Bioprocessing technologies, cleaning agents, and even packaging can create stresses that impact drug quality. Understanding these stresses is the first step towards addressing them, says Tapan Das, PhD. senior director of product development at Bristol Myers Squibb, the author of a new study examining how production affects the quality of ingredients and finished drugs. Das had previously published a paper on the topic two years ago.

“While there are several common stress factors across drug substance manufacturing, product manufacturing, and packaging, there are some specific ones to the unit operations in substance or product manufacturing,” he points out.

In drug substance production host-cell proteins (HCPs) are the most obvious example of a potential stress factor, according to Das, who had published a paper.

“Residual levels of certain host cell proteins have the potential to negatively impact patient safety as well as purity, stability, and consistency,” he tells GEN. “Some of the residual HCPs are enzymes that are known to degrade protein and excipients in long- term storage. To minimize HCP-related risks, HCPs should be controlled to low levels.”

Mechanical forces, both those in the bioreactor and those applied during downstream steps, are another example of a stress factor.

“Forces used in the bioreactor during fermentation and harvest can cause cell rupture that can result in the release of intracellular reducing enzymes such as thioredoxin reductase, which in turn can enhance formation of half antibody species due to reduction of disulfide bonds,” continues Das, adding that to mitigate against such mechanical damage, bioreactor developers have introduced new technologies like air-sparging to maintain an oxidative environment that supports healthy cell growth.

Material stresses

Vaporized hydrogen peroxide (VHP) is used to sterilize bioprocessing technologies, packaging materials, and systems. It is also a potential stress factor.

“Residual levels of VHP are found adsorbed to primary packaging materials, for example, vials and stoppers, and other surfaces, such as silicone tubing,” explains Das. “VHP then transfers to liquid DP during filling operation, which subsequently may cause protein oxidation.”

“Biopharmaceutical manufacturers should perform engineering runs to assess the sensitivity of a given protein to oxidation by VHP, according to Das.

But sterilization reagents are not the only potential stress factors drugs encounter during the packaging process.

“In vials, therapeutic proteins can come into contact with micron-size glass fragments due to glass delamination,” says Das. “The resulting ‘protein-coated’ glass micro-particles increase the likelihood of negative immune responses to the drug.”

Again, testing during engineering runs has emerged as industry’s preferred solution. Many therapeutic protein developers now trial a range of vials with each new product candidate to minimize the risk of delamination.