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Successful scale-up and BLA filings for products manufactured by microbial biomanufacturing require strategic planning.
In the high-stakes world of microbial biomanufacturing, there are dozens of critical moments and crucial decisions to be made on the path from clinical trials to regulatory approval to commercial manufacturing. Planning and executing both scale-up and a successful biologic licensing application (BLA), however, may be two of the most significant moments in the regulatory pathway.
First and foremost, the financial, intellectual, and time investment in developing a biopharmaceutical product through microbial fermentation is high. Tens and even hundreds of millions of dollars are at stake. Errors, lack of knowledge, and poor planning can have catastrophic effects on a project, leading to tens of millions of dollars lost or even projects being discontinued for budgetary reasons.
But a well-planned scale-up and soundly executed BLA, implemented with an experienced contract development and manufacturing organization (CDMO), can save pharmaceutical companies months of wasted time and money. When development timelines are measured in years and investments are measured in eight and 10 figures, planning and execution are of the highest importance.
When moving from early stage proof-of-concept to clinical and then commercial stages, the crucial steps of scaling up a microbial product and garnering regulatory approval both become significant steps. Both these undertakings require a full understanding of the goals, the process, the facilities, the safety, and the demand for the bio/pharmaceutical by the manufacturer or CDMO and its partners. Scale-up planning and the development of the BLA work in concert to help all of the collaborators define, plan, forecast and execute the development of the product and reach its market potential (see Figure 1).
Once the proof-of-concept has been achieved, a manufacturer must develop a full understanding and plan for scale-up. All partners, which could include biotechs, bio/pharma companies, and CDMOs, must understand and agree on the goal, the process, the development plan (including potential deviations), production, and manufacturing. In addition, all partners should also be addressing questions about demand, scale, budget, and details of the supply chain.
Preparing to scale up and file for a BLA requires that the manufacturer answer these questions so they can test and understand the boundaries of their project’s parameters: process design, plant fit, process robustness parameter characterizations, and design space, to name a few. If the project isn’t properly planned, one might not be able to ramp up supply quickly enough due to a lack of capacity and/or throughput. If the manufacturer scales too high, then it will build up inventory, and the shelf-life or stability of the product may be at risk. That product may need to be scrapped, which is an expensive error. Conversely, if the scale is too low, the manufacturer might not be able to produce enough product or substance, which results in a loss of market opportunity.
With an increased focus on smaller next-generation biologics, such as antibody mimetics and novel scaffolds as well as vaccines (e.g., subunit vaccines, plasmid DNA, and messenger RNA), interest is shifting back toward microbial biomanufacturing. There is also an increase in microbial biologics as the method of choice in both fighting infectious diseases as well as in oncology, which contribute to the rising use of microbial biomanufacturing as an effective and cost-efficient manufacturing platform.
Microbial biomanufacturing can reduce development timelines and costs. Starting a project with microbial fermentation is quicker and easier than using mammalian cells because microbial cells are easier and more convenient to access. Because a plasmid is used in these situations, there is no need to select a particular clonal line; thus, the upstream function is easier and quicker when working with bacteria.
Microbial biomanufacturing’s technical requirements, however, increase the already inherent complexity of biologic drug development. Unlike mammalian cell culture, where platform processes are routinely used, microbial manufacturing requires customized processes tailored to the characteristics of each specific molecule, leading to variations in product titer, yield, and process approach. These variations have a broad impact on several elements of development and manufacturing, from analytics to a regulatory filing as well as on the facility and the manufacturing process itself (1).
Additionally, microbial processes include the fermentation of microbes in bioreactors to produce enough product for each stage of development, from early to later stages, including clinical trials and commercial manufacturing. Each scale-up must be executed in consecutively larger bioreactors (e.g., 0.5 L–10 L for early stages up to 15,000 L for later stages and commercial) with scale factors ranging from thousands to millions.
Scale-up of the process to accommodate larger batch sizes brings a host of additional variables that must be taken into account. One example is the use of buffers. Corrosive buffers can be prepared and used in single-use plastic bags for small batch production at an early stage, but, when it is time to move to larger stainless-steel equipment, single-use bags cannot be used. This is just one of the dozens of elements that must be considered as the product moves through each stage of development that demands ever-increasing batch sizes. It is critically important for a biotech company to focus both on the early planning of process scale-up and BLA activities to maximize its chances of success. Approaching the project with a view of the entire process will decrease the potential for costly setbacks and secure a right first time (RFT) approach.
Ideally, a biotech company will choose an experienced and high-quality CDMO that will work as a partner/advisor throughout the project’s entire scope—with the end goal as its primary focus. A detailed and accurate plan can only be developed when the entire process and the final goal are considered when planning its lifecycle.
Approaching the development of a microbial biopharmaceutical by focusing only on individual phases or stages will often lead a manufacturer down the path of delays, setbacks, rework, and millions of dollars wasted or lost in potential sales. A common fundamental error is to select the microbial host strain and develop it without regard for its suitability for large-scale production. Often, new opportunities are conceived by professionals who don’t have relevant technology commercialization experience. They may realize that commercial engineering input is needed but don’t realize that the input is best when given at the earliest point possible (1). This serial approach can lead to costly mistakes and delays, whereas an experienced CDMO will have the entire project in mind when making major decisions, such as which microbial strain to employ.
Whichever partner a biotech chooses, that partner should understand and advise on the entire product lifecycle: assessment, development, process, analytics, production, the regulatory landscape, validation, manufacturing, and optimization (see Figure 2). Often, CDMOs are the partners that have insight into the entire lifecycle. They can build a detailed vision of the early-, mid-, and late-stage process development. They can also plan out the BLA and manufacturing process. The initial investment is negligible compared to the total project cost and the potential losses that poor or narrow planning can cost.
Unfortunately, there are myriad opportunities in the development of a microbial product for oversights and shortcuts as the result of working with multiple partners rather than an integrated one. The consequences of this can range from inconvenient to catastrophic.
For example, a biotech can engage with one CDMO to get a product to Phase I or II and then work with another to scale up for the next phase or the BLA. Since the biotech company partnered with two different CDMOs that may have different manufacturing processes, revisions may be needed and, sometimes, complete redevelopment. In addition, microbial manufacturing requires customized processes for each specific molecule, and, therefore, working with multiple partners can lead to potentially unwanted surprises, such as additional plant adaption, a higher level of capital expenditure, longer batch and cycle times, and a resultant higher cost of goods. These circumstances can happen at every stage of development, but its impact is highest at the later stages of development.
The financial investment to scale up a microbial process to manufacturing scale can be greater than the cost to develop the production microbe and lab-scale process. This can be $100 million to $1 billion, including intermediate process validation (pilot and demo scales) and construction and start-up of the manufacturing plant (1). The annual operating cost of the manufacturing plant is in the same order of magnitude. The time required to transition from lab-scale to manufacturing is typically three to 10 years. Under these circumstances, the financial risk is high, so a deterioration in process performance during scale-up will be costly and disruptive, potentially leading to project failure. Short of failure, even incremental (5–10%) under-performance and/or delays (three to 12 months) during scale-up will substantially reduce financial returns and undermine stakeholder and customer confidence. So, when scaling up microbial processes, it is imperative to get it right and to get it right the first time (1).
During the manufacturing process, it is imperative for biotech companies to work alongside the appropriate strategic partner in order to help prevent any surprises and deviations and get the product ready for the commercial phase.
There is some flexibility in time and budget for scale-up, but there is little flexibility or negotiation in a regulatory filing.
For a BLA, a highly defined approach to determine the parameters, scientific method, the development and manufacturing spaces, and equipment for the product is important. In a BLA application, there is a focus on the process and the scale-up, but the analytics are equally, or more so, important because the analytics validate the quality and attributes of the product. Because a large percentage of delays in BLA approvals is due to chemistry, manufacturing, and controls (CMC), which can be as much as 18 months, it is important for biomanufacturers to devote time to ensuring that the methodology for safety and consistency is laid out in addition to the process details. A focus on RFT is crucial to avoiding significant costs associated with rework as well as loss of opportunity (see Figure 3).
A quality CDMO is also aware that a successful BLA application or approval is not the finish line. Post BLA filing, manufacturers may undergo on-site audits from regulators while running the first commercial batches. A quality CDMO is prepared for those audits, making them a critical part of the preparation and approval plan.
Once a BLA is approved and the product is moved to commercial-scale manufacturing, processes must be maintained within regulatory boundaries but must also be optimized for efficiency. If manufacturing is built out correctly, a CDMO can continually optimize post-launch to improve efficiency in yield, batch time, cycle time, and other key performance indicators. Manufacturing build-out must be done correctly, however, within regulatory boundaries and built into the BLA. If the BLA boundaries are set too narrow, there is almost no chance of improving the process. Designing the right space, equipment, and regulatory strategy is not only part of a successful filing but also gives companies the “license” to continually optimize manufacturing.
Developing and manufacturing microbial biopharmaceuticals demands high financial and long-term investments, making a RFT approach a priority for most bio/pharmaceutical and biotech companies. Two elements in the lifecycle of a biopharmaceutical—scale-up and the BLA—are particularly vulnerable to mistakes due to poor planning or inexperience. Those mistakes, which can cost a drug developer months or years and millions of dollars, can be mitigated or avoided with detailed planning, experience, and a holistic view of all phases (rather than just each phase one at a time). Mistakes made in early phases can become catastrophic at scale-up and during the BLA. Working with a CDMO that has a complete line of service from strain development through manufacturing, however, will not only help a bio/pharmaceutical or biotech company avoid costly missteps but will also facilitate the saving of time and money.
1. J.S. Crater and J.C. Lievense, FEMS Microbiol Lett. 365 (13) fny138 (2018).
About the author
Stéphane Varray, PhD, is senior director, head of Commercial Development, Microbial Business Unit, at Lonza.
Vol. 35, No. 8
When referring to this article, please cite it as S. Varray, “Outlining Successful Steps for Scale-Up and BLA Filings,” BioPharm International 35 (8) 22–26 (2022).