Risk-Averse Fill/Finish Industry Embraces Change

As medicines shift from one-size-fits-all treatments to personalized and small-batch drugs for rare diseases, the fill/finish industry is modernizing to address changing manufacturing needs. Parallel pressures to rapidly advance drugs while reducing cost and maintaining sterility assurance and high safety standards are accelerating the pace of change (1–4).

While switching to single-use technologies and adopting automation may not appear to be major changes, at the fill/finish stage of drug development-the final step of packaging before the drug moves into patients-there is a need to develop and adapt, but no room for error. Beyond the top priority of patient safety, there’s the matter of clinical success. By the time therapies reach fill/finish, pharmaceutical companies have already spent millions of dollars to advance their drug. A milestone payment or ability to raise the next round of venture capital frequently hinges on this step. For many startups, it is all or nothing.

Even for companies with ample funding, mistakes at the fill/finish step can directly impact their bottom line. Major pharma companies aren’t immune to challenges: in February 2018, safety violations found at a large pharmaceutical company’s fill/finish facility delayed a key drug approval by more than a year, allowing a competitor to get to market first and reap first-mover sales (5).

Given these high stakes, fill/finish manufacturing is a notoriously risk-averse industry. In this context, today’s changes are even more remarkable. In fact, we’ve never seen such rapid changes in the industry. This is an exciting time for the field, and modernizations that help reduce costs, speed development, and increase product safety will ultimately benefit patients.

Product diversity increases 

Multiple macro trends are converging to drive industry change. First, the quantity and diversity of drugs in clinical development are rising-ingeneral, the number of new drugs approved by the US Food and Drug Administration (FDA) is rising (see Figure 1), and the diversity of drugs in development is increasing as well. A report by Pharmaceutical Research and Manufacturers of America (PhRMA) detailing the biopharmaceutical pipeline as of August 2016 found 9500 projects in clinical development, of which 822 were covered by an orphan drug designation awarded by FDA (diseases affecting 200,000 or fewer patients in the United States) (6). A significant number of projects involved biologics, including 731 cell or gene therapies, 173 DNA or RNA therapeutics, and 188 conjugated monoclonal antibodies (6).

Individualized therapies are also on the rise: for the past three years, more than 20% of the new molecular entities approved by FDA were classified as personalized medicines (7–9). In 2017, a record-breaking 16 personalized therapies were FDA approved (10). These trends are mirrored in European drug approvals. In 2017, of the 92 new medicines recommended for approval by the European Medicines Agency (EMA), nearly 40%, or 35 medicines, were new active substances (11).

Pharmaceutical industry growth is also expected in the Asia Pacific region. Of particular interest is China, potentially the second-largest pharma market in the world. While historically only a third of FDAapproved medicines were available in China, the country’s government is fundamentally changing drug development to close this gap. Changes include acceptance of foreign clinical trial data, paperwork reduction, and streamlining clinical trials and will support product development and commercialization, increasing the need for fill/finish technologies (12).

As a result, the fill/finish industry is experiencing a need for highly flexible manufacturing equipment. Small-batch products are on the rise, requiring automated systems that can robustly handle frequent product shifts. In response to these pressures, single-use technologies, automated systems, robotics, and modular technologies are increasingly adopted. The historically risk-averse fill/finish industry is embracing change (1–4).

Shifting to single-use technologies

While stainless-steel systems have been used for decades in clinical fill/finish manufacturing, the equipment is expensive to install and qualify and requires dedicated cleaning methods with associated time and expense Resistance to change, however, is now overcome by market demands. It can be simpler to use and dispose than developing and/or improving cleaning methods (13–15).

Single-use technologies eliminate between-batch cleaning time, shortening turnover times, increasing capacity, and reducing costs (13–15). It is estimated that the total time saved using disposables ranges from four months to more than a year (16).

Additionally, disposable products remove risk of cleaning deficiency, manufactured in the same plant with rapid turnaround (13–15). Higher-potency products are also on the rise, with approximately 25% of new chemical entities (NCEs) in development deemed “potent” (17). Disposables significantly reduce the risk of cross contamination in a multi-product facility, an area of high regulatory scrutiny (13–15).

In contrast to stainless-steel systems, which are expensive to modify, manufacturing changes are much more cost efficient to implement with single-use technologies. This flexibility is particularly beneficial for customers at the early stages of development, when future adjustments are likely (18).

AMRI, for example, has adopted multiple single-use disposables, including single-use glass, or ultralow-density polyethylene (uLDPE) formulation and filling vessels, pre-assembled, irradiated filters and filling lines, and single-use isolators for operator protection to minimize the potential for product contamination. These risk reductions have been viewed favourably by external auditors and regulatory agencies, allowing auditors to quickly move beyond a focus on fill/finish, which, prior to the development of single-use systems, was an area of significant regulatory scrutiny (20). In addition to regulatory advantages, single-use disposables offer rapid process turnover and increasing capacity utilization.

It is important to note that single-use systems do not present a foolproof solution; risks are not eliminated with such technologies. Employee training remains critical in regard to successfully implementing sterility assurance management as well as from a safety perspective, particularly as increasing numbers of potent drugs are progressed to clinic.

Automating fill/finish

Automation has disrupted the banking, travel, and auto industries, and has reached fill/finish manufacturing. While data may support the manual fill/finish process’ ability to control sterility assurance, automation and fullyclosed systems’ ability to further lower risk and reduce risk to operators is highly attractive (21).

Indeed, FDA has cited automation as key for improving operator safety, reducing human errors, and improving drug quality (20). In 2016, an estimated 40% of fill/finish tasks were automated (see Figure 2).

Introducing an automated filling with closed restricted access barrier system (cRABS) (see Figure 3) within an existing cleanroom facility allows one to focus on developing modular single-use systems, including isolator containment, to maximize product diversity and expedite process turnaround. Vendor relationships and qualification are crucial to this philosophy and, when established, allow technical teams to focus on maximizing throughput, including key internal sterilization processes for filling lines and cleanroom suites.

cRABS delivers the sterility assurance levels required by regulators while allowing for swift changeover from product to product.

Automated filling systems within barrier systems and format-free robotics have the major advantage of removing humans from cleanroom sterile core, thereby eliminating the primary source of environmental contamination (22). Automation also provides safety benefits for workers, protecting operators from potential exposure to potent products.

Robotics technology offers the opportunity for operator free, isolator-based processing of highly potent, small-volume parenterals with 100% in-process control (IPC), maximizing safety and sterility assurance and minimizing product loss. They bring flexibility in supporting multiple container types with limited or no change parts (23).

Ideally, an automated fill/finish system is designed and built within a new cleanroom facility; however, often it is the case that existing facilities are upgraded/retrofitted. Designing from scratch gives the freedom to achieve optimum process flows and minimize space utilization, an important factor in considering the build and regular running costs of an aseptic facility. In upgrading, process flows may need to be adapted and, while not compromising sterility assurance, may require focused training and monitoring. Routine aseptic interventions change from manual filling/stoppering to transfer processes and machine assembly. Risk is reduced; however, training and routine qualification remain critical to a robust process.

Essentially, while automation and robotics inevitably reduces direct operator involvement and headcount, there will still be a need for human involvement to appropriately qualify processes and maintain and trouble shoot any equipment issues.

Mix-and-match modular systems

In seeking maximum flexibility to support diverse product scales and allow rapid turnaround in production batches, modular systems are highly attractive and work well with automated systems and robotics. Modular systems enable plug-and-play capabilities, including switching out filling lanes, bags, or filters with universal sterile connections.

This ability allows significant scalability, providing companies with the ability to smoothly execute fill/finish on batch sizes ranging from less than 500 mL up to more than 100 liters. These rapid access flexible systems reduce impact on operator safety, which is particularly important with today’s highly potent APIs.

Vendor selection critical

Nearly 40% of fill/finish operations are outsourced (19). As the industry adjusts to meet the changing needs of biopharmaceutical drug development-including smaller batch sizes, desire to lower costs, and speed time to market-fill/finish providers that can offer technologies to address these needs will be in demand (1–4).

In addition to meeting technical requirements, an often-overlooked criterion during vendor selection is cultural fit. Relationships with fill/finish manufacturers will last for years-potentially from preclinical development to commercialization-so it is crucial to find a partner who delivers technically and with flexibility, but whose style and approach aligns with yours.

With a solutions-oriented, culturally aligned partner offering modern solutions for the fill/finish process, you will be well positioned to bring ultra-safe products to market as quickly and cost efficiently as possible. It is part of the goal we share to bring safe medicines to patients faster and more efficiently.

References

1. “Overview of Aseptic Fill/Finish Manufacturing,” Biorealty.com, September/October 2004.
2. R.A. Rader and E.S. Langer, “Fill-Finish Innovation,” Contractpharma.com, Mar. 13, 2013.
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4. L.D. McLeod et al., “Fill and Finish forBiologics,” Bioprocessintl.com, June 1, 2011.
5. E. Palmer, “FDA Form 483 Shows Pfizer Repeating Same Mistakes at Troubled Fill-Finish Plant,” Fiercepharma.com, Feb. 16, 2018.
6. G. Long, “The Biopharmaceutical Pipeline: Innovative Therapies in Clinical Development,” Phrma-docs.phrma.org, July 2017.
7. FDA, “Novel Drugs Summary 2015,” FDA.gov, January 2016.
8. FDA, “Novel Drugs Summary 2016,” FDA.gov, January 2017.
9. FDA, “Novel Drug Approvals for 2017,” FDA.gov, December 2017.
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12. S. Ellis, “China’s Fledgling Biotech Sector Fizzes into Life,” Nature Biotechnologyonline, DOI: 10.1038/nbt0118-8, Jan. 10, 2018.
13. J. Markarian, BioPharm International29 (5) 2016.
14. B. Tyson, “How Single Use Systems Could Revolutionize Fill Finish Changeover,” NNE.com, www.nne.com/techtalk/speed-up-fill-finishchange-over-with-single-use-systems/, accessed May 11, 2018.
15. C.J. Smalley, “Single-Use For Fill-Finish: Is It Worth The Risk?,” Pharmaceuticalonline.com, Nov. 7, 2016.
16. C. Roth, “Disposable Technology-Use of Disposable Technology in Clinical Fill & Finish Manufacturing: Benefits & Considerations,” Drug-dev.com, April 2014.
17. “High Potency Drugs-From Molecule to Market,” Pharmafile.com, Sept. 6, 2017.
18. J. Markarian, Pharmaceutical Technology10 (7) 2017.
19. R. Hernandez, BioPharm International29 (9) 2016.
20. FDA, “Pharmaceutical cGMPs for the 21st Century-a Risk-Based Approach,” FDA.gov, September 2004.
21. H. Forcinio, BioPharm International30 (5) 2017.
22. C. Fuchs and S. Mauri, “Why Change is Inevitable in Aseptic Manufacturing?” Fedegari.com, January 2016.
23. “Robots’ Role in Flexible Fill-FinishLines,” Pharmtech.com, 18 Jan. 2012.

About the authors

Iain MacGilp, PhD, Iain.MacGilp@amriglobal.com, heads manufacturing, and Martin Reid, Martin.Reid@amriglobal.com, heads quality assurance at the Glasgow facility of AMRI, a global contract research and manufacturing organization.

Article Details

Pharmaceutical Technology
Vol. 42, No. 9
September 2018
Page: 34–38

Citation

When referring to this article, please cite it as I. MacGilp and M. Reid, “Risk-Averse Fill/Finish Industry Embraces Change," Pharmaceutical Technology 42 (9) 2018.