Fill-finish processing comes after upstream bioprocessing, formation of the active agent by cell culture or fermentation, and downstream purification; this is when the final product has the greatest value, and, thus, the most to lose to a product failure. So at these later stages of development, tried-and-true processes tend to be what’s used. Innovation can introduce elements of risk, expense and regulatory work into bioprocess operations. This includes the formulation, mixing or other preparation of the active agent into its final form, e.g., liquid or lyophilized powder, and filling and sealing within final containers, which increasingly include prefilled syringes and other delivery systems.

Fill-finish is a critical part of biopharmaceutical manufacture, and any mistakes at this point can potentially lead to product mis-formulation, contamination or improper packaging. These can result in safety issues, production failures and loss of expensive product.

Because of this, Fill-Finish operations are often not thought of as demanding substantive innovation. The underlying nature of Fill-Finish operations today is largely mechanical, involving the moving, manipulation and packaging of liquid and solid dosage forms. Many Fill-Finish operations, such as filling of vials, are virtually unchanged from decades prior. Much is repetitive; liquid dosage forms undergo essentially the same processes and handling as most other similarly vialed pharmaceuticals. Associated with this, Fill-Finish manufacturing processes have changed relatively little in recent years and generally use the most well-established methods and equipment. Innovation in this area is something to be avoided until needed.

New Fill-Finish Innovations 2010-2012
Despite the relatively stable nature of the industry, areas of innovation are emerging. To identify other areas of innovation, our 9th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity¹ asked 302 global bioprocessing directors and end-users to consider the new products and services their suppliers develop for the industry. Our objective was to identify ‘problems in need of solutions.’ We identified 21 key areas of innovation of interest to end-users, and 40 areas of innovation that suppliers to this industry are currently working on.

When it comes to innovation, our 302 global respondents were looking at other areas in the chain, citing disposable products, including bags and connectors (40.0%), probes, sensors, etc. (36.1%), chromatography products (32.2%), bioreactors (31.7%), purification products (28.9%). Compared to these, Fill-Finish services were relatively low on the list, at 15.6% of end-users in 2012. This has remained relatively constant over the past three years.

We also evaluated the differences between how respondents in the U.S. compared those in western Europe and the “Rest of World” in terms of their needs for solutions associated with new products or services. In Fill/Finish areas, we found that “ROW” countries were significantly more interest in fill finish services, and other services, such as formulation, validation and cell line services. These services areas are presumably lacking in “ROW” countries.

What are Suppliers Doing About It?
There is a growing need for improvements in Fill-Finish. Over the past couple years, we have found a notable increase in the percentage of suppliers to this industry who are investing in new technologies in Fill-Finish areas. Our global study also evaluated where industry suppliers are putting R&D resources. We separately queried 185 global vendors to identify, among other things, what investments are being made into new technologies. Of the 40 areas identified, the largest percentage was focused on creating new ‘bioprocess development services/bioprocess modeling’ (46.5%). In comparison, Fill-Finish innovation investment is relatively low on the list. However, this has grown significantly over the past year. Our data show that “Finishing: Lyophilization” and “Finishing: Packaging materials” are areas of strong investment among suppliers.

Innovations in Fill-Finish
Novel delivery systems, such as complex disposable injectors and cartridge-based reusable pen injectors, have required and resulted in a number of specific associated technological advances in Fill-Finish. Filling fluids or solids into these and other types of containers and sealing these with complete lack of microbial and chemical contamination is never a simple task, and even such things as glass vials undergo constant but slow incremental innovations. Fill-finish operations also benefit from and often involve improvements in materials, such as plastics for more reliable seals and less leaching, and biologically-inert surface coatings for glass and metal container surfaces.

Many of the innovations in Fill-Finish involve mechanical engineering, such as pushing machinery to go faster with greater throughput. Associated with this, Fill-Finish equipment manufacturers continually seek to make their machinery more efficient, reliable (lower failure rates) and cost-effective. This often involves scale-up (and, sometimes, scale-down) of machinery and operations to tailor them to the needs of specific products. CMOs perform the great majority of biopharma Fill-Finish, and thus are among the leaders in terms of actively developing, evaluating and adopting technologies and equipment that improve productivity and reduce risks of contamination and process failure.

Fill-finish innovations include a distinct trend for increased use of isolator technology. Isolators, exemplified on a small-scale by glove boxes, and related restricted access barrier systems (RABS) with somewhat lower operating standards, essentially involve individually enclosing all the process equipment and flow within sealed, no-release, no-contamination enclosures or other physical containment. Isolators completely remove or isolate human operators from the environment surrounding the product.

Isolators are enclosed, usually positively pressurized units with high efficiency particulate air (HEPA) filters supplying ISO 5 airflow in a unidirectional manner to the interior. Air is typically recirculated by returning it to the air handlers through sealed ductwork. There are also differences in cleaning and decontamination between RABS and isolators, with isolators operating at higher standards. This isolation of the product from the non-sterile surrounding environment and operators is particularly important for the many biologics that cannot be terminally sterilized. Many proteins are simply not capable of withstanding heating or other chemical/physical processes used for sterilization, requiring fully aseptic processing to maintain product sterility.

By adding increased certainty regarding sterility, use of isolator technology can simplify Fill-Finish operations and reduce costs. For example, with Fill-Finish equipment individually enclosed, there is less need for equipment to be housed in large expensive high-end clean rooms. The use of fully-enclosed systems, which can now involve use of single-use bags, much as with upstream bioprocessing, serves to assure product sterility and eliminate operator-originating contamination. There are also added benefits of eliminating releases of product and occupational exposures, which can be a critical requirement with many highly potent or toxic products. Isolators or their equivalent are also being adopted for mainstream bioprocessing; Xcellerex promotes individual containment of its single-use bioreactors within glass-walled isolator enclosures. These are then housed in clean rooms operating at a lower level than would otherwise be needed.

Patheon, a CMO involved in solid and liquid dose manufacturing and Fill-Finish, has developed a single-use tabletting process. Tony Pidgeon, senior manager, Global Science and Technology at Patheon Inc., notes that Patheon continues to develop single-use systems for Fill-Finish of clinical trial materials. Mr. Pidgeon has been involved in the design and implementation of many innovative systems for clinical trial sterile dosage forms.

A Mature Industry Niche
Fill-Finish for biologics is a relatively mature, primarily industrial activity, concentrating on efficient product formulation and packaging. Fill-Finish, much more than bioprocessing, involves complex mechanical engineering — filling, fluid and solid dispensing and sealing systems. Fill-finish professionals tend to more be engineers rather than scientists. And Fill-Finish professionals, like this industry, are rather conservative, seeking the safest process, including the safest in terms of lowest regulatory and business risks.

Most of the recent dramatic innovations in bioprocessing, notably the adoption of single-use/disposable equipment and increases in product yield/output, have not moved into Fill-Finish operations (with some exceptions, such as single use storage bags, tubing, and filling tips). However, Fill-Finish was among the first areas to adopt silicone and other single-use tubing and manifolds in place of stainless steel piping. Broader issues in bioprocessing, such as the difficulties with downstream purification processes keeping up with increased upstream yields, generally do not affect Fill-Finish operations, which rarely are the major bottlenecks in product manufacture. Much as with other aspects of bioprocessing, Fill-Finish involves intermittent intensive campaigns.

Multiple industry surveys have shown that industry decision-makers foresee few significant changes in Fill-Finish technologies in the near future. Fill-finish is not as innovation-driven as active agent development and manufacture, and many Fill-Finish operations are among the most commonly outsourced aspect of biomanufacturing. In our annual study, we estimated that Fill-Finish operations are outsourced to CMOs for about 75% of clinical and 85% of commercial biopharma supplies. Fewer than 25% of drug innovator companies now do more than 10% of their product Fill-Finish in-house. So, any current discussion of Fill-Finish generally involves discussion of CMOs, which provide the great bulk of these services, ranging from the most routine to incredibly high-tech handling and packaging.

The Fill-Finish industry is characterized by a wide diversity in the magnitude of its operations. These range from manual filling and sealing of products for clinical trials supplies to filling and sealing of tens or even hundreds of thousands or millions of units daily, e.g., as with some vaccines. The industry perpetually faces the quandary that to be optimally cost-effective generally requires operating at the very largest scale using the fastest process lines and biggest equipment, but the higher the capacity of a facility or process line, the more likely it is to be idle much of the time.

Compared with other aspects of bioprocessing, the Fill-Finish industry currently has much excess (unused) capacity, e.g., some equipment and processing lines may only be used a few times per year. Companies, whether primary manufacturers or CMOs, need to use and keep their equipment busy, in order to attain acceptable cost-effectiveness and return on their operations. Between current excess capacity and the need to use equipment and facilities, Fill-Finish CMOs are rather cost-competitive. Overall, other than products with specialized needs, there currently is no problem with CMO Fill-Finish capacity and availability. If anything, there appears to be excess capacity, with some industry consolidation likely to occur, particularly for CMOs offering standard processes or having insufficient or excess capacity, operating at the wrong scales, for the jobs they take on.

Fill-Finish Industry Growth
Fill-Finish activities and the primarily CMO-based Fill-Finish industry have been growing at the same rate as overall biopharma manufacturing, i.e., 10%-15% annually. Biosimilars are be-coming a major factor affecting more Fill-Finish CMOs. Overall, CMOs are reporting an annual 10%-15% increase in projects due to biosimilars, particularly those now in development for the U.S. market in coming years. These products reinforce the ongoing trend seen in bioprocessing of manufacturing being done at smaller scale, whether due to attaining higher yields or less product demand. With biosimilars, more companies will be manufacturing more competing products, with more projects/ products going to Fill-Finish CMOs, while the market and manufacturing requirements for the original innovator/reference products decrease. Thus, biosimilars and other follow-on products are resulting in more work for more CMOs, but at smaller scale.

Conclusions
Although Fill-Finish is not the most active area for biopharma innovations, it does operate at the point of highest product value, and so advances related to risk reduction, product quality, and efficiency will certainly bring improvements to this segment. Fill-finish is inherently more mechanical and repetitive than other aspects of biopharma manufacture, and innovations tend to be incremental, such as improved equipment performance. But Fill-Finish remains very critical to biopharma manufacture. Fill-finish operations are mostly performed by CMOs, which dominate what has become a distinct Fill-Finish CMO-based industry. The use of isolator technology, enclosing Fill-Finish equipment in its own contained, controlled environments, is a major ongoing trend. CMOs are among the leaders in both the development and adoption of this and other new Fill-Finish technologies, so expect more innovations in this area to result from partnerships between the CMOs and their equipment suppliers. 

CASE EXAMPLE Cook Pharmica is an example of a CMO that has been significantly implementing isolator technologies. Jo Anne Jacobs, manager, Technical Sciences, Drug Products, Cook Pharmica, noted, “Regulatory bodies are demanding more stringent sterility assurance requirements, so we expect isolator technologies and single-use systems to continue to advance. Complete removal of operators from the environment surrounding the product has become the expected standard.” Commenting on the use of isolators vs. RABS with less-stringent isolation, Ms. Jacobs noted, “The isolator will most likely fully supplant RABS in the future. Isolator systems can be installed and operated in Grade C/D areas and allow for minimal to no sterile gowning requirements. This also leads to lower operational costs from the standpoint of utilities. RABS systems offer excellent product and personnel protection, but must be installed and operated in a Grade B space which requires traditional cleanroom gowning.” Cook believes that as regulatory bodies promulgate more stringent sterility assurance requirements, the use of isolator technology and single-use systems will continue to increase. Innovation in this area will support that goal, and will reduce the need for dedicated stainless steel tankage for aseptic liquid handling.

Survey Methodology The 2012 Ninth Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production in the series of annual evaluations by BioPlan Associates, Inc. yields a composite view and trend analysis from 302 responsible individuals at biopharmaceutical manufacturers and contract manufacturing organizations (CMOs) in 29 countries. The methodology also included over 185 direct suppliers of materials, services and equipment to this industry. This year's survey covers such issues as: new product needs, facility budget changes, current capacity, future capacity constraints, expansions, use of disposables, trends and budgets in disposables, trends in downstream purification, quality management and control, hiring issues, and employment. The quantitative trend analysis provides details and comparisons of production by biotherapeutic developers and CMOs. It also evaluates trends over time, and assesses differences in the world's major markets in the U.S. and Europe.

Reference

1. 9th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity, April 2012, BioPlan Associates, Inc. Rockville, MD www.bioplanassociates.com

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Ronald A. Rader is senior director, Technical Research, and Eric S. Langer is managing partner, both at BioPlan Associates (www.bioplanassociates.com), a biopharma marketing research and publishing company, with more than 22 years of experience evaluating this and other life sciences segments. For more information about this article, contact elanger@bioplanassociates.com or 301-921-5979.