Introduction
The pharmaceutical industry has for a long period developed small molecule drugs such as acetylsalicylic acid. However, the period after 1970, has been characterized by a revolution in biotechnology resulting in the development of biologic medicines. One of the major biotechnological advancement has been mapping of the human genome leading to therapies such as stem cell and gene therapy. There has been a great investment in biologics. In 2009, the most five prescribed pharmaceutical products were large molecule products (Rozek, 2013). In United States, over a hundred different biologic agents have been approved for use (Pharmacy Practice News, 2013).
According to Amgen (2014), biologic medicines are large molecules obtained from living cells and are used in the detection, prevention and management of disease. They include monoclonal antibodies, therapeutic proteins and DNA vaccines growth factors and interleukins (Morrow, 2004). Biologics have transformed the way diseases are managed. While small molecule drugs or SMD mainly manage disease symptoms, biologics target and modify the underlying causes. As such, biologics have made a huge impact in changing the lives of individuals suffering from serious illnesses such as auto-immune disorders and neurological disorders. They are also targeted for conditions that have no cure and for patients that have failed to heal from the conventional small molecule drugs (Pharmacy Practice News, 2013). There exist a number of differences in the properties of small molecule products and large molecule products and their production as we shall discuss in this essay.
Properties
SMD's are small molecules weighing less than 100 Da, and their simplicity enables them to be fully characterized using analytical techniques. On the other hand, Biologics are 200 to 1000 times larger than SMD and have complex structures. This complexity makes it difficult for them to be characterized (Amgen, 2014). SMD’s rarely trigger an immune reaction due to their small size. Biologics are highly likely to trigger an immune response. Due to their large size, they are recognized as invaders by the immune system. Tiny contaminated areas of the biologics may cause secretion of antibodies. However, the effects of these antibodies have been shown to be benign.
This immunogenicity by biologics is bi-directional. It has the potential to augment response or cause destruction. Cytokines and hormones do not trigger a response; however, they delay drug elimination by acting as repositories for therapeutic proteins. Factors that affect immunogenicity also include the route of administration and duration of therapy. The period of therapy has a positive correlation with immunogenicity. Severe adverse events are correlated to subcutaneous drug administration and the intravenous route. This is because cells that are responsible for innate immune response are found under the skin (Zhao, Ren, & Wang, 2012).
Pharmacokinetics and Pharmacodynamics
SMD yields therapeutic effects by altering the structure and functions of endogenous factors such as cell surface receptors. Biologics target particular genotypes and protein receptors. Due to their relative stability, SMD’s are administered through a range of routes including oral and parental. On the other hand, biologics are highly vulnerable to enzyme degradation owing to their large and complex structures. Therefore, the most recommended route of administration is parenteral (Prueksaritanont & Tang, 2012).
SMD’s penetrate body tissues through passive diffusion and some through active transport. The small size of SMD’s and non-selective binding enables them to be distributed in several body tissues. Biologics are distributed via connective transport and transcytosis. Distribution is slow and limited due to their size and targeted binding (Prueksaritanont & Tang, 2012).
SMD’s are metabolized by CYP enzymes and the compounds that escape metabolism are eliminated through biliary and renal excretion. Biologics are metabolized into amino acids and peptides in tissues and while on transit through the lymphatic system by circulating phagocytes. The large molecules have a unique elimination linked to their binding on target cells. Following their internalization into the cell, they are degraded in a process characterized by target-mediated disposition (Prueksaritanont & Tang, 2012). To some extent, they are also eliminated via renal and biliary excretion.
Production and Manufacturing
Production of small molecules is well defined set of chemical reactions (Pharmacy Practice News, 2013). This enables the drugs to be produced in uniform considerable quantities. It is easy to scale up and change the manufacturing process. Small molecule drug batches are released based on specifications for the substance and final product. Before the release for human use, they undergo clinical trials to extrapolate results in a large population. This process enables researchers to forecast the expected outcomes.
One of the greatest complexities associated with SMD’s is that while the active ingredient of a chemical drug is well characterized, the active component is usually part of a large macromolecule. The macromolecule is usually a modification of a biological component that may be well characterized (Zhao, Ren, & Wang, 2012).
The production process of biologics is more complex and difficult to scale up from the laboratories hence; it tends to yield small quantities (America's Biopharmaceutical Research Companies, 2013). Biologics have relatively low stability and require controlled physical conditions such as light and temperature. The liquid form has more potential for degradation if shaken; their structure is destroyed. This high sensitivity makes them more difficult to produce than SMD's (Amgen, 2014). Characterizing the biological macromolecules is complicated by the fact that they have a range of identical components in the molecules, the surface proteins, and folding patterns vary widely.
Biologics are produced through genetic engineering in a process that involves gene identification, cloning, and protein expression. DNA is isolated from human cells and inserted into bacteria or yeast. The role played by the protein in the disease process is established through cell-based bioassays. The cell line exhibiting most potential is identified and grown in bioreactors through careful monitoring techniques. The biological drug is then isolated and purified by means of advanced techniques (Amgen, 2014).
Stepping up this laboratory process is a challenge as it requires strict control of variability to maintain quality standards. This process requires approximately 250 in-process tests to ensure stability, safety and efficacy while SMD’s require about 50 chemical tests to test for identity and purity (Pharmacy Practice News, 2013). Changing the manufacturing process presents significant challenges since construction and validation of the new set of facilities is costly and time consuming. This is because the sensitivity of cells requires highly specialized and complex aseptic processes, storage and testing
Attempts to produce the proteins consistently are largely affected by interruptions in the manufacturing process (Zhao, Ren, & Wang, 2012). These interruptions not only compromise the safety and quality of the end product, they also delay supply of urgent medicines. The manufacturers have to put risk measures in place to ensure a continuous process and consistent drug supply.
While small molecule drugs require clinical trials, large molecules undergo pretreatment genetic testing eliminating the need for clinical studies. Moreover, the studies would be wasteful since biologics are not targeted to heterogeneous populations (Amgen, 2014).
Reference List
America's Biopharmaceutical Research Companies. (2013). Medicines in Development: Biologics Research Promises to Bolster the Future of Medicine. Pharma Research, Progress, Hope.
Amgen. (2014, March). Retrieved from Amgen Website: http://www.amgen.com/pdfs/misc/Biologics_and_Biosimilars_Overview.pdf
Morrow, T. (2004, September). Defining the Difference: What Makes Biologics Unique. Retrieved from NCBI Website: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3564302/pdf/bh0104024.pdf
Pharmacy Practice News. (2013). Understanding Key Differences Between Biosimilars and Small Molecule Generics. McMahon Publishers.
Prueksaritanont, T., & Tang, C. (2012). ADME of Biologics-What Have We Learned From Small Molecules. AAPS Journal, 410-415.
Rozek, R. (2013). Economic Aspects of Small and Large Molecule Pharmaceutical Technologies. Advanced Economic and Business, 258-269.
Zhao, L., Ren, T.-h., & Wang, D. (2012). Clinical Pharmacology Considerations in Biologics Development. Acta Pharmacologica Sinica, 1339-1347.
