Biologic Drug Development: A Comprehensive Introduction

Biologics are a comparatively new class of drugs, nonetheless based on an ancient principle: utilizing living organisms to obtain substances that positively affect health. This approach, however, has expanded from using, e.g., plant parts for curative reasons to biotechnological methods in biologic drug development and manufacturing. These biopharmaceuticals now span from cell and gene therapy over antibody therapies to ADCs (antibody-drug conjugates) in cancer therapy.

In this article, we'll provide detailed information on biologics, covering their exact definition, the distinction from biosimilars, different types, and their development and manufacturing.

What are biologic drugs?

Biologics in pharma are a class of drugs derived from living organisms or their components – e.g. animals or microorganisms. These biological products are characterized by their complex molecular structures, often consisting of proteins, sugars, or nucleic acids.

Unlike conventional drugs, which are typically synthesized chemically or using plants and composed of small molecules, biologics are large molecule drugs. This distinction is important because the manufacturing process for biologic drugs involves living cells, which can result in a higher degree of variability compared to the more controlled synthesis of small molecule drugs. Additionally, biologics often target specific proteins or parts of the immune system, making them particularly effective for treating conditions with complex underlying mechanisms. [[1]] [[2]]

Single-use bioprocessing: learn more

Types and examples of biologics

Biologic drugs encompass a diverse array of therapies derived from living organisms or their components. One prominent type of biologic drug is monoclonal antibodies, which are engineered to target specific proteins or cells in the body. These antibodies have revolutionized possibilities in rheumatology and the treatment of various diseases, including autoimmune conditions like rheumatoid arthritis and psoriasis.

Another type of biologics includes vaccines, which stimulate the immune system to produce antibodies against specific pathogens. Vaccines have been instrumental in preventing infectious diseases such as hepatitis B and influenza, offering widespread protection to populations worldwide.

Cell-based therapies represent a groundbreaking advancement in cell biologics medicine, involving the transplantation of blood cells or tissues to treat conditions like leukemia or certain types of cancer. These therapies harness the regenerative potential of stem cells to repair damaged tissues and restore normal function.

Additionally, cytokines and interleukins are biologic molecules that regulate immune responses and inflammation. Drugs targeting these signaling pathways have shown promise in treating diseases characterized by dysregulated immune responses, such as rheumatoid arthritis and inflammatory bowel disease. Further types of biologics include blood components, somatic cells, hormones, tissues, and allergenics.

Examples of FDA-approved biologics and exemplary fields of application include:

• Humira® (Adalimumab): Rheumatoid arthritis, Psoriasis, Psoriatic arthritis
  
• Remicade® (Infliximab): Rheumatoid arthritis, Crohn’s disease, Psoriasis
  
• Enbrel® (Etanercept): Rheumatoid arthritis, Psoriatic arthritis
• Bild safety efficacy biologics biosimilars single use support

Sources: [[3]] [[4]] [[5]] [[6]]

Mechanism of action: How do biotherapeutics work?

Biotherapeutics employ a variety of mechanisms to exert their therapeutic effects, leveraging advances in gene therapy, biotechnology, and our understanding of the immune system. One key mechanism involves targeting specific cells or pathways within the body, such as T-cells or components of the immune system, to modulate immune responses and combat disease.

Gene therapy, a cutting-edge approach in biomedicine, aims to treat genetic disorders by introducing or modifying genes within target cells. By delivering therapeutic genes or gene-editing tools, gene therapy can correct genetic mutations or enhance cellular functions, offering potential cures for previously untreatable conditions.

Biologic medications, including monoclonal antibodies and cytokine inhibitors, function by binding to specific molecular targets involved in disease processes. For example, monoclonal antibodies may block inflammatory signals or neutralize harmful proteins, thereby alleviating symptoms and halting disease progression.

Generally speaking, there are four categories of biologics:

• Tumor necrosis factor (TNF) inhibitors
  
• Interleukin (IL) inhibitors
  
• B-cells inhibitors
  
• T-cells inhibitors

Sources: [[7]] [[8]]

Biologics vs. biosimilars - what's the difference?

Biologics and biosimilars are both types of biological drugs, yet differ in some aspects. Biologics are original therapeutic products derived from living organisms or their components. These drugs are complex in structure and require specialized manufacturing processes.

Biosimilars, on the other hand, are highly similar versions of approved brand name biologics, developed to be comparable in terms of quality, safety, and efficacy. They are produced via biotechnological methods as well, but unlike generic versions of small molecule drugs, biosimilars are not identical copies of their reference biologics due to the inherent complexity of biological molecules.

While biosimilars undergo rigorous comparative testing to demonstrate similarity to the reference biologic, including analytical, preclinical, and clinical trials, there may be minor differences in composition or the manufacturing process of biosimilars. However, these differences do not impact safety or effectiveness when used as intended.

Even though the main focus between biologics and biosimilars lies on their structural similarity, there are some distinct differences concerning:

• Safety and efficacy of biologics and biosimilars
  The most important feature of both biologics and biosimilars is their efficacy and their safety for patients. The FDA and other national health organizations ensure that both product types are safe to use through rigorous testing and thorough evaluation. The main criterion for biosimilars is that manufacturers have to prove that there are no undesired side effects for patients as compared to the original biologic. [[9]]
• Production cost
  Production costs can vary significantly depending on the specific drug. However, in some cases it can be said that biosimilars are less expensive to produce than their reference biologic. As manufacturers are able to rely on FDA findings concerning the effectiveness and safety of the reference product, this can save costs during manufacturing and improve patient access. [[10]]
• Manufacturing process of biologics and biosimilars
  Biologics are cultured in organisms like living cells or bacteria, which are very sensitive to changes in the manufacturing process and prone to contamination through microorganisms if not handled with care. After the cells have grown and reproduced the desired proteins, they can be harvested and purified. Efficient manufacturing of biosimilars  starts with the characterization of the reference biologic. Once the structure has been established, the next step is cell line development. The main goal is always the establishment of similarity to the reference product. A number of clinical trials and tests makes sure that there are no undesired effects that are different from the reference product.
• Regulations and approval process
  To prevent any undesired side effects and guarantee safety for patients, the development, manufacturing, processing, and packaging of biologics is highly regulated and has to follow specific guidelines set by public health institutions. Among those are cleanroom requirements as well as a number of clinical trials that these prescription drugs have to go through before they can gain FDA-approval on the U.S. market. The level of regulations is just as high for biosimilars. However, the approval process is more geared towards proving the interchangeability between biosimilar and reference product, while the process for biologics concentrates more on proving that it is compliant in terms of safety and efficacy. [[12]]

Biosimilars development - learn more

Developing and producing biologicals: Stages and practices 

The development of biologics involves a number of stages to ensure their safe and effective production. This chapter provides an overview of the practices within the biomanufacturing process, which may be found along upstream and downstream processes.

Upstream processes include cell line development, cell culture, and harvest, while purification and formulation are typical downstream steps. And in all of these phases, fluid and cold chain management plays a vital role.

Fluid management in biological drug development

Fluid management in biological drug development involves the precise control of liquids throughout the production process. This includes the transfer of media and reagents during cell culture, as well as the handling of harvested cells and purified proteins during downstream processing.

Challenges in fluid management arise from the need for precision and efficiency in dosing and mixing, as slight deviations can impact product quality and yield. Additionally, the risk of product loss due to leaks during fluid transfer poses efficiency challenges.

To mitigate these issues, biomanufacturers employ advanced technologies such as automated liquid handling systems and single-use disposable components. These aseptic filling solutions for biologics enhance precision, reduce contamination risks, and improve overall process efficiency.

Aseptic filling of biologics

Freezing biologics

Freezing biologics is a necessary step prior to frozen storage and transport. Controlled freeze and thaw processes in the production of biosimilars and biologics offers distinct advantages over uncontrolled freezing, as it can help to maintain product quality.

Plate freezing provides uniform cooling to temperatures as low as -80°C, reducing the risk of inhomogeneous cooling and preserving a biologic’s integrity. They provide direct contact between containers or biologicals and the cooling plates, allowing direct and efficient heat transfer.

Innovative cryogenic freezers offer precise control over freezing rates down to even lower temperatures (around -170°C), allowing for tailored preservation conditions for biologics like certain gene-modified cell therapies.

Freezing of biologics

Biologics ultra-cold storage

Temperature-controlled storage of biologics is required for maintaining stability and integrity, ensuring their efficacy and safety throughout their shelf life. Biopharmaceuticals are often sensitive to temperature fluctuations, which can lead to degradation and loss of potency.

To provide temperature-controlled storage, biopharmaceutical companies utilize specialized storage freezers that maintain precise temperature ranges. These systems are designed to provide stable and uniform conditions, minimizing the risk of temperature excursions that could compromise product quality. Additionally, temperature monitoring systems are employed to continuously track storage conditions and alert personnel to any deviations.

Ultracold storage of biologics

References

1. What are "Biologics" Questions and Answers, https://www.fda.gov/about-fda/center-biologics-evaluation-and-research-cber/what-are-biologics-questions-and-answers , Published 02.2018
2. Biologicals, https://www.who.int/health-topics/biologicals#tab=tab_1, Published
3. What Are "Biologics" Questions and Answers, https://www.fda.gov/about-fda/center-biologics-evaluation-and-research-cber/what-are-biologics-questions-and-answers, Published
4. HUMIRA® (adalimumab) injection, for subcutaneous use., https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125057s410lbl.pdf, Published
5. REMICADE (infliximab) Label - accessdata.fda.gov., https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/103772s5359lbl.pdf, Published
6. Enbrel (etanercept) Label - accessdata.fda.gov, https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/103795s5591lbl.pdf, Published
7. , Published 1970-01-01
8. Biologics for RA and Other Autoimmune Conditions, https://www.arthritis-health.com/treatment/medications/biologics-ra-and-other-autoimmune-conditions, Published 10.2016
   
9. “Biosimilar and Interchangeable Biologics: More Treatment Choices”. Food and Drug Administration. , https://www.fda.gov/consumers/consumer-updates/biosimilar-and-interchangeable-biologics-more-treatment-choices, Published April 18, 2024
10. Differentiating biosimilarity and comparability in biotherapeutics, http://dx.doi.org/10.1007/s10067-016-3427-2, Published 2016-10-12
11. Comparing Originator Biologics and Biosimilars: A Review of the Relevant Issues, http://dx.doi.org/10.1016/j.clinthera.2017.03.014, Published 2017-04-15
12. Biosimilars: Key regulatory considerations and similarity assessment tools, http://dx.doi.org/10.1002/bit.26438, Published 2017-08-26

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