 is Industry Market Manager Biopharma, Pharma EMEA - Brenntag GmbH.

René Hilmes

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For more than a century, chemically synthesized medicines such as aspirin and paracetamol have helped treat fever, pain, and inflammation (1,2). The constantly improving understanding of the genetic roots of many diseases has led to the development of a new generation of biological active agents (3). The ongoing development of so-called biopharmaceuticals is linked to the establishment of new development processes and new specific challenges in the choice of starting materials. The manufacturing technology for biopharmaceuticals can be divided into upstream and downstream process steps (4). The upstream biopharmaceutical production of APIs refers to the first stages of the production of biopharmaceuticals (5). This includes several processes, including cell line selection, culture media selection, growth parameters, and process optimization to achieve optimal conditions for cell growth and biopharmaceutical production (4). Processes used in the production of biopharmaceuticals rely on diverse basal medium formulations containing more than 50 essential nutrients, such as amino acids, vitamins, trace elements, and additional chemicals. Compared to chemical drugs, biopharmaceuticals are more difficult to produce, and have more than one route of application and unique pharmacokinetics. Their advantages are high selectivity and efficiency, target specificity, and low toxicity. It is especially these advantages that make them particularly interesting for use in personalized medicine (5).

APIs can be produced traditionally (chemically) and have a high degree of stability. Here the molecules are exposed to extreme conditions (high pressures, high temperatures, solvents, etc.). The production of biopharmaceuticals is based on living systems, which only tolerate narrow temperature and pH windows to produce the API. Protein-based biopharmaceuticals are produced using genetically modified cells. Viral vector-based biopharmaceuticals are infectious viruses that can be used to express the desired API recombinant via 

) cells. Patient cell synthesized biopharmaceuticals are typically produced using human cells and transduced via a lentivirus. Figure 1 summarizes the four different starting points for producing APIs (6).

 Four starting points for API production.

The challenge in biopharmaceutical production of ensuring safety and quality

The lessons of the past, in which a few biopharmaceuticals were contaminated, have led to the current best practice, which relies on three pillars: the selection of appropriate starting and raw materials with a low risk of containing adventitious virus; testing of cell banks and in-process materials to ensure they are free from detectable viruses; and finally, the incorporation of steps to remove and inactivate potential undetected adventitious and endogenous viral contaminants during purification of the product (7). Regulatory guidelines are essential for patient safety. There is no “one-size-fits-all” approach for the different types of pharmaceutical drugs. Biopharmaceuticals are absolutely different from classical chemical APIs.

Ensuring that all components of the biopharmaceutical manufacturing process are free of impurities is one of the pillars to produce a high-quality and clean API product.

It is widely acknowledged that risk-assessment strategies play an important role in the successful implementation of manufacturing processes for biopharmaceutical API production. They assist in the establishment of appropriate specifications for raw materials and help ensure the implementation of effective testing approaches. The development of test methods to verify the identity and quality of materials used in biopharmaceutical manufacturing can help to prevent the use of unsuitable raw materials, thereby providing a solid foundation for a successful process. Whereas pharmacopeial standards may not be a 100% perfect solution, they do provide valuable tools for users of these materials. They can save them time and expense that would be required if they were to develop and validate test methods themselves. Raw materials that have been processed under good manufacturing practice (GMP) conditions and meet the requirements set out in compendial monographs have established a certain level of quality. Nevertheless, it is still necessary to prove their suitability for use in the process. For instance, pharmaceutical-grade citric acid is available for use as a cell culture supplement (process step upstream), and its quality could be tested against existing monographs. However, to establish its quality, it may be helpful to also assess the impact of the albumin’s lot-to-lot variability on cell growth, its stability in the process, and possible interactions with other processing components. Many regulatory guidelines indicate that raw materials should be included in the manufacturing strategy, but they do not describe exactly how to do this. The question arises as to why there are still no exact conditions and standards in known guidelines regarding the choice of raw materials in the upstream process. As there is no exact definition of what quality a raw material should have, theoretically any quality of raw material from Table I can be used for production of a biopharmaceutical API.

 General grades and their characteristics (8).

The European Medicines Agency publishes scientific guidelines on human medicines that are harmonized by the International Council for Harmonisation (ICH). The ICH publishes harmonized scientific guidelines for pharmaceuticals, accepted by regulatory authorities and industries in Europe, Japan, and the United States (9,10).

There are two ICH guidelines in the “Specifications” chapter, one for chemical drugs (ICH Q6A) (11) and one for biopharmaceuticals (ICH Q6B) (12). However, none of the ICH guidelines describe what quality a material should have that is to be used in the upstream process to produce an API. In ICQ 7, the decision to select the quality standard is left to the manufacturer of the API.

The raw materials used (media, buffer components) may provide the potential for growth of microbiological contaminants. Depending on the source, method of preparation, and the intended use of the API or intermediate, control of bioburden, viral contamination, and/or endotoxins during manufacturing and monitoring of the process at appropriate stages may be necessary

Impurities influence product quality, stability, and efficacy, so their levels need to be minimized (14). The use of pharmacopeial standards can bridge the gap between the lack of guidelines and the minimum requirements of the raw materials for the upstream process, as they can be tools for traceability and compliance. Reference standards can be used as calibrators to ensure that substances are used in a consistent manner, meet the same specifications, and are then transferred to consistent production.

Downstream manufacturing processes remove two types of impurities: product-related, such as unwanted molecular variants, and process-related, such as residues of cell culture components and substrates. These must be reduced to acceptable levels to ensure product safety (15).

Not all methods used in the downstream process lead to the removal of all contaminants that arise during the upstream process. This is one of the reasons why it is important to ensure that the starting materials are of high quality and purity right from the start, to reduce contamination to a minimum. The removal of lipopolysaccharides and endotoxins, for example, is complicated and causes high costs in the downstream process when removing these. It would therefore make sense to choose purely endotoxin-free starting materials, set out in an ICH guideline, to improve this process and minimize the risk (16). Downstream process costs, which currently account for the majority of costs, could be reduced by using higher quality products that do not contain endotoxins from the outset (17). Today, about 80% of the cost to produce and purify a biopharmaceutical active molecule is found in the downstream process section (18).

Quality through strategic partner selection and tailor-made services

Various regulatory guidelines emphasize the importance of including raw materials in manufacturing strategies. However, they often lack specific instructions on how to achieve this. Pharmacopoeia standards can fill this gap by providing compliance tools. For example, reference standards can serve as calibrators to ensure consistent material usage and adherence to specifications, promoting uniform manufacturing practices.

The use of pharmacopoeia standards can mitigate the risks associated with manufacturing products at multiple sites.A careful selection of suppliers ensures that only the highest quality products are used in the upstream biopharmaceutical manufacturing process. Adhering to strict standards and rigorous testing protocols, can also ensure the quality of raw materials. The investment required for manufacturers of starting materials for the biopharmaceutical process to conduct appropriate tests according to pharmacopoeia standards is significant. Due to the absence of explicit guidelines stipulating that upstream materials must adhere to a corresponding standard, and given that quality is often considered secondary during the laboratory development phase, some manufacturers opt not to produce according to these standards. However, to provide assurance in these instances, testing of these raw materials should be done according to pharmacopoeia standards. This ensures that biopharmaceutical API manufacturers receive the quality required by pharmacopoeia standards, facilitating the production of high-quality APIs. Frequently, raw material manufacturers package their products in a manner that suits their own economics but may not be suitable for the end customer. Repackaging supplier-packaged goods to meet the specific requirements of the API manufacturer, offers a customized solution. The development of new biopharmaceutical APIs through the various clinical phases takes time and therefore attention should be paid at the beginning of the development phase to ensure that high quality raw materials are used in order to ensure that the production of the APIs will continue in the coming years, assuming that exact requirements for the origin of the raw materials in the bioprocess are defined at some point.

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Articles

Biopharmaceutical production faces the challenge of ensuring the quality of raw materials due to a lack of specific guidelines. By implementing effective risk assessment strategies and working with reliable, selected solution providers, biopharmaceutical manufacturers can minimize these challenges and improve product quality.