Manufacturing biologicals is tricky. A major concern is the risk of microbial contamination, jeopardizing product safety and causing high costs. But there are solutions for decreasing the risks.
Making monoclonal antibody (mAb) drugs? Safety first
In releasing a biomedicine, the last thing a biopharma company wants is for people to be harmed. This makes the risk of bioburden, and how it can be prevented, a major issue for drug safety.
Thankfully, businesses and regulatory agencies share the same goal—to make every product safe and effective. Manufacturers and suppliers might have concerns with production economy, security of supply, and other operational issues, but their number one priority is always the health of the patient.
Bioburden management is key
A major area for safety improvement is bioburden management. High up on any list of critical quality attributes (CQAs) for mAbs, you will likely find a requirement for the absence of microbial contamination. Apart from the potentially tragic impact on patients, the economic consequences of a batch failure are enormous. For the mAb blockbusters, a month production stop can result in lost revenues of up to USD 1 billion. A typical QA investigation could cost USD 20 000. These are big and scary numbers (Table 1).
Table 1. Potential financial impact of a bioburden incident in biopharmaceutical manufacturing
|Issue||Potential impact and cost|
|Commercial impact||Up to USD 1 billion in lost revenue1
- Loss of reputation by customers, authorities, patients
- Long lead time due to low inventory
- Lost business to competitors
- Penalties in rare cases
|Failed production lot/scrap batch||Up to USD 1 million2|
|QA investigation||Up to USD 20 0003|
|Sanitization of facility and equipment||Up to USD 100 0004|
|Resin must be discarded||Up to USD 3 million5|
1. Up to USD 1 billion lost revenues/month for blockbuster drugs
2. 2000 L bioreactor with 5 g/L expression level. Cost of mAb production USD 100/g
3. USD 120/h labor cost. 1 week of investigation by three people
4. USD 120/h labor cost. 4 weeks by five people
5. Based on large-scale column size and resin costs
Because mAbs are always produced from living cells in complex processes, managing bioburden is a sizeable challenge. Filtration can make sure microbes are absent in the final product and using low pH elution during protein A capture chromatography can safeguard against some viruses. However, there are still many bioburden risks in both upstream and downstream bioprocessing (1). Recently, there have been some welcome developments. For example, single-use products have been introduced as a viable alternative to stainless steel equipment. This has resulted in greater simplicity and better control over routes for microbial contamination.
Whenever new approaches are introduced, there is an initial period where suppliers and users justify switching, based on experience and good science. Next comes a period where the new technologies are accepted, based on the pros and cons compared to previous options. In the case of single-use technology, choice is mainly influenced by the scale of operation and need for production flexibility.
Other factors to bear in mind include preferences regarding bioburden control, staff experience, and facility constraints. And, of course, there are costs to be accounted for. Where previously there would be concerns over disposal of cleaning agents, these are replaced by how to dispose of the single-use items. Costs for building and operating a traditional steel-piped plant are replaced by costs for raw materials such as larger warehouses and increased levels of inventory.
De-risking the production environment
Both biological manufacturers and suppliers of equipment and raw materials such as filters, resins, and bags need to maintain continuous vigilance. This should be based on risk analysis and risk mitigation/preventative action. Most of the failures reported to the FDA indicate lack of inspection/maintenance at potential microbial entry points, such as valves and connections. Presumably microbial contamination was not foreseen in the original risk analysis—an oversight that is certainly thought provoking.
Controls for bioburden focus strongly on preventing contamination, as emphasized in current guidance for industry from various regulatory bodies (2,3,4). This can be particularly challenging when processes involve many incoming raw materials and a variety of manual operations. Suppliers can play their part (Table 2). Firstly, through developments like single-use technology. And secondly, by controlling bioburden in more conventional raw materials that have contact with the product, like filters and resins.
Products designed for bioprocessing should also address cleaning and sanitization as an important aspect of product use. This focus is apparent in large-scale columns for the manufacture of biologicals, where vast improvements have been made in recent years (5). These issues are best dealt with by collaborative efforts involving dialog between all parties, and in many ways suppliers are the most willing to collaborate.
Table 2. Challenges related to bioburden addressed by suppliers.;
|Challenges related to bioburden addressed by suppliers|
|Control of microbial contamination in raw materials that have contact with product, e.g., filters, resins, bags, and disposables.|
|Control of endotoxins in above raw materials.|
|Design of potential bioburden entry points, e.g., connections, valves, diaphragms, closures, and sensors/monitors.|
|Transfer operations from one process step to next, e.g., stages in downstream purification.
Column packing, unpacking, and repacking.
|Development of cleaning and sanitization protocols for re-used raw materials, e.g., filters and resins.|
Barriers to change
There are still many different routes to eliminating bioburden. The present dogma from the regulatory authorities is that choices should be made based on good science; by applying quality by design (QbD) principles, best practices can evolve. However, two factors are creating barriers:
1. Change must be justified by experiments, which cost time and money. This makes our industry understandably conservative. It is hard to displace methods that have always worked in the past, especially when there are safety and efficacy concerns.
2. Commercial advantages devised by one company are not shared within a community of competing firms. Companies do not share best practice.
There is a vital role here for suppliers of enabling technologies. For example, in the production of mAbs, productivity has been a major concern over the years. This has resulted in the evolution of protein A column chromatography resins, which offer much higher binding capacities and higher flow rates. At the same time, they safeguard the unique selectivity that helps assure mAb purity (and thereby safety and efficacy). At the same time, they offer the universality that allows the establishment of mAb platform processes. Using these resins makes excellent economic sense for companies that have several mAbs in the pipeline (6–8).
Technology suppliers are here to help. We are, after all, travelling the same road with the same ultimate destination: towards safe and effective biopharmaceutical products that improve patients’ lives.
In other articles, we will look at sources of bioburden you might have missed and how to address them.
You can also learn more from bioburden case studies in an article from American Pharmaceutical Review.
1. Suvarna, K. et al. Case studies of microbial contamination in biologic product manufacturing. Am. Pharm. Rev. 14(1), 50–56 (2011).
2. Guidance for Industry. Sterile drug products produced by aseptic processing — Current Good Manufacturing Practice. U.S. Department of Health and Human Services Food and Drug Administration (2004).
3. EU guidelines for Good Manufacturing Practice for medicinal products for human and veterinary use. Annex 1 Manufacture of sterile medicinal products (2008).
4. EU guidelines for Good Manufacturing Practice for medicinal products for human and veterinary use. Annex 2 Manufacture of biological active substances and medicinal products for human use (2012).
5. Application note: Sanitization and endotoxin clearance in AxiChrom columns. GE Healthcare, 28929042 Edition AE (2014).
6. Kelley, B. Industrialization of mAb production technology: the bioprocessing industry at a crossroads. MAbs 1(5), 443-452 (2009).
7. Gronemeyer, P. et al. Trends in upstream and downstream process development for antibody manufacturing. Bioengineering 1(4), 188-212 (2014).
8. Bolton, G. et al. The role of more than 40 years of improvement in protein A chromatography in the growth of the therapeutic antibody industry. Biotechnol. Prog. 32, 1193-1202 (2016).