Ensuring the Safety, Quality, and Identity of Biopharmaceutical Raw Materials - Going beyond pharmacopeial requirements is essential for the quality and safety of raw materials. - BioPharm

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Ensuring the Safety, Quality, and Identity of Biopharmaceutical Raw Materials
Going beyond pharmacopeial requirements is essential for the quality and safety of raw materials.


BioPharm International
Volume 27, Issue 8, pp. 28-29
ADAM GAULT/SPL/Getty Images

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.

Standard methods
The definition of “raw material” in the biopharmaceutical industry encompasses a range of ingredients that are process-related or components for the final product, including cell lines, resins, active drug substances, and excipients, as well as container closures. A variety of methodologies, therefore, are commonly required for the testing of source materials, in-process materials, and excipients, according to Alex Perieteanu, director of biopharmaceutical services in the Life Science Services business of SGS Canada. “Fingerprinting methodologies such as Raman, near-infrared, Fourier-transform infrared, and nuclear magnetic resonance spectroscopy are among the most common tests employed to ensure the identity of raw materials,” he says.  

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.

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Start with meeting requirements
“The decision to use any analytical test requires an understanding of the purpose of the test, how the results of that test will be used, and which tests provide the same data in a different format and thus perhaps are non-value-added,” says Perieteanu. “Appropriate control strategies are thus required to ensure the safety, quality, and identity of raw materials used at any stage of a process, from cell culture and growth to the final product ingredients and packaging.” He adds that the strategic goal is to achieve this control in the most efficient manner using necessary distinct and orthogonal analytical techniques to provide the necessary data.

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.  

Then go beyond
The pharmacopeia requirements should be viewed as a basis that may be reasonably complemented by additional acceptance criteria, according to Anant. “While a supplier’s certificate of analysis will provide valuable information and often data derived from compendia methodologies, it is strongly recommended that additional testing be performed by the manufacturer, at minimum identity testing,” Perieteanu agrees.

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
Host-cell contaminants can pose a significant safety concern. Enzymatic analytical methods with photometric evaluation (tests for the absence of proteases) and electrophoretical methods with dye staining are standard methods that are both reliable and sensitive, according to Anant. With enzymatic analytical methods, however, enzyme activity can be influenced by the salt concentration, pH, temperature, substrate concentration, and the presence of a large amount of macromolecules, while electrophoretical methods require careful control of the viscosity and complexity of the sample, and the separation should be aligned within the linear range for the molecule of interest. For host cell protein (HCP) testing, Perieteanu notes that enzyme-linked immunosorbant assays (ELISA) are a sensitive method but represent a relatively low throughput approach. 

“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
Alternative raw material testing methods may be of interest for several reasons, including upcoming changes in regulatory requirements, to address a product issue that has arisen downstream, or to improve upon existing tests. The first step in adopting alternative methods, at least in the latter two cases, is to provide a strong justification for replacement of the existing method. Once that has been achieved and accepted, other factors must be considered, such as the availability of needed equipment; establishment the equivalence of the method to the compendia or otherwise commonly accepted method, including validation; and recognition that greater sensitivity and specificity may uncover new issues, according to Perieteau. “Preparedness to investigate any unknown phenomenon observed when testing using a new methodology is a must,” he asserts. “Often more modern methodologies yield additional data such as unknown peaks or other discrepancies, and the root cause, whether it is analytical or true, should be investigated,” Perieteanu adds.

“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
Cynthia A. Challener is a contributing editor to BioPharm International.

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