Sterile pharmaceutical drug development presents unique production challenges. As biopharmaceuticals continue to grow in popularity and biosimilars become more commonplace, research and development in the area of sterile drug production will only continue to evolve.

The 2016 Nice Insight CDMO Outsourcing Survey found that 66% and 50% of respondents’ businesses were engaged in the development of new biologic entities and biosimilars, respectively.1 Further, global spending on medicine in general is expected to hit $1.3 trillion by 2014 — up approximately 30% from 2013 — and the demand for biopharmaceuticals is increasing in response to growth in emerging markets and the surge in oncological innovation.2

Due to their complex makeup, biopharmaceutical drugs require aseptic conditions at nearly every stage of production and, with most drugs designed for parenteral delivery, this challenge is further amplified. As investing in and maintaining aseptic systems presents a challenge for pharmaceutical companies, many are engaging contract development and manufacturing organizations (CDMOs) who have the expertise and agility required to guarantee safe production from initial formulation through the final, critical step: fill-finish. Though bottling is likely to remain as the primary-packaging market’s largest category at 22% of the market, biopharmaceuticals are propelling the use of parenterals, which are expected to make up approximately 17% of the packaging market in the coming years.3

As the overall pharmaceuticals packaging market is expected to exceed $100 billion by 2019 and aseptic fill-finish lines require an investment in time, financial resources and expertise to guarantee continued product quality/purity, it is likely that companies will continue to work with experienced CDMOs who can help their products reach the market quickly and safely.3 For CDMOs looking to stand out and develop lasting partnerships in the industry, this in turn means that advanced, sterile fill-finish capabilities and thorough inspection systems will need to be maintained to keep up with growing trends in the biopharmaceuticals market.

Patient Safety Relies Heavily On Fill-Finish

A sterile product is only as good as the fill-finish line through which it must travel. To help guarantee that biopharmaceuticals and parenterals remain as pure and safe as possible, an aseptic fill-finish process is critical. With the requirements of the Drug Supply Chain Security Act (DSCSA) and the larger Drug Quality and Security Act (DQSA), from the US FDA, set to come into effect in the next few years, it is now an opportune time to implement fill-finish improvements globally. Though DSCSA requirements focus on product traceability and secondary packaging more than primary packaging sterility, compliance may require additional fill-finish processes and engaging a skilled CDMO is often the most cost-effective way to ensure sterility while meeting upcoming regulations.4

One such CDMO is Cenexi. Headquartered in Fontenay-sous-Bois, France, Cenexi has been serving the global pharmaceuticals market since 2004, with complete autonomy since 2008. With extensive experience in sterile drug products, needle-free injection systems, galenical drug forms and cytotoxic (including antibody drug conjugates, or ADCs), and the addition of two renowned manufacturing sites with excellent regulatory records, Cenexi has rapidly built a strong reputation for drug manufacturing as well as fill-finish expertise, lyophilization capabilities, innovation and high quality standards.

In recognition of growing fill-finish needs — outsourced by 28% of respondents — and the complexities of product handling in regards to more complex and/or higher potency compounds, Cenexi operates a sterile product development center to support its production of pre-filled syringes, lyophilized medications and one of the highest ampoule production volumes in Europe.1 In other words, by pairing experience with state-of-the-art facilities designed to aseptically manage production demands, Cenexi is positioned to maintain sterility at every stage in the production process.

Parenteral Packaging, Lyophilization, Cytotoxic Processing

Most new drugs tend to be heat sensitive and susceptible to contamination at every stage of development and production, including packaging. These risks require that sterile conditions are maintained until the drugs are ready for shipment and, with these additional precautions in mind, it is easy to understand why many companies outsource packaging services related to biopharmaceuticals and other drugs requiring parenteral administration. The 2016 Nice Insight CDMO Outsourcing Survey found that 44% of respondents outsourced parenteral manufacturing/packaging.1

As advancements in research and medications for several biopharmaceutical-dependent therapies continue to surge, with oncology alone expected to contribute $100 billion to global spending in 2018, it is likely these outsourcing trends will continue.2 Though the majority of medications (51%) have traditionally been taken orally, the push in oncological R&D in particular, including new immunotherapies such as PD-1 and CDK inhibitors, will contribute to the more widespread use of parenteral and/or intravenous medications (29% of medications).2

Having already implemented Six Sigma and QbD, Cenexi produced more than 280 million aseptic ampoules in 2015.

Injectable dosage forms are extremely challenging to produce primarily due to heat, humidity, and/or oxygen sensitivity. With that, high-potency compounds, including certain cytotoxins, add additional complications that limit the number of CDMOs capable of handing certain operations. To combat these challenges, some CDMOs offer lyophilization processes that can improve output and quality without affecting stability.6,7 At the lab level, lyophilization is relatively manageable, but full-scale implementation can be costly and outsourcing to a CDMO with lyophilization services — reported by 36% of respondents in The 2016 Nice Insight CDMO Outsourcing Survey — can often ease the financial burden.1

With its acquisition of the Thissen production site at Braine l’Alleud in Belgium, Cenexi has over 20 years of experience with lyophilization and 90 square meters of freeze drier space in Europe to support demand. As many sterile drug products are unstable in liquid form and lyophilization offers a greater shelf life — up to three years, rather than a few days for the same drug in liquid form — demand is likely to increase partnering with a CDMO to take advantage of existing cGMP facilities and established expertise.5,7 Further, when producing complex ADCs that combine the targeting power of monoclonal antibodies and the cancer-fighting strength of cytotoxins, the partnership of a company like Cenexi becomes even more valuable.8 Of course, even the best fill-finish process supported by aseptic manufacturing needs a strong product quality system and rigorous inspection procedures.

Robust Inspection To Reduce Particulate Risks

While traditional, small-molecule pharmaceuticals can normally undergo terminal sterilization procedures, including heat or irradiation, this is not an option for biopharmaceuticals; as these procedures adversely affect purity or damage the drug, biopharmaceuticals must be produced under aseptic conditions and all containers and closure mechanisms must be sterilized in advance of filling.7 Maintaining an aseptic process requires the training and monitoring of personnel, environmental monitoring, proper facility design (including HVAC) and process simulation, but thorough inspection procedures are also critical.7 In 2013, it was estimated that 190 million liters of fluid were administered intravenously to patients annually and, given the increase in parenterals (primarily due to biopharmaceuticals) it is likely that number has increased.9

Many of these drugs are contained in ampoules, and understanding the cause of particulate contamination — including environmental factors, packaging materials and interactions between the drug and the packaging — and implementing thorough inspection processes can minimize contamination of finished products.9 One approach to eliminating contamination is the use of programs such as Six Sigma and Quality by Design (QbD), which work to build quality into the finished product by developing an in-depth understanding of all processes, compounds and suppliers.9 Having already implemented Six Sigma and QbD, Cenexi produced more than 280 million aseptic ampoules in 2015. Implementing these systems, however, can be challenging and, even when in place, contamination can occur. To further combat contaminants and irregularities, Cenexi complements its aseptic production with the use of both pinhole detection technology and visual inspection.

There is no perfect solution, but with parenteral drugs bypassing most immune system functions and particulates capable of causing both short and long-term complications, processing precautions are critical at every stage.9 Aseptic conditions must be maintained to eliminate microbial contamination and robust inspection — manual and/or automated — should be anything but an afterthought. Fortunately, partnering with a CDMO like Cenexi allows pharmaceutical companies to take advantage of manufacturing expertise and state of the art facilities where sterility and quality are inherent parts of every vial, ampoule and syringe.

 

References

  1. The 2016 Nice Insight Contract Development & Manufacturing Survey.
  2. Global Outlook for Medicines Through 2018. Rep. IMS Institute for Healthcare Informatics. Nov. 2014. Web.
  3. Wright, Tim. “Contract Packaging Market Trends.” Contract Pharma. 2 June 2016. Web.
  4. “Drug Supply Chain Security Act (DSCSA): Title II of the Drug Quality and Security Act of 2013.” U.S. Food and Drug Administration. Web.
  5. Zadbuke, Nityanand, Sadhana Shahi, Bhushan Gulecha, Abhay Padalkar, and Mahesh Thube. “Recent Trends and Future of Pharmaceutical Packaging Technology.” National Center for Biotechnology Information. 5.2 (2013): 98-110. Web.
  6. Fernandez, Carlos R, and Douglas A. Jonas. “Complex Aseptic Manufacturing Outsourcing: Tips and Tactics for Optimizing Your CMO Partnership.” Contract Pharma. Apr. 2009. Web.
  7. McLeod, Lorna D, Anne S. Montgomery, and Cheryl Scott. “Fill and Finish for Biologics.” BioProcess International. 1 June 2011. Web.
  8. Butler, Mark, Vince Cebular, Sam Halaby, George Petroka, and Thomas Woody. “Trends in High Tox Manufacturing.” Pharmaceutical Processing. 26 Aug. 2014. Web.
  9. Challener, Cynthia A. “Parenterals, Particulates, and Quality by Design: The Parenteral Manufacturing Industry Is Taking Action to Address Particulate Contamination Issues.” Pharmaceutical Technology. 2 Nov. 2014. Web.