Tag Archives: SISPQ

FDA Researchers Explore Fundamental Chemical Reaction that Could Threaten the Quality of Therapeutic Protein Products

In a recent news release the FDA described research it has conducted regarding detection of protein carbonylation, an oxidative reaction that may occur in therapeutic protein drug products during manufacture, storage, use, and transport potentially causing structural alterations and threatening stability, quality, and clinical efficacy of such products. FDA scientists have refined an antibody-binding assay with high sensitivity to detect protein carbonylation allowing many samples to be studied in a short period of time under a variety of conditions. The assay is being used to study the tendencies of various protein products to undergo oxidative carbonylation and whether containers and chemicals that contact proteins may start or speed up these reactions. The goal is to develop methods such as addition of stabilizing agents to counteract protein carbonylation in order to maintain stability, purity, and potency of therapeutic protein products and to avoid any harmful adverse reactions such as unwanted immune responses.

See https://www.fda.gov/Drugs/NewsEvents/ucm571068.htm

 

Full FDA Story:

The potential for biotechnology to transform medicine remains immense, with several therapeutic protein products already having come into widespread clinical use and hundreds of proteins under clinical investigation. For the FDA, the regulatory oversight of therapeutic protein development poses a great challenge, not only because of the increasing number of products, but also because proteins, by their very nature, are highly variable, and compared to small-molecule drugs, more likely to undergo chemical reactions over time. Chemical reactions that occur in these proteins (for example, during storage in vials before administration to patients) can have a significant impact on protein function. For FDA scientists in the CDER Office of Biotechnology Products (OBP), these reactions are of great interest because they can directly impact the quality, safety, and efficacy of protein products.

For decades—before the biotechnological revolution and the rise of therapeutic proteins—FDA drug reviewers focused primarily on small-molecule drugs. Aspirin, for example, contains only nine carbon atoms, whereas the modern protein product bevacizumab contains well over 6,000 carbon atoms. In general, proteins also contain sulfur atoms (bevacizumab has 44!), and biochemists have long known that sulfur-containing molecules are prone to undergo reactions related to the presence of unstable oxygen and other atoms in our environment. (Proteins are not the only molecules that undergo such oxidative reactions. The rusting of iron tools and statues, where iron atoms interact with oxygen atoms in the air and water, is also oxidative.) In some instances, oxidized proteins can be damaged in various ways, which could in turn trigger an unwanted immune response in patients. This feature is a unique concern with therapeutic proteins.

Recently, biochemists have begun to investigate the exact locations of oxidative reactions within large intact protein molecules. Laboratory researchers in OBP, for example, have published important new information (see References) concerning protein carbonylation, which entails the addition of a single atom of oxygen, originating from the environment, to discrete carbon atoms (rather than sulfur atoms) within protein molecules. Although protein carbonylation has been recognized within the context of disease and age-related conditions, its occurrence during the manufacture, storage, use, and transport of therapeutic proteins is a relatively new area of study. For pharmaceutical quality scientists, key issues include: understanding the different tendencies of various protein products to undergo oxidative carbonylation; identifying the role that containers and chemicals that contact proteins may have in these reactions; and discovering reliable methods for specifically and consistently detecting and controlling carbonylation.

To detect protein carbonylation, the OBP team has refined an antibody-binding assay that takes advantage of the reactivity of the “carbonyl group,” which is the name given to the carbon- and oxygen-atom grouping that occurs upon protein carbonylation. Carbonyl groups that form in proteins can make the entire protein molecule less stable and lead to damage after degradation or aggregation. By exposing the carbonyl groups that are formed in proteins to a laboratory reagent known as DNPH, the OBP team found that different proteins undergo carbonylation at different levels and at specific sites. The rate and site of carbonylation can depend on temperature, time, and other variables, such as the presence of small amounts of metals that accelerate protein oxidation reactions. The laboratory also investigated the tendency for certain additives in drug formulations to start or speed up these reactions. The methods developed by the team allow many samples, under a variety of conditions, to be studied in a short period of time. Moreover, the method is sensitive enough to detect as little as a single carbonylation modification within a large protein molecule.

The findings of the OBP team may help protein drug developers produce therapeutic proteins under optimized manufacturing conditions, potentially with structural alterations or by adding stabilizing additives that could prevent harmful carbonylation reactions. More stable protein drugs could offer a longer shelf life, reduced risk of quality problems, and more predictable clinical performance. Understanding reactions such as protein carbonylation may result in improved versions of current drugs or new drugs with superior stability, purity, and potency. Above all, the goal is to have safe and effective high-quality protein products available for patients. 

Sentry BioPharma Services offers temperature sensitive biological product management to pharmaceutical companies, hospitals and organizations with need for validated  GMP storage, labeling, kitting and temperature-sensitive drug distribution services.  For more information about how Sentry’s GMP services can help protect the integrity and delivery of your biological products to patients, contact Sentry via email or by phone at 1-866-757-7400.

Consultants Day at Vetter Development Services

Sentry BioPharma Services was pleased to be invited to speak at Vetter Development Services, Consultant Day which took place in Chicago, IL on June 22, 2016.

The theme for the conference was “Your Molecule’s Journey”.  The objective of the conference was to inform pharmaceutical consultants of the unified service offerings of Sentry and Vetter (see diagram below).  The combined services take a molecule after discovery from formulation to end patient.  Alongside Vetter’s and Sentry’s presentations were talks by CMC Biologics on drug discovery and development and by FedEx Custom Critical on issues surrounding drug distribution and delivery worldwide.

Sentry Vetter Brochure P2

Vetter Development Services, Inc., located in Skokie, Illinois, is a premier contract development and manufacturing organization (CDMO).  Vetter is a global leader in the fill & finish contract manufacturing of aseptically prefilled syringe systems, cartridges, and vials. It is a family-owned, independent company with facilities both in Germany and the US, as well as offices in Singapore and Japan. Vetter’s focus is on providing state-of-the-art biopharmaceutical manufacturing, from early clinical development and scale-up to commercial filling and packaging of parenteral drugs. They provide support every step of the way, guiding your drug product through development, regulatory approval, launch, and life cycle management. Vetter offers biotech and pharmaceutical companies a foundation of experience spanning more than 35 years including dozens of product approvals for novel pharmaceutical and biotech compounds.

Mr. Tim J. Mitchell, President of Sentry BioPharma Services, presented a talk entitled:  “Protecting Product Integrity Throughout the Supply Chain”.  Mr. Mitchell had this to say about the meeting, “Through our many years of experience at Sentry we have encountered numerous issues arising from the supply chain of drug products.  I shared several stories and this example highlights the key points of my talk.”

A few years ago a large multinational pharmaceutical company (“LMP”), which is a Sentry client today, contacted Sentry concerning the +2°C to +8°C GMP storage and distribution of a sizable quantity of a new commercial vaccine which was to be imported from Europe.  We were told that LMP would handle all pharmaceutical cold chain logistics activities and we should be ready to receive the product on a certain date.  The receipt date came and went with no vaccine delivery.

The vaccine was held up in customs at O’Hare International Airport, the port of entry.  Ten days go by and finally the product arrives at Sentry.  There was concern about the vaccine strength, identity, safety, purity and quality (SISPQ) because the LMP knew that the temperature data loggers would have stopped working days earlier.  However, this issue became moot.

The pharmaceutical company ultimately had hired “Bob’s Trucking” to pick up the vaccine at O’Hare and delivery it to Sentry.  The shipping manifest called for a refrigerated truck with a temperature set point of +5°C.  Unfortunately, Bob was unclear on the differences between Centigrade and Fahrenheit so he placed the shipment in a reefer truck with a temperature set point of +5°F.

“It is a dismal situation for a company to devote the significant resources to develop and manufacture an expensive medication which can save lives and have it all ruined by avoidable mistakes during the last miles of the pharmaceutical supply chain to patients,” Mr. Mitchell pointed out.

“The scenario above is too common today regardless of present day technical advancements.  Sentry’s foreign trade zone (FTZ) could have provided a different and much better outcome for the vaccine distribution process.  Instead of clearing customs at the airport, the vaccine could have been sent directly to Sentry and placed in its validated +2°C to +8°C GMP storage environment.  While at Sentry, the product could have cleared customs and obtained FDA approval.  Once this was accomplished the vaccine would have entered U.S. commerce and could have been distributed to hospitals, clinics and ultimately to patients.”

Sentry BioPharma Services is a contract service organization (CSO) which supports the life science industry by offering GMP temperature-controlled storage, global drug distribution, FDA-compliant labeling and packaging services and importation support utilizing Sentry’s Foreign Trade Zone (FTZ).  Drug development and commercialization require continuous temperature monitoring and control.  Sentry’s diverse offerings protect product integrity throughout the pharmaceutical supply chain.  Sentry’s validated software, GMP storage and drug distribution facility, industry expertise and stringent quality standards support this objective throughout manufacturing, packaging, storage and distribution.

To learn more about how Sentry BioPharma Services can protect your products’ integrity throughout the pharmaceutical supply chain, please, contact Sentry via email or by phone at 1-866-757-7400.