The biologics market represents the leading of novel therapeutics. With advancements in DNA technology and increasing investments in personalized medicine, growing rate is even twice the growth rate of small molecule therapeutics.

In this article, we will answer to the 7 top questions about biologics development and manufacturing.

1. Which are the differences in the development between biologics and small molecule drug products?

The most significant difference 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. While, biologics 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, resulting in increased development costs.

You might be also interested in reading: Biologics vs. Small Molecule Drugs: Which Are Better?

2. Which are the most common problems during early phases in biologics development?

The most common problems during early phases are: solubility, protein denaturation and degradation pathways. For example, biologic drug substances are often susceptible to denaturation in contact with certain surfaces commonly used in primary packaging. Also, 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. Which considerations should I get for the formulation of biologic drug products?

Biologics are vulnerable at every stage of the development process, and they need to be formulated accordingly. Points formulation scientists need to consider include exposure to oxidation and agitation, as well as drastic changes to pressure, and temperatures outside the normal limits can make the formula unstable.

And during the production process itself, freezing and thawing the product can have an effect; it needs to be protected from extreme conditions. But it doesn’t stop there – biologics are generally administered by infusion or injection, so the formulation must account suitably for the delivering device.

4. What are common challenges for analytical development?

Because analytical development is the cornerstone of process control, the knowledge of the various analytical techniques for characterization is fundamental. Some classic techniques are ELISA and electrophoresis (as a binding, potency, and identification methods).

Chromatography is also a very important technique and is often coupled with a separation technology to elucidate a consistent impurity profile, which is one of the many challenges 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 53Biologics’s approach to this critical step in the drug development process?

53Biologics uses a combination of chromatography, mass spectrometry, and electrophoretic techniques to characterize drug substances. Our team have over 15 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. What makes biologics so difficult to manufacture compere to drug product?

The fragility of biological macromolecules and the sensitivity of the living cells that produce biologics impart complex manufacturing requirements for fermentation, aseptic processing, storage, and testing. Although the active ingredient of a chemical pharmaceutical is usually a unique molecule subject to well-established analytical tests, for biologics, the active component often is a portion of a large macromolecule. That macromolecule is in turn a modification of the original protein or polypeptide and other biological substances that may not be clearly characterized. Protein and polypeptide products can contain variable complexes, meaning that they have variable numbers of identical components in the molecules. Also, biologics may have differences in their surface sugars (glycosylation) or folding patterns, depending on how they are produced. With biologics, there is also potential for microbiological contamination of the starting materials.

You might be also interested in reading: Optimizing Upstream and Downstream Processes in Biologics Manufacturing can Help Reduce Inefficiencies and Cost

7. Which are the implications of several promising technological advances in gene therapies?

Scientists are able to develop specialized treatments for difficult-to-treat or untreatable diseases through cell and gene therapies, like orphan diseases, tumor-targeting cancer therapies, and neurodegenerative disorders, just to name a few.

For example, the knowledge gained will help in targeting future therapies. Replacement gene therapy, which targets diseases such as hemophilia caused by the lack of a protein, is one direction of research.

RNA interference allows better characterization of the function of a specific gene or DNA fragment. Antisense molecules (small pieces of DNA or RNA) prevent production of the protein encoded in that blocked DNA or RNA, effectively “knocking out” the gene. The knockout procedure also is used to determine the function of a specific gene in laboratory animals. This knowledge then can be extrapolated to corresponding human genes. The physical manifestation of a trait or disease is usually the culmination of many steps involving a protein-to-protein chain reaction, starting from gene expression and going through a cascade of small events in which a molecule is changed by enzymes and then handed off to other enzymes for further changes.

Do you have any other questions about Biologics Development and Manufacturing? Please let us know!

At 53Biologics, we support every stage of drug development, from early phase clinical trials through drug approval and commercialization. Our clients have relied on our expertise, technology, track record, and regulatory infrastructure to advance the launch of their novel biological products. We will be happy to answer any other question you might have about developing and manufacturing biologics.