Nearly all of our pharmaceutical clients are in the pre or early clinical phase, conducting feasibility studies and producing the material needed for Phase I. The focus is almost entirely on the safety and efficacy of the candidate as well as producing material. There is little time or financial resources to focus heavily on the manufacturing process or scale up, but these considerations do play a critical role when it comes to regulators. Innovators are keenly aware of the regulatory process ahead but will often defer these activities until they secure a CDMO partner or commit to adding the expertise in house, while they focus on the immediate task at hand.
Why start thinking early about the regulatory process?
To answer this question, it is important to consider that the manufacturability of the product is just as important as the documentation required for a new drug application. Regulators will look closely at the manufacturing process to determine whether it is robust, scalable and reproducible. Quality by Design(QBD) involves considering a systematic evaluation, understanding, and refining of the drug formulation and manufacturing process. Regulators want to see that QBD is a key pillar in the development process and was considered early on. This creates a challenge for innovators who must balance the need to speed up the development process or produce material while ensuring that the foundation for scale up is being considered. To ensure success not only for the product but also with regulators, there are some key areas to focus on:
· Determine early on if you have a scalable expression system and manufacturing process
· Identify how you can de-risk the process and ensure QBD
· What is needed to support a successful tech transfer either internally or with a CDMO partner
The expression system
Protein expression can be challenging in a microbial system. High level expression of many recombinant proteins in Escherichia coli can lead to the formation of aggregated proteins (including inclusion bodies) or misfolded soluble proteins, both of which are not biologically active. It is not enough to simply achieve high titers, but rather a high concentration of a correctly folded, soluble protein. Challenges in producing sufficient titers of quality product in this early phase should be a red flag that scale up issues are sure to come.
Ensuring QBD
One way to ensure QBD is to consider an approach or technology catered to a specific protein. Since every protein is unique, a tailor-made expression vector can help optimize both titers and solubility. Spending the time at this critical stage to identify an optimal expression vector is a key element in the QBD concept. By developing an expression vector catered to each protein, robustness and repeatability are greatly improved. Also, the documentation out of this development process will be critical in supporting later regulatory filings. If the in-house expertise in developing an expression vector catered to your unique protein is lacking, this may be a good opportunity to work with an outside partner that has extensive experience with expression vectors for challenging applications.
Supporting successful scale up; reducing manufacturing costs
If the above work to identify an optimal expression system is done, scale up results in a much more predicable outcome. The combination of well-documented research along with a catered expression vector identified at this early stage will make hand off a much easier process. With this “blueprint”, the CDMO partner or manufacturing group will start with their best foot forward and have a much higher likelihood of success.
It should also be noted that identifying an optimal expression systems could significantly help a business’s profitability in the long run. Higher titers of quality product may reduce the batch size required for clinical material which may translate to capital cost savings as well as reduced consumables. If the drug is approved, a great expression vector will also reduce commercial manufacturing costs. Helping to eliminate the trial and error and troubleshooting process a CDMO partner may face during tech transfer will also translate to cost savings. Although these considerations do not directly impact regulatory concerns, they are important to keep in mind as an additional motivation to spend the extra effort during the early development stage.
Vectron’s Approach
Unique problems require unique solutions. If every protein is unique and presents unique challenges to achieve multi-gram yields of biologically active protein, then every expression vector should be unique, too. In Vectron, we have developed a suite of technologies to build unique expression vectors for each protein. This includes VB Expression, a modular expression vector for combining proprietary expression elements in various configurations; and VB Evolution, a directed evolution approach to discover/create entirely novel expression vectors that have been evolved to give maximized yields of soluble protein. VB Expression and VB Evolution are based on Vectron’s profound understanding of manipulating and engineering expression cassettes based on the Pm promoter and the use of RK2 minimal replicons for stable expression. This results in unique expression vectors that give higher titers than what can usually be achieved with conventional expression vectors that are not optimized for every protein.
We have now extended our expression platforms with a recently acquired secretion technology, VB Secretion. This technology is based on genetically engineered E. coli cells that allow for the directed secretion of proteins into the extracellular environment. As far as we are aware, this is the first technology for directed secretion of proteins in E. coli to be commercially available. This brand-new technology is expected to substantially reduce downstream costs and issues for many industrially manufactured proteins.
Vectron’s expression technologies can help ensure a stable, highly productive platform for scale up and save development time, as well as facilitate regulatory validation. A typical project takes 2-6 months, and the deliverables are a research cell bank with all documentation describing the work that has been performed and the expression vector that has been developed.
Summary
Ensuring regulatory success begins with a reliable expression system. Applying a QBD approach early on in the development process not only provides a more predictable outcome but begins to build the SOPs documentation and protocols for scale up and regulatory filings. The benefit of this approach is a more streamlined scale up whether it be in house or with a CDMO. One way to maximize success, particularly with difficult to express proteins, is working with a development partner with expertise in this area. Vectron Biosolutions has this unique experience and has already developed a modular expression vector with proprietary expression elements in various configurations. This ‘unique solution for unique problem’ approach helps our partners successfully move through their development process while building the foundation for a successful regulatory submission.