Biopharmaceutical Manufacturing

Principles, Processes, and Practices

Gary Gilleskie, Charles Rutter, Becky McCuen

• Publisher: De Gruyter
• Year: 2021
• ISBN:
  9783110617016
• Edition: 1
• Topic: Biological Sciences
• Subtopic: Biotechnology
• Index: Biological Sciences

Biopharmaceuticals, medicines made by or from living organisms (including cells from living organisms), are extremely effective in treating a broad range of diseases. Their importance to human health has grown significantly over the years as more biopharmaceutical products have entered the market, and now the biggest selling drugs in the world are biopharmaceuticals. Biopharmaceutical Manufacturing: Principles, Processes and Practices provides concise, comprehensive, and up-to-date coverage of biopharmaceutical manufacturing. Written in a clear and informal style, the content has been influenced by the authors' substantial industry experience and teaching expertise. That expertise enables the authors to address the many questions posed over the years both by university students and professionals with experience in the field. Consequently, the book will appeal both to undergraduate or graduate students using it as a textbook and specialized industry practitioners seeking to understand the big picture of biopharmaceutical manufacturing. This book:

Chapter 1 An introduction to biopharmaceutical products

Because this book is focused on the processes and methods for manufacturing biopharmaceuticals, a logical starting point is an in-depth discussion of the output of these processes – biopharmaceutical drug products – to establish a clear understanding of what exactly is being produced. As you will see, biopharmaceuticals are a class of medicines that is among the most effective and biggest selling in the world. Their active ingredients are complex biological molecules and components (e.g., proteins, viruses, and cells) that are used to treat, prevent, and, in some cases, cure illnesses that medicines produced by chemical synthesis alone often cannot. Their development has had significant societal impact and marks one of the great achievements of modern science.

This chapter provides an overview of biopharmaceuticals by addressing the following questions:

• What are biopharmaceuticals, how are they different from more conventional medicines such as aspirin, and why is it worth making the distinction?
• What are some examples of biopharmaceutical products and the diseases they treat?
• What exactly are the components of biopharmaceutical drug products, and how are these products administered to patients?
• What quality attributes are critical for biopharmaceutical drug products?

1.1 Definitions and background

Let’s start by answering the question, “What is a biopharmaceutical?”

1.1.1 Biopharmaceuticals

The term biopharmaceutical has a number of different definitions that depend on whom you ask. In this book, we take a broad view of biopharmaceuticals and define them as pharmaceuticals (that is, medicines) inherently biological in nature and manufactured by or from living organisms (including cells from living organisms) [1]. Examples include humans and human cells, animals and animal cells, plants and plant cells, and microorganisms.

An example of a biopharmaceutical that most are familiar with is insulin, which is used to treat diabetes. Insulin is a protein hormone produced by the pancreas that helps to regulate the metabolism of carbohydrates by keeping one’s blood sugar from getting too high or too low. Diabetes is a disease that occurs when the body does not make enough insulin (Type 1) or does not use it properly (Type 2), resulting in high blood glucose levels. If glucose levels stay elevated for an extended period, complications such as heart disease, stroke, high blood pressure, neuropathy (nerve damage), kidney disease, vision loss, and others may arise [2]. Treatment for type 1 diabetes requires that a patient take insulin to make up for the insulin the body does not produce. Treatment for type 2 diabetes may or may not involve taking insulin.

So how is insulin for therapeutic use made? From its first use in the 1920s until 1982, all insulin was animal sourced. Specifically, insulin was extracted from pig and cattle pancreases and injected into human patients. Insulin produced in this way saved millions of lives but produced adverse reactions in many human patients. In addition, only three days’ worth of insulin for a diabetic patient could be prepared from a single pig pancreas [3]. Then in October 1982, the U.S. Food and Drug Administration (FDA) approved an insulin product made in a very different way: Humulin^®, developed by Genentech and marketed by Eli Lilly. Humulin^® became the first insulin analog produced through recombinant deoxyribonucleic acid (DNA) technology – that is, through genetic engineering – and, notably, the first recombinant medicine approved for use in the United States. Recombinant technology is discussed in more detail in the next section. In the case of Humulin^®, E. coli was manipulated to produce human insulin through the addition of a gene (a segment of DNA that codes for a certain protein) for human insulin [4]. Most insulin (or its analogs) in use today is produced through recombinant DNA technology and produced in either E. coli or yeast, such as Saccharomyces cerevisiae. Producing insulin through genetic engineering allows for greater control over production – and results in fewer adverse reactions – compared to using pig and cattle pancreases as the insulin source.

Many insulins are now on the market. These products represent one of many different types of commercially available protein therapeutics that are produced by genetic engineering of cells. Many more examples are discussed throughout this chapter.

It is worth noting that some writers limit their definition of biopharmaceuticals to only those medicines that have been produced through genetic engineering techniques. While genetic engineering has opened up a world of possibilities for production of biomolecules, the definition of biopharmaceutical used in this book encompasses all medicines made by or from living organisms; this includes medicines from non-engineered organisms or cells. Numerous examples exist, but let’s consider one with which you are likely familiar: flu vaccine. Many types of flu vaccine are on the market, and most are produced using natural (i.e., non-genetically engineered) sources. Vaccines aim to prevent diseases, in contrast to therapeutics such as insulin, which treat existing diseases. Vaccines often consist of live attenuated or inactivated virus that resembles the disease-causing virus and stimulates the body’s immune system, without causing illness, to build defenses against the virus. Consider the specific example of Flucelvax^®, a seasonal flu vaccine made from four different influenza virus strains. Each virus strain is grown in Madin-Darby Canine Kidney (MDCK) cells [5]. The cells are not genetically engineered; however, because the different virus strains are propagated in MDCK cells, Flucelvax^® fits our definition of biopharmaceutical. After propagation, each virus strain is inactivated, disrupted, and purified. The four virus strains are then pooled to produce the vaccine.

We take a broad definition of biopharmaceuticals in this book because, whether or not genetically engineered cells are used, many similarities exist in manufacturing operations and regulatory expectations for products produced by or from living organisms. It is worth noting an exception to our definition of biopharmaceuticals. Medicines based on small molecules that can be produced from cells, such as antibiotics, are generally not classified as biopharmaceuticals, even though they seem to fit our definition, because (1) the active molecule is much smaller than a protein therapeutic or the antigen that makes a vaccine, for example, and (2) the process for production, particularly after the culture step, is different from processes used to produce large molecules such as proteins and larger viruses.

1.1.2 Recombinant medicines explained

Let’s start this discussion by considering DNA. DNA is a macromolecule that consists of four chemical bases and exists within cells. DNA provides the code – via transcription to ribonucleic acid (RNA) and translation of RNA to prot...