Follow-on biologics (FOBs, or biosimilars) differ from generic small-molecule compounds and pioneer biopharmaceuticals in several ways. Those differences affect aspects of their regulatory approval pathway, analytics, and marketing (1). Many biological active pharmaceutical ingredients (APIs) are actually incompletely characterized dynamic mixtures of macromolecules with slightly different primary compositions or higher-order structure (microheterogeneity). Those properties of macromolecules (unlike small molecules) are greatly influenced by their individual manufacturing process.

Emerging regulatory guidelines for follow-on biologics are clarifying aspects of their development (2). Nevertheless, product sponsors continue to see challenges in such areas as

• bioanalytics and comparative assay development
• clinically meaningful definitions of biological activity
• worldwide harmonization of acceptable data
• product commercialization strategies (3).

Despite significant progress, satisfactory product– and market-segment–specific understanding of these issues remain to be achieved (4, 5). Market dynamics and regulatory uncertainties contribute some unique issues that require consideration in development of such noninnovator products as FOBs and the new molecular entity biosuperiors (sidebar “FOB-specific factors). For example, many FOB business models require sponsors to keep investment and operating costs low, development times and costs reduced, and production formats adaptable and flexible. Single-use technologies (SUTs) and single-use systems (SUSs) in common use today typically allow or specifically support such considerations.

 

Single-Use Technology

 

Manufacturers of biotherapeutic molecules not only have SUTs to support many unit operations, but are increasingly presented with a variety of solutions from a growing number of vendors. Systems supporting a growing number of manufacturing operations begin upstream with disposable mixing, transfer, and filtering for buffer and culture media preparation. Single-use bioreactors that facilitate disposables-based production systems up to the 2,000-L scale and support full monitoring and control capability are used in approved product manufacturing (Figure 1). Single-use filtration, centrifugation, and chromatographic systems (including large-scale membrane chromatography) are at various levels of acceptance, and offerings now support such operations as viral clearance, drug substance storage, and formulation and fill (6).

 

SUTs in manufacturing provide benefits such as cost savings, process efficiency, and heightened safety (7, 8). Costs savings begin with a reduction in capital requirements and process footprints by eliminating entire operations as well as their associated service and validation procedures. Efficiency is gained through such features as greatly reduced process turnaround time, ease and safety in product changeover, and economy of site-to-site transfer or replication. SUTs offer specific and even unique advantages in process development (PD) and operations while maintaining many values of the classical materials they replace. Here I review specific features afforded by SUTs that relate to biosimilar-specific PD and manufacturing requirements (see sidebar “FOB-Specifice Factors”).

 

Process Development Speed

 

PD for an FOB can be quite different from the procedures developed for an originator molecule. For example, much may already be known about the highly related progenitor product’s functional, physicochemical, and clinical characteristics, including from postmarketing experience. Other differences can be problematic — such as a heightened demand for speed to market — for such reasons as

• concerns from competitor launch schedules
• sponsor’s requirement of early cash flow
• catching up due to legal hurdles and regulatory delays
• FOB-unique commercialization strategies
• filing-specific reference-product data exclusivity.

SUTs have supported a number of classic efficiencies that contribute to an accelerated development schedule, while also offering unique development time-saving features. Because they do not require clean-in-place (CIP) or steam-in-place (SIP) operations, SUTs accelerate up-front facility design and construction schedules. By lessoning facility requirements, they can be installed in simplified or existing manufacturing suites, thereby saving many months of time. Because the reusable non–product-contact hardware for such systems as single-use mixers (SUMs) and single-use bioreactors (SUBs) can be constructed and installed in as little as two months, SUTs remarkably reduce equipment design and build times. Decreased or eliminated services also greatly shorten the time spent in facility, equipment, and process qualification and validations. Custom designed, multiple overwrapped, freezable, and presterilized flexible bioprocess containers (BPCs) facilitate establishment and validation of good manufacturing practice (GMP) cold chain and good storage practices.

 

FOB-Specific Factors Affecting Development and Commercialization

 

Developing clinical and technical guidance/standards (e.g., delay of original FDA guidance/standards and current revision of EMA guideline on similar biological medicinal products)

Biologics Price Competition and Innovation Act (BPCIA) versus Hatch–Waxman procedure differences (e.g., data exchange between sponsors of reference molecule and follow-on biologic, FOB)

Developing statutory and patent context (e.g., Amgen’s new Enbrel patent award)

Type, amount, and source of product understanding required to establish high similarity versus safety and efficacy (e.g., FOB sponsor clinical requirements versus originator’s filing)

Process development and operational flexibility demand (e.g., BPCIA-determined potential case-by-case “fingerprint identification” and the “two-step” approach)

FOB production platform or format influences on entity critical quality attributes (CQA) (e.g., product microheterogeneity)

FOB-specific commercialization requirements (e.g., slower than expected uptake in the European Union)

Business and marketing distinctions (e.g., growing understanding of how clinicians view noninterchangeable bio-“generics”)

FOB initiative in its infancy: product attrition and industry consolidation anticipated (e.g., US biosimilars marketing has just begun with a few products)

Limited reduction in selling price from innovator drug (e.g., ∼30% reduction observed)

Geographical market distinctions in product class understanding by clinicians and the medical industry (e.g., compare among United States, European Union, India, and Japan)

Technical, clinical, and business distinctions between individual FOB product categories (e.g., establishing that enzymes, monoclonal antibodies, vaccines are “highly similar” to the r
eference entity)

Interchangeability and comparability (similarity) — timing and geographical distinctions (e.g., compare US and EU regulatory guidelines, intentions and schedules)

Table 1: SUT support of FOB-specfic PD and manufacturing demands

 

SUTs provide a number of “flexibilities” (see sidebar “SUT Flexibilities”) that can greatly reduce process development time. Many SUSs support an “open architecture” approach, providing flexibility in designation of integral components. From operating systems to connectors (among many other components), an end user can select required components from a particular vendor. That produces benefits from reduced cost to maintenance of previously qualified components. The specification of a customized single-use assembly is easily altered even after initial design. During the development process, that affords the ability to easily and rapidly respond to changes or updates in required process equipment, components, or process flow. The frequency of development or trial runs can be accelerated because of significantly reduced turnaround times (e.g., often a matter of a few hours). Many SUS skids are very easily relocated (even wheeled) to new physical locations within a plant. That not only opens new doors of opportunity to process developers but can self-shorten PD time. Because it is sometimes possible with a SUS production train to use raw materials and even products of greatly divergent type and regulatory classification (e.g., virus or animal-product containing), the design of trial runs and production of clinical trial material can be simplified and overall schedules shortened.

 

SUT Flexibilities Providing Ease and Economy in PD

 

SUTs support process flexibility through the following examples:

Open architecture of subcomponents (e.g., operating systems and monitoring probes)

System and unit operation modularity (e.g., from skids to containers to manifolds)

Hybrid (classical plus SUT) capability (e.g., classical columns and monitoring probes in SUS)

Process flow/configuration latitude (e.g., layout, porting, and connectivity changes)

Product type/classification change (e.g., serum-containing to animal-product free)

Future-proofing or operational flexibility (e.g., change ease/economy supports updates)

Geographical relocation ease (e.g., SUT support equipment move to new site)

Physical location latitude (e.g., undedicated building or manufacturing suites)

Process platform latitude (SUT support all animal cells/culture media)

Process format latitude (e.g., microcarrier/suspension culture support)

Process mode latitude (e.g., batch, fed-batch, and perfusion culture)

Process scale latitude (e.g., rapid, inexpensive scale-up and scale-out)

Scheduling ease (e.g., extremely short changeover times)

 

Process Development Economy

 

Safety, validatibility, and efficiency are some overriding goals in PD. In FOB development, however, some goals increased emphasis. Because of high capital and infrastructure costs, development and commercialization of biopharmaceuticals is an expensive proposition to begin with (in the range of 10× that of small-molecule drugs). To supply adequate quantities of drug worldwide at competitive prices, biosimilar drugs require even greater manufacturing economy than do their progenitors. That demand is exacerbated by dramatically increased competition once multiple entities appear on the market resulting in such consequences as price erosion. Other stresses are imposed by commercialization uncertainties within this highly yet diversely regulated market (9). Some manufacturers in developing countries, although operating under less stringent guidelines (e.g., WHO), have the absolute requirement of very low up-front costs. “High initial investments are still a major barrier for new entrants to the biosimilar market,” observes Frost & Sullivan research analyst K. Srinivas Sashidhar(10). Such challenges were recently articulated for FOB production in China (11).

The reduced production suit size required by small-footprint SUBs and SUMs greatly reduces facility design, construction and consequent costs. Significant savings come when you consider service requirements, such as the severely reduced (and in some cases eliminated) requirement for regulated water and steam, due to the elimination of CIP and SIP systems. Three related, but distinct financial advantages are associated with the installation and operation of single use over conventional glass and steel systems.

First, examination of the depreciable equipment costs with the indirect material costs of the disposable consumables reveals that total manufacturing costs from using SUT over many years are often significantly less than that from conventional systems. In addition, because of reduced capitalized cost of smaller facility requirements and reusable containment equipment of SUSs, initial costs are dramatically reduced. Because the fraction of (reduced) manufacturing cost from the disposable elements of a SUS is deferred to the time of use, there is also the advantage of converting fixed to variable costs. Finally, when increasing production capacity, SUS provide easy and inexpensive “scaling out” for higher production or surge capacity.

 

Process Development Efficiency

 

Many aspects of biosimilar development and commercialization are well-served by a high degree of flexibility in the manufacturing process. In the United States, the Biologics Price Competition and Innovation Act (BPCIA) grants the FDA authority to implement an abbreviated pathway for biosimilars. Many essential elements of a biologics license application are provided in the act, and it gives the FDA discretion to decide requirements case by case (12).

In general, while accelerated pathways promise reduced hurdles in filing, they may complicate the review process. FOBs based upon earlier approved biologics are already a reality in much of Asia and Europe, exemplified by the multiple FOB forms of such drug products as somatropin, epoetin, filgrastim — yet this is not the case everywhere. In the United States, biosimilar draft guidance documents providing the abbreviated approval pathway from CDER were significantly delayed, and to date only a few FOBs (of the modern, engineered-type addressed here) have been approved.

Although regulatory guidance is more advanced in some geographies than others, the establishment of similarity and/or interchangeability for each specific product type is nowhere completely understood or articulated (13). Many potentially critical quality attributes have been only poorly defined, for which the type and complexity of analytical procedures needed to support their approval are debated. For example, the industry still lacks compendial guidelines for specific glycoprofiling methods. Presently, the US Pharmacopeia (USP) is drafting two compendia — USP 212 and USP 210 — on oligosaccharide and monosaccharide analysis, respectively (14 a>). Because existing relevant standards and guidelines that exist are so new, amendment and supplementation is anticipated. In fact, a revision of the EMA guideline on similar biological medicinal products (e.g., CHMP/BMWP/42832/2005) is expected.

That all can mean delays or changes in relevant understandings by a sponsor while establishing a chemistry, manufacturing, and controls or even such primary filing elements as target product quality or safety profiles. The ongoing patent developments with Amgen’s Enbrel product illustrate how difficult it is for even an established manufacturer like Merck to anticipate and prepare for specific opportunities (15). Further failures, rejections, and delays are even more likely as FOBs move toward antibodies and other more complex biologics.

FOB sponsors must ensure that they do not infringe on intellectual property surrounding a parent molecule. The path between avoiding infringement and creating satisfactory manufacturing performance can put a very high value in process adaptability. Here again, there is great power in the many flexibilities SUTs provide (see sidebar “SUT Flexibilities”). Of interest here is the ease of materials component selection and change supported by the previously described open-architecture approach. Even more important is the latitude in the configuration of process flow that is exquisitely supported by many disposable systems. Flow paths, porting, and connectivity can be developed and altered in an iterative way — with or without actual fabrication of intermediate designs. In fact, there is little difference between assemblies designed for testing than those for actual manufacturing — illustrating the ease of alteration at any time in a development lifecycle.

The utility of SUTs has been demonstrated for all major animal cell lines and production modes, including Chinese hamster ovary (CHO) or hybridoma cells in fed-batch or perfusion production modes. That supports using the precise format determined to yield the most efficient production while avoiding any particular methods or paths deemed undesirable for such reasons as intellectual property infringement.

 

Operational Efficiency and Flexibility

 

The overall FOB paradigm — manufacture of product with a new process and efficiency having quality and quantity similar to a legacy product — places a high value in operational efficiency and flexibility. As procedures for establishing biosimilarity become better understood, the consequence or implication of a follow-on’s chemistry, manufacturing, and controls (CMC) to primary or secondary structure can create demands for process modification. For many companies, there remains final definition and understanding of technical and clinical requirements for establishing

• comparability of an originator product following a manufacturing change
• comparability of a new FOB following such a change
• degree of “similarity” of an FOB in development to the reference molecule.

That — and the lack of experience some FOB sponsors have in manufacturing protein biologics — can result in heightened revisions and iterations in development activities.

Biopharmaceuticals themselves have distinct product lifecycle and change-control considerations. Reasons for this include increased complexity of a product, raw materials, and analytical methods. FOBs introduce yet their own marketing and lifecycle management considerations as well as regulatory and statutory complexity, uncertainty, and change. Because there may not be sufficient data in an abbreviated filing on such topics as long-term safety, sponsors will be conducting several postmarketing (Phase 4) risk–benefit assessments.

That there is yet no clear path forward toward interchangeability (and certainly no automatic substitution) is determining particular sales and marketing requirements for biosimilars. The oligopolistic competition environment of biosimilars directly influences such marketing considerations as price elasticity. Moreover, there are yet other factors in play here, such as the growing probability of competition from biobetters, other new molecular entities, and even promising small molecules for traditionally protein biological indications (16) (Figure 2).

 

Many characteristics of SUTs supporting favorable operational economics (both initially and postvalidation) and ease of process improvement are providing value in addressing such concerns (17). The modularity of SUSs, from skids to tubing, support ease of improvements in individual components or process flow (Figure 3). Newer application data are demonstrating SUS flexibility in process format and production mode through a range of implementations, easing process changes and updates (18).

 

SUTs support a nimble process and facility for operational flexibility and efficiency of change management in the face of

• after-market study and corrective action and preventive action demands
• consequence of continual process improvement initiatives
• changes in demand, especially at multiproduct facilities.

Such “future-proofing” is provided by SUTs’ low initial depreciable equipment costs, their amenability to open architecture and undedicated manufacturing suits, and their overall ease of process train reconfiguration. Furthermore, efficient support of hybrid assemblies (those built from single-use and reusable components) can be critical, because there continue to be some specific process components that are either unavailable or not yet desirable as disposables.

SUSs have been engineered to accommodate such approaches through such means as incorporating appropriate connectivity. John Bonham-Carter, vice-president of sales and business development at Refine Technology, notes “We routinely interface our ATF system equipment with single-use bioreactors in GMP production applications, and find these hybrid assemblies provide robust and reliable performance” (19). There are also nontechnical obstacles, such as

• avoiding innovator product secondary (i.e., process) intellectual property
• developing biosimilar-specific data-exchange details
• the trend toward patent-term extensions and adjustments.

Finally, an increased tendency toward partnership has been noted — even unlikely
ones — such as between Samsung electronics and the CRO Quintiles or Fujifilm and Kyowa Hakko Kiron (20). This creates additional value in a manufacturing process that is readily transferable, easily replicated, and even physically transportable. Using SUTs, the very pieces of equipment and consumable materials used in process developed at one location can easily be shipped to another. Or the same model of equipment and product contact material elements can be purchased from the original supplier and shipped to a new location. Such unique options in large-scale manufacturing provide obvious time and cost benefits — especially when considering their impact in the risk-based determination of the type and extent of inspection, validation, or comparability protocol development required.

Author Details
William G. Whitford is senior manager for the bioprocessing market in Thermo Scientific Cell Culture and Bioprocessing at Thermo Fisher Scientific, 925 West 1800 South, Logan, UT 84321; 1-435-792-8277; bill.whitford@thermofisher.com.

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