Fill/Finish Capacity Use for Biologics

Until recently, the handling of sterile liquids in the pharmaceutical industry has relied on decades-old techniques and technologies. During the past 10 years, however, biologics have taken a prominent role in the drug-development pipeline.  The value of these drugs, sometimes measured in tens of thousands of dollars per dose, has put greater pressure on biologics downstream fill and finish operations. The increased scrutiny from regulators and the greater product value have initiated industry improvements so that quality, safety, and cost-efficiency remain high at this crucial late stage in manufacturing.  

BioPlan recently prepared a white paper identifying trends among in-house fill and finish operations for recombinant therapeutics (1). This research excluded outsourced operations and CMOs. BioPlan found significant differences between industry capacity and capacity use for these large-molecule facilities, compared with the constraints currently being experienced in small-molecule fill and finish, which have in some cases even led to drug shortages at the hospital level.  

In biologics in-house operations, BioPlan found trends that include the increased use of isolator technologies, more high-speed operations, and other innovative approaches. Findings regarding capacity use indicate that in-house manufacturers, on average, continue to have additional available fill-and-finish vialing, pre-filled device, and lyophilization capacity:  

• Utilization averaged 55% for lyophilization

• 58% for pre-filled devices

• 70% for vialing.

At present, there is sufficient capacity, even without adding shifts or additional equipment. This finding is in contrast to the situation with small molecules, where some facilities are working at near-capacity, and facility consolidation, regulatory actions, closures, and the use of less efficient legacy equipment have created bottlenecks and even serious drug shortages at the hospital level.

The state of in-house fill/finish capacity
BioPlan’s in-house biologics fill/finish market analysis evaluated the capacity for recombinant biologics and compiled information from 89 candidate facilities in the US and Europe. More than 50 industry participants were surveyed at facilities, equipment suppliers, and consulting groups.

Regarding vialing, capacity utilization averaged 70%; this figure represents the average for biopharmaceutical in-house manufacturers, which generally produce at most a few products at each facility. While this indicates that a relatively large flex or expansion vialing capacity may be available among current primary manufacturers, in-house facilities are not designed  for, nor are they capable of, running at maximum capacity, due to down-time, maintenance, and cleaning/validation.

For pre-filled devices and syringes (PFS), an even greater amount of flex capacity was found. Pre-filled syringe and cartridges fill-finish capacity averaged 6.75 million per shift; the average PFS fill/finish capacity utilization was 55%, suggesting considerable expansion capacity potential among those facilities doing in-house PFS fill-finish.

Finally, with regards to lyophilization capacity, which averaged 760 square feet among those facilities with these data available, utilization averaged 58%, again indicating room for expanding manufacturing output.

Overall, the largest scale manufacturing operations tend to be concentrated among just a few companies, with this the case for in-house fill/finish. Most of those largest-capacity facilities are based in Europe.

Activities outsourced by biomanufacturers
Although BioPlan’s white paper analysis focused on in-house fill-finish capacity, other BioPlan research found that eight in 10 biopharmaceutical manufacturers worldwide outsource at least some fill/finish operations today, up from 6 in 10 in 2010 (2). In fact, fill/finish operations are one of the most commonly outsourced activities, behind only toxicity testing (86.8% outsourcing to some degree) and analytical testing of other bioassays (89% outsourcing).

The results of BioPlan’s annual report also show that, in volume terms, fill/finish operations are one of the most heavily outsourced activities: Respondents estimated outsourcing (on average) 37.9% of the fill/finish operations at their facilities, ahead of areas like toxicity testing (35.4%) and validation services (19.9%) (see Figure 1).

Available in-house capacity implications
The excess capacity available to in-house manufacturers of biologics may allow expansion of in-house fill/finish operations without adding shifts or equipment. Capacity, however, is commonly misrepresented as being related to machine speed or lyophilizer chamber capacity in vials. In-house fill/finish operators also note that equipment turnaround time, cleaning, and sterilization (in situ and ex situ) also need to be considered when calculating efficiencies. In this analysis, capacity utilization was defined as the “typical estimated usage of fill/finish capacity per shift”/“maximum capacity per shift”, using current number of shifts, and production equipment.  As noted, a facility could significantly increase capacity by adding shifts, if needed.

Future trends
The fill/finish industry will likely depend on ramp-up of technologies and capabilities both in-house and at CMOs. Future trends will include:  

• Fill and finish CMOs are becoming larger, through mergers and acquisitions.

• CMOs will continue to install state-of-the-art fill/finish equipment, mostly to support clinical manufacturing. Biopharmaceutical CMOs will do less sub-contracting of their fill and finish to specialized CMOs.

• Fill-Finish CMOs in India and rapidly developing countries are handling increasing amounts of biopharmaceutical products, mostly for domestic and lesser-regulated international commerce.

Conclusion
In-house biologics fill/finish operations are unique from contract manufacturers’ business strategies.  In addition, comparing small molecule in-house vs large molecule/recombinant biologics leads to significantly different conclusions.  The lower capacity use rates for biologics can be partly explained by the more recent installation of higher technology equipment, RABS/isolators, and automation.  The effect of end-product value is likely also a factor.  

Newer technology adoption will impact utilization rates at both in-house and outsourced service providers (CMOs) as legacy equipment is replaced; however, this area requires further research. Fill/finish operations represent one of the top activities projected to be outsourced at significantly greater levels in the future.  In fact, nearly 28% of global industry respondents to BioPlan’s annual study indicate they will be outsourcing more of their fill/finish projects over the next 24 months.  

Decisions in this area are likely to be based on efficiency, cost effectiveness, and capacity availability as the industry makes critical in-house vs outsource decisions. For CMOs to compete for fill/finish business, data indicate that it’s increasingly important that they position themselves as having state-of-the art equipment, especially in fill/finish services.

References
1. BioPlan Associates, Trends in Aseptic Bioprocessing Capacity for the Fill and Finish of Recombinant Biologics: An Analysis of US and European In-house Capacity and Capacity Utilization (BioPlan Associates, December 2014).
2. BioPlan Associates, 11th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production(Rockville, MD, April 2014).

Article DetailsBioPharm International
Vol. 28, Issue 1
Pages: 14-17
Citation: When referring to this article, please cite it as E. Langer, "Fill/Finish Capacity Use for Biologics," BioPharm International 28 (1) 2015.