Ensuring the Safety, Quality, and Identity of Biopharmaceutical Raw Materials
Testing of the raw materials used in biopharmaceutical manufacturing to ensure their identity, purity, and the levels and types of impurities present is both crucial and required. It is necessary to conduct methods specified in regional pharmacopeias (Europe, US, Japan) and other standards and regulations. Additional testing is often also performed to minimize the possible impacts of other substances found in raw materials that are not covered by specific testing requirements. The use of alternative methods is also pursued if there is a significant advantage, such as a measurable reduction in the testing time, or when conventional techniques do not satisfactorily demonstrate that the regulatory requirements are met. Extensive validation of such alternative methods is required to demonstrate their equivalency to the corresponding compendia methods.
These methods are, however, limited in their applicability when testing larger biopharmaceuticals. Perieteanu also notes that the above methods tend to lack the required sensitivity for potentially detrimental process- or product-related impurities. Other techniques such as mass spectrometry (MS) are too expensive and complex to consider for routine raw material testing. As a result, other approaches such as Western blotting, capillary electrophoresis (CE), and high-performance liquid chromatography (HPLC) are often used to provide information both on the identity and the purity of the product. Retention of samples for future investigations and photographic libraries of raw materials and packaging have proven useful at EMD Millipore, according to regulatory affairs advocate Janmeet Anant.
Start with meeting requirements
Of course, substances described in pharmacopeias should comply with the requirements of the respective substance monographs, according to Anant. Specifically, the biopharmaceutical industry relies on a series of compendia tests and 21 CFR regulations to ensure that “materials used in the manufacturing of drugs,” including those substances used to produce the drug product or added directly to the final formulation, as well as filters, chromatography resins, and processing systems, are safe for use in pharmaceutical manufacturing.
Anant points to tests for the absence of proteases, DNases (exo- and endonucleases), and RNases, which provide supportive information for biopharmaceutical production that is sensitive to enzymatic activity but are currently not described in pharmacopeias. “These tests are valuable because they provide information that can help minimize risks to sensitive processes,” he explains.
Consideration of the other components in biopharmaceutical raw materials that may react, transform, or combine with other ingredients in the matrix is important, agrees Perieteanu. While many components present in biopharmaceutical raw materials are well-characterized and can be evaluated using standard United States Pharmacopeia (USP)-type panel tests, he recommends the use of forced degradation studies to gain a thorough understanding of the individual chemical and physical behavior and tolerances. “Experience with a class of biopharmaceuticals may help reduce the total number of required analyses, but the methods ultimately chosen should consider the manufacturing processes and critical material attributes,” Perieteanu observes. He also notes that risk-assessment tools and risk-management strategies can be used to define at which stage in the manufacturing lifecycle particular tests should be performed, and critical quality attributes can often be understood through implementation and adherence to quality-by-design principles. “Ultimately,” he concludes, “continuous evaluation of all data, including those from stability studies, will help rationalize and reduce the test panel to only the essential tests that satisfy safety, integrity, sterility, quality, and purity requirements.”
Newer methods of interest
“Newer multiplexing platforms provide an improved detection range over their ELISA counterparts with the benefit of being able to test hundreds of samples for dozens of HCPs in minutes,” he says. Another “emerging” technique is two-dimensional ultra high pressure liquid chromatography (2D-UHPLC) coupled with ion mobility MS, which is orders in magnitude more sensitive than traditional HPLC and not as limited as ELISA-based methodologies in the number of HCPs that can be detected at once. “With continued advances in automated data analysis, MS methodologies are likely to gain significant ground in the future,” Perieteanu believes.
Take care when adopting alternative methods
“Overall,” says Anant, “the industry is looking for more economical, sensitive, and efficient methods for raw material testing.” One example is rapid microbiological methods, which have a clear time advantage and are growing in importance. The challenge is the complete validation of the alternative method, which requires time, personnel, equipment, paperwork, and confirmation that the alternative method meets the requirements of various regional compendia, particularly where test methods and limits are not harmonized across geographies, according to Anant. “A simple comparison of the standard method with the alternative method is not sufficient. A complete validation of the method in the presence of the product must be completed, and the sensitivity and regulatory acceptance of the alternative method should be established.”
About the Author