BioPharm October eBook: Best Practices 2018

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6 BioPharm International eBook October 2018 Low-quality raw materials or impu- r ities in the raw mater ials can impact other qualities of a biologic, including shelf life. Fortunately, integration of process control pro- cedures during the development of manufacturing processes, includ- ing managing the supply chain for raw materials, can catch or pre- vent many issues from harming the final drug product. W here a n i ma l- der ived prod- ucts are used in the development or manufacture of biologics, there is also an inherent risk of adven- titious agent contamination. Raw materials of animal origin bring a risk to the manufacture of bio- logicals, and this risk is applica- ble to historic cell banks and seed viruses as well as to the finished products. Residual DNA or host cell DNA can be a contaminant present in biologicals that are co-purified with drug substances. These types of DNA can have a negative effect, therefore, manufacturers of bio- logicals must ensure that the final products derived from continuous ma m ma l ia n cel l l i nes conta i n acceptable levels of host cell DNA. Foehr (Pacific BioLabs): Poor quality raw materials can impact biologi- cal drug production in many ways. Poor production yields, minor or major changes in the quality attri- butes of the biologic, and costly delays or failed lots are just a few of the perils. Cells can be very sensi- tive to small changes in growth con- ditions. The growth media, serum source, growth factors, cytokines, and other additives should be tested to ensure lot-to-lot consistency. The testing may involve simple assess- ments, such as physical appearance, pH, and osmolality, or may include more complex analysis, such as potency tests, immunoblot, mass spectrometry, and chromatography- based impurity analysis. Changes in raw materials can cause slower growth of cells, low production rates of the biotherapeu- tic, and changes in characteristics of the protein, such as post-trans- lational processing and potency. These changes may impact the qual- ity attributes and cause shifts to the product specifications over time. In the worst situation, a production lot may fail specifications and need to be repeated, causing costly delays. RAW MATERIAL VARIABILITY BioPharm: Is raw material variability an issue, and if so, how do bioman- ufacturers address this challenge? Bulpin (MilliporeSigma): The pro- duction of a biologic drug requires raw materials ranging in complex- ity from mammalian cell lines that produce a biologic and media and media components used to 'feed' the production, to filters and gels used in the purification process. In addition, when considering that manufacturing of biologic happens at different sites around the world and contingencies for backups are needed for each, the number of suppliers and the number of raw material products can seem over- whelming. Each of these raw mate- rials can have lot-to-lot quality differences. Testing of each compo- nent used in drug production and monitoring products of each phase during production and lot release testing for a variety of attributes informs the production teams of any issues that should be addressed. F o e h r ( P a c i f i c B i o L a b s) : G o o d quality, reputable vendors of raw materials have tight controls over production and low variability lot- to-lot. However, sometimes differ- ent vendors are used, products are discontinued and supply chains are disrupted, or lower-cost sub- stitutes are introduced to the raw materials list. When these changes occur, it is important for biomanu- facturers to test the raw materials. It is a good idea to have a solid baseline of information and, if nec- essary, bridge the gap between old and new suppliers of raw materi- als. Comparison studies are helpful in these situations. Using reliable, "Raw materials of animal origin bring a risk to the manufacture of biologicals, and this risk is applicable to historic cell banks and seed viruses as well as to the finished products." —Bulpin, MilliporeSigma "However, sometimes different vendors are used, products are discontinued and supply chains are disrupted, or lower- cost substitutes are introduced to the raw materials list." —Foehr, Pacific BioLabs Biopharma Laboratory Best Practices Raw Materials Testing

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