SAMPLE-PRODUCER’s KEY TERMS

Upstream

The upstream process is defined as the entire process from early cell isolation and cultivation, to cell banking and culture expansion, until the final harvest. The upstream part of a bioprocess refers to the first steps where microbes or cells (e.g., bacterial or mammalian cell lines) are grown in bioreactors.

Upstream processing involves all steps related to inoculum development, media development, genetic engineering to improve the inoculum, and optimization of growth kinetics to enhance product yield. Fermentation generally consists of two parts: upstream and downstream. After product development, the next phase is the purification of the product to achieve the desired quality. When the cells reach the desired density, they are harvested and transferred to the downstream section of the bioprocess.

Cell culture is the process of growing cells under controlled conditions, generally outside their natural environment. In practice, the term "cell culture" now typically refers to the cultivation of cells derived from multicellular eukaryotes, especially animal cells. However, plant, fungi, insect, microbial, and even virus cultures are also common.

The downstream process in a bioprocess refers to the stage where the cell mass from the upstream is processed to meet purity and quality requirements. Downstream processing is usually divided into three main sections:

Cell disruption
Purification
Polishing

Think of it as separating your biologic drug from all the other ingredients it was made with.

Downstream

Downstream processing refers to the recovery and purification of biosynthetic products, particularly pharmaceuticals, from natural sources such as animal or plant tissue, or fermentation broth. This process also includes the recycling of salvageable components and the proper treatment and disposal of waste.

Downstream processing is an essential step in the manufacture of pharmaceuticals such as antibiotics, hormones (e.g., insulin and human growth hormone), antibodies (e.g., infliximab and abciximab), and vaccines. It is also critical for producing antibodies and enzymes used in diagnostics, industrial enzymes, as well as natural fragrance and flavor compounds.

The removal of insolubles is the first step, involving the capture of the product as a solute in a particulate-free liquid. For example, this involves separating cells, cell debris, or other particulate matter from the fermentation broth that contains an antibiotic. Typical operations to achieve this include:

Filtration
Centrifugation
Sedimentation
Precipitation
Flocculation
Electro-precipitation
Gravity settling

Additional operations, such as grinding, homogenization, or leaching, may be required to recover products from solid sources like plant and animal tissues, and are usually included in this step.

The next stage is product isolation, which focuses on removing components that differ significantly from the desired product. For most products, water is the primary impurity. Isolation steps are therefore designed to remove most of the water, reducing the volume of material to be handled and concentrating the product. Techniques involved in product isolation include:

Solvent extraction
Adsorption
Ultrafiltration
Precipitation

Product purification is performed to separate contaminants that closely resemble the product in physical and chemical properties. As a result, the steps in this stage are expensive to carry out and require sensitive and sophisticated equipment. This stage contributes a significant portion of the overall downstream processing cost. Examples of operations used in product purification include:

Affinity chromatography
Size exclusion chromatography
Reversed-phase chromatography
Crystallization
Fractional precipitation

Product polishing refers to the final processing steps, which conclude with packaging the product in a form that is stable, easily transportable, and convenient for use. Typical unit operations at this stage include:

Crystallization
Desiccation
Lyophilization (freeze drying)
Spray drying

Depending on the product and its intended use, polishing may also include sterilization steps and procedures to remove or deactivate trace contaminants that could compromise product safety, such as viruses or pyrogens.

Some product recovery methods can combine two or more stages into a single step. For example, expanded bed adsorption (Vennapusa et al., 2008) enables the removal of insolubles and product isolation in one process. Similarly, affinity chromatography can often achieve both isolation and purification in a single step.

Licensing

Out Licensing — This occurs when you have a drug that you want someone else to develop, co-develop, or market for you.

Example 1: If you are a small biotech company with a limited budget, you might not be able to afford all the development stages and clinical trials for your promising drug. In this case, you can license your drug to a larger company, and they will develop or co-develop it. If the drug is successful, they will pay you a licensing fee.
Example 2: Suppose you run a successful pharmaceutical company in the Philippines and have a great biologic drug that you know would do well in South America. However, you don’t have any presence in that market. You can license the drug to a South American company, which will handle the local clinical trials, marketing, and sales for you.

In Licensing — This is the opposite of out-licensing. In this case, you pay another company to develop, co-develop, or market their pharmaceutical product.

Preclinical

Before pharmaceutical companies start clinical trials on a drug, they conduct extensive pre-clinical studies. These studies involve in vitro (test tube or cell culture) and in vivo (animal) experiments using a wide range of doses of the study drug to obtain preliminary data on:

Efficacy
Toxicity
Pharmacokinetics

These tests help pharmaceutical companies determine whether a drug candidate has sufficient scientific merit to proceed to further development as an Investigational New Drug (IND).

Clinical Trials

All clinical trials have two main goals when testing a drug:

To determine whether the drug works well enough — this is called "efficacy" or "effectiveness."
To assess whether the drug is safe enough — this is called "safety."

(After all, you don’t want to sell dangerous drugs that don’t work to the public!)

Clinical trials are separated into four phases:

Phase	Aim	Notes
Phase 0	Pharmacodynamics and pharmacokinetics in humans.	Phase 0 trials are the first-in-human trials. Single subtherapeuticdoses of the study drug or treatment are given to a small number of subjects (10 to 15) to gather preliminary data on the agent's pharmacodynamics (what the drug does to the body) and pharmacokinetics (what the body does to the drugs).[27] For a test drug, the trial documents the absorption, distribution, metabolization, and removal (excretion) of the drug, and the drug's interactions within the body, to confirm that these appear to be as expected.
Phase 1	Screening for safety.	Testing within a small group of people (20–80) to evaluate safety, determine safe dosage ranges, and begin to identify side effects. A drug's side effects could be subtle or long term, or may only happen with a few of people, so phase 1 trials are not expected to identify all side effects.
Phase 2	Establishing the efficacy of the drug, usually against a placebo.	Testing with a larger group of people (100–300) to see if it is effective and to further evaluate its safety. The gradual increase in test group size allows less-common side effects to be progressively sought.
Phase 3	Final confirmation of safety and efficacy.	Testing with large groups of people (1,000–3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow it to be used safely.
Phase 4	Sentry studies during sales.	Postmarketingstudies delineate additional information, including the treatment's risks, benefits, and optimal use. As such, they are ongoing during the drug's lifetime of active medical use.

Biologic Drug

A biopharmaceutical, also known as a biologic medical product, or simply a biologic or biological, is any medicinal product that is manufactured in, extracted from, or semi-synthesized from biological sources.

Biopharmaceuticals are distinct from pharmaceutical products that are chemically synthesized in ways that do not involve biological processes, typically from petrochemical precursors.

Examples of biopharmaceuticals include:

Vaccines
Blood or blood components
Allergenics
Somatic cells
Gene therapies
Tissues
Recombinant therapeutic proteins
Living cells used in cell therapy

mAb (Monoclonal Antibody)

Monoclonal antibodies are similar to the antibodies that the human immune system uses to fight bacteria and viruses. However, they are custom-designed (using hybridoma technology or other methods) to specifically counteract or block any given substance in the body, or to target a specific cell type.

Examples of monoclonal antibodies used for various diseases are typically listed in reference tables.

Biosimilar

A biosimilar is a copy of a biologic drug whose patent has expired. Unlike small-molecule drugs, biologics have high molecular complexity and can be highly sensitive to changes in the manufacturing process.

Manufacturers of biosimilars do not have access to:

The originator's molecular clone and original cell bank
The exact fermentation and purification processes
The original active drug substance

They only have access to the commercialized innovator product. Because of this, differences in impurities and/or breakdown products may occur, which can have serious health implications. This raises concerns that biosimilars might perform differently compared to the original branded version.

Biobetters

Biobetters are drugs that take the active component of a biosimilar (so the effectiveness is already known) and improve it by adding or modifying components to make it better.

This allows companies to:

Sell the improved product at a higher price
Patent the new formulation

For example, normal insulin for diabetics needs to be injected daily. Some Korean companies are developing a biobetter insulin that would only need to be injected once a week.