Right now, the process of biologics development and manufacturing is an ever-evolving area. Many new products, largely produced by recombinant DNA, are introducing new treatments for previously untreated diseases, or more targeted, effective treatments for today’s health challenges.
On the surface, these products seem wildly diverse: monoclonal antibodies, vaccines, hormones, interferons, interleukins, thrombolytic factors. But they have one thing in common—they are all complex protein molecules that need many more development and manufacturing effort than the conventional chemical-based molecules. Because of the unique physicochemical characteristics related to biologics, the formulation of biopharmaceuticals is in many ways different from conventional chemically based drug formulation. The differences between small and large molecule development are so great that large pharmas wanting to enter the biologics business have bought smaller biopharma companies, instead of re-engineering their own labs.
The challenge for biologics production lies in the fact that there are numerous sequential processes involved; such as fermentation, harvesting, lysis, recovery, filtration, purification, formulation, filling, and packaging to obtain the product in a highly purified manner which is a prerequisite for making a safe and effective therapeutic medicine of optimal quality. In addition, each one of these processes requires tighter control and more frequent QC measurements than a small chemical molecule.
Today, there are at least 800 therapeutic proteins in the development/approval stage, and quite a few have been approved. One of the reasons behind having this large number of products still in the development stage is that it is not easy to characterize and formulate a protein molecule. This is not just because it is thousands of times bigger than the conventional chemically based drug molecule, but it is because a protein’s activity is based on multi-layered structural features. For example, the protein molecule cannot be fully characterized without elucidating its primary, secondary, tertiary and quaternary structure. To do so, you need to utilize a multitude of analytical instrumentation to understand and predict all four of them. At the same time, all of these structural features need to be intact to ensure a therapeutic activity.
The development and manufacturing of a small molecule drug product is a relatively simpler process. For example, it takes only a few analytical instruments (such as GC and HPLC) to assay and identify impurities that may be found in the final product. In contrast, you will need to utilize numerous analytical methods to characterize and test your biopharmaceutical drug product, such as SDS-PAGE, NMR, X-ray crystallography, FTIR, to mention just a few. In addition, many of these methods must be used in a way that each technique complements the other, as there is no single instrument capable of giving a definitive answer on your protein structure.
When it comes to stability, the structure of a protein molecule is not infinitely stable in the folded state, as it is mostly affected by production conditions. This immediately affects the protein molecule therapeutic value. To make the situation even more complicated, not all proteins respond to these conditions in a similar manner. For example, during production, most proteins undergo denaturation-renaturation cycles during extraction and purification. In addition, some physical/chemical conditions can have permanent impact such as temperature, pH, and pressure. This is why it is important to study the stability of the protein molecule in the range from pH 3 to 10 before starting any formulation development. In general, stability can be optimized by avoiding unneeded agitation, minimizing the amount of air in the vials, and adding excipients that are more surface active than the protein itself. The way to maintain the pH of a protein solution is to add an appropriate buffer. However, adding a buffer may affect the formulation’s overall stability. For example, the rate of deamidation appears faster in phosphate or bicarbonate buffers than in acetate or chloride buffers.
Also, solubility depends on the pH value, as does physical and chemical stability. There is usually a close relationship between optimum solubility and stability. Minimum solubility is observed around the iso-electric point (pI) of the protein molecule. Usually, one would determine the pH range for obtaining the proper solubility and concentration for dosage and then optimize the stability afterwards.
For oral chemical dosage based on a small chemical molecule, you don’t need to employ a sterile manufacturing environment. However, when it comes to a biopharmaceutical drug product manufacturing, you need to implement sterile manufacturing conditions whether you are manufacturing solid, liquid, or inhalation dose.
Pharmaceutically, freeze-drying is the most common process for ensuring long-term storage stability of proteins. Freeze-drying proteins enhances physical stability by inducing a rigid protein structure, due to the reduced molecular mobility in the solid compared to protein solutions.
Further, the scale up process is a quite different challenge in biologics, too. Often, drug products developed in academic labs are transferred to manufacturing environments without proper scale up. This can make the manufacturing process purely manual, with each batch handled and evaluated by an army of technicians. This creates the potential for human error and inconsistent batches often results in a non-conforming product.
What we mentioned is just a glimpse of light. But as you can see, biopharmaceutical drug development presents many challenges for new biologics and biosimilar alike. Why? Because the quality, purity, and potency of the product is a direct result the process characteristics. It is highly unlikely that you will have the exact process to manufacture the same protein molecule as another manufacturer. But you can have similar processes to manufacture similar protein molecules that address the same physiological disorder or disease, and this is why you hear the word “biosimilar” compared to generics in small molecule drug development.
At Synergy Bio, we have the technical expertise to help you start the development process of biologicals the right way. We’ll help you work with the FDA and develop a master plan. We’ll also be you subject matter experts in auditing your process and product manufacturing processes before the regulators conduct preapproval inspections.
What challenges are you seeing with biologics development and manufacturing? How are you selecting your analytical test methods? We’d love to hear from you; contact us for a deeper conversation.