Developing and Manufacturing Biologics: Your Top 7 Questions Answered

The biologics market represents the leading edge of novel therapeutics and is the fastest-growing cross-section of the pharmaceutical industry—by some accounts, increasing as much as eight percent annually, or twice the growth rate of small molecule therapeutics. With advancements in DNA technology and increasing investments in personalized medicine, the sky is the limit for the biologics industry.

1. How is biologics development different from traditional, small molecule drug products?
   
   The most significant differentiator between biologics and small molecules is the way they are made. Small molecules are manufactured using synthetic chemistry techniques and are generally easier to characterize, purify, and control. Biologics, however, are often produced using recombinant DNA technologies and living cell cultures. As a result, these complex molecules are highly sensitive to environmental changes, susceptible to changing impurity profiles, and can provide inconsistent yield^[1], resulting in increased development costs.

2. What key preformulation studies should be performed during early phase development?
   
   Common hurdles encountered during early phases are solubility, protein denaturation, and degradation pathways. For example, biologic drug substances are often prone to denaturation in contact with certain surfaces commonly used in primary packaging. In addition, the pH solubility range is often very narrow compared to small molecule active pharmaceutical ingredients (APIs). Therefore, characterization studies to mitigate these challenges are critical to formulation development.
   
   
3. What special considerations are there for the formulation of biologic drug products?
   
   Many excipients used for small molecule drug products don’t work well with biologics. However, most biologic formulations are aqueous and contain reagents that are readily available. Once the formulation is under development, additional work must be performed to assess the drug substance’s ability to withstand freeze/thaw cycles, aggregation, shearing, as well as microbial activity, freedom from endotoxins, and so on.

4. What are common challenges for analytical development?
   
   Because analytical development is the cornerstone of process control, in-depth knowledge of the various analytical techniques for characterization is paramount. Some of the methods for binding, potency, and identification employ classic techniques such as ELISA and electrophoresis. Chromatography is also a very important technique and is often coupled with cutting-edge separation technology to elucidate a consistent impurity profile, which is one of the many challenges unique to biologics. As previously stated, however, structural characterization remains one of the most difficult steps in the development process and often involves a number of orthogonal techniques.

5. Structural characterization requires a high level of expertise. What is Alcami’s approach to this critical step in the drug development process?
   
   Alcami uses a combination of chromatography, mass spectrometry, and electrophoretic techniques to characterize drug substances. Our chemists have over 25 years of experience working with these molecules and techniques. We have extensive knowledge of peptide maps, amino acid analysis, and mass spectrometry-based sequencing technology to build a comprehensive profile of biologic therapeutics.

6. Is drug product manufacturing for biologics any different?
   
   In general, the drug product manufacturing process is relatively simple. Because nearly all biologics are parenteral and the drug substance is often already in a solution, few steps are required beyond dilution, filtering, and final processing. However, environmental controls are often needed to help ensure the drug substance isn’t exposed to significant heat, agitation, or microbial contamination.
   
   
7. How are cell and gene therapies affecting treatments for diseases with genetic implications?
   
   Scientists are able to develop specialized treatments for difficult-to-treat or untreatable diseases through cell and gene therapies. These forward-looking therapies can be used for orphan diseases, tumor-targeting cancer therapies, and neurodegenerative disorders, just to name a few. For example, amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by misfolding of proteins for which there is no cure. Novel gene therapies that have the power to correct this defect are in development and could extend the life expectancy or quality of life for thousands of patients affected by this disease. This is just one case of hundreds of cell and gene therapies in development across the globe.

In Summary
The Alcami laboratory network and suite of biologics services support every stage of drug development, from early phase clinical trials through drug approval and commercialization. For decades, our clients have relied on our expertise, technology, track record, and regulatory infrastructure to advance the launch of their novel biological products.

[1] Consistent yield can be accomplished, but is a challenge from a development perspective, especially relative to small molecules.