A Guide to Drug Development for Biologics: Overcoming Formulation and Manufacturing Challenges

What are Biologics?

A biopharmaceutical product (commonly referred to as a “biologic”) is defined as a pharmaceutical drug product manufactured in, extracted from, or semi-synthesized from biological sources. Biologics include vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins.

Biologics are expected to capture significant growth revenue over the next five years. Companies traditionally seen as “small molecule” manufacturers have pivoted their emphasis and pipelines towards biologics, and the global biologics market could reach U.S. $479.7 billion by 2024.¹ In 2019, 8 out of 10 best-selling prescription drugs were biologics (See Figure 1), with market forecasts predicting a global 10.9% compound annual growth rate (CAGR) for biologics products through 2024.

Figure 1: Top 10 Biologic Drug Products of 2019 by Global Revenue

Product Name	API	Indication	Owner	2019 Global Product Sales
Humira	Adalimumab	Rheumatoid Arthritis, Other Inflammatory Conditions	AbbVie	$19.2B
Keytruda	Pembrolizumab	Cancer	Merck	$11.1B
EYLEA	Aflibercept	Macular Conditions	Regeneron Pharmaceuticals	$7.5B
Opdivo	Nivolumab	Cancer	Bristol Myers Squibb	$7.2B
Avastin	Bevacizumab	Cancer	Genentech	$7.1B
Rituxan	Rituximab	Cancer, Rheumatoid Arthritis, Others	Genentech	$6.5B
Stelara	Ustekinumab	Crohn’s Disease, Ulcerative Colitis, Others	Janssen Immunology	$6.4B
Herceptin	Trastuzumab	Cancer	Genentech	$6.1B
Enbrel	Etanercept	Rheumatoid Arthritis, Other Inflammatory Conditions	Amgen	$5.2B
Remicade	Infliximab	Crohn’s Disease, Ulcerative Colitis, Others	Janssen Immunology	$4.4B

Biologics are complex, large-molecule substances that require sophisticated technology and controlled processes to manufacture. Successfully developing and commercializing a biologic requires a nuanced understanding of the scientific, logistical, and regulatory challenges specific to biologics. Here, we’ll provide an overview of common safety, manufacturing, and analytical challenges biopharmaceutical firms encounter during product development.

Safety Challenges

Improperly sourcing biological material can lead to product contamination and subsequent safety issues, creating significant production challenges and adversely affecting public health. In serious cases, failure to acquire suitable source material can ruin a product’s development cycle entirely. As noted by a recently-published review in Nature Biotechnology, these events can cost tens of millions of dollars in investigation, cleanup, corrective actions, lost sales, and manufacturing downtime.²

Noteworthy historical examples of biologic contamination include the contamination of poliovirus vaccine with simian virus 40 (SV40), as well as the widespread transmission of viruses such as human immunodeficiency virus (HIV) to hemophilia patients undergoing treatment. The Nature study correctly asserts that despite contemporary advances in process and protocol, viral contamination remains a serious risk during the production of cell culture-based recombinant proteins.

Accordingly, internal development teams and contract drug manufacturing organizations (CDMOs) working with biologics must implement rigorous and proactive vetting, including supply chain validation, to proceed with confidence. Partnering with suppliers that provide proof of viral inactivation, for instance, is one of several ways to mitigate risk prior to taking biological source material through extraction and development. A single contamination event can jeopardize an entire manufacturing facility for months or years, so it’s imperative that manufacturers establish trustworthy, airtight supply chains.

To help prevent contamination and other serious adverse events during production, the World Health Organization (WHO) published Good Manufacturing Practice (GMP)-based guidelines for the manufacture, control, and testing of biological products for human use, from “starting materials and  preparations” (including seed lots, cell banks, and intermediates) to finished products. The document, published in 2007, covers a wide range of established best practices in the areas of labeling, batch documentation, pathogen containment, and much more.³

To effectively mitigate risk and develop with confidence, organizations currently (or soon-to-be) working with biologic products — especially living organisms and cell lines — should be intimately familiar with these GMP guidelines and able to implement relevant protocols across all project areas.

Formulation and Manufacturing Challenges

In addition to the considerable safety and supply chain challenges associated with biologic development, formulation and manufacturing present unique challenges that require a strategic, well-planned approach to project management.

Derived from organic tissue, biologic products are generally not as physically robust as small molecules.

• Given their molecular structure and inherent instability, they are difficult to form into capsules or tablets, which is why most biologics are developed for injection
• Unstable material also prevents the use of terminal sterilization at the end of product development, necessitating aseptic processing and adding further operational complexity
• Additionally, many products are vulnerable to protein aggregation, especially if the product in question is a pre-filled syringe or vial ³

In general, environmental conditions play a highly influential role in manufacturing outcomes.

• Biologics are frequently temperature and light-sensitive, as well as susceptible to degradation or shearing during filtration
• Because biologics are typically lyophilized, they must be kept frozen to maintain physical stability, meaning freeze-thaw cycles must be carefully managed to avoid loss of product
• To avoid unexpected setbacks, oxygen, temperature, agitation, and other environmental attributes must be considered and controlled for during relevant product development stages, including early-stage development

Because defining a final biologic product is difficult, regulatory bodies are placing increased emphasis on the manufacturing process controls that help a developer reliably reproduce products to meet target specifications. However, given the many dynamic challenges that appear during manufacturing, achieving this goal can be difficult without experiential knowledge of biologic mixing, filtration, and other process parameters.

Analytical Challenges

Unlike small molecules, which typically consist of a single chemical entity that can be well-characterized, biologics are complex mixtures including multiple chemical entities with varying sizes and attributes. In general, large proteins and peptides are more difficult to characterize, making biologics among the more difficult entities to analyze using traditional imaging and assays.

To effectively analyze these products, many companies focus on identifying the critical components and methods required to demonstrate consistency of components contributing most significantly to a product’s target therapeutic indication.

• Stability evaluation may necessitate complex analytical methodologies, and assays for biological activity, where applicable, should be part of pivotal stability studies
• Appropriate physicochemical, biochemical and immunochemical methods for analyzing the molecular entity and quantitative detection of degradation should also be part of the stability program (when a product’s purity and molecular characteristics permit use of these methodologies)

Biologic analysis, unlike small molecule analysis, must consider both purity and activity. Manufacturers typically must assess not only the purity but also loss of biological activity at multiple points during processing.

Today, there is a relative lack of consistent, established standards informing effective biologic analysis, making experience in this specific discipline even more valuable. According to the WHO GMP guidelines:⁴

Active substances in biological products are often too complex to be fully characterized by utilizing physicochemical testing methods alone and may show a marked heterogeneity from one preparation and/or batch to the next. Consequently, special considerations are needed when manufacturing biological products in order to maintain consistency in product quality.

And analytical testing isn’t the only area of biologic development that’s evolving. Because biologics are an important and rapidly growing segment of the pharmaceutical industry, regulatory guidance is constantly shifting. In February 2020, the FDA revised their definition of a “biological product” to include all proteins. According to the Agency, the definition now captures “any alpha amino acid polymer with a specific, defined sequence that is greater than 40 amino acids in size.” This change is part of a larger effort to harmonize biologic filings under the Biologics License Application (BLA) framework instead of the traditional New Drug Application (NDA) framework.

The FDA hopes this change will help encourage the development of biosimilars (generic versions of biologics) and clarify the analytical and safety testing needed to prove equivalency to a marketed biologic. This example illustrates a key point—in order to bring a biologic to market, whether novel or generic, one must understand the interconnected nature of safety, scientific, and regulatory considerations that go into these products.

Advantages of Working with an Experienced Biologics CDMO

Working with an experienced biologics CDMO is one of the most effective ways to proactively plan for the highly dynamic safety, manufacturing, validation, and regulatory challenges you will face during the development of your biologic product. The team at LLS Health has deep and proven experience taking biologic products from early stage development to market commercialization, and we’re ready to learn more about your biologic today.

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Source: Lubrizol