Stages of Biologics Drug Product Manufacturing

Biologics drug manufacturing, from cell culture to quality control, is very precise. See formulas are combined to manufacture life-saving therapies in this in-depth guide.

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Biologics Drug Manufacturing

A “biologic,” often referred to as a biopharmaceutical product, is a pharmaceutical drug derived from biological sources, including extraction, semi-synthesis, or manufacturing. Biologics encompass a wide range of products, such as vaccines, blood components, gene therapies, tissues, and therapeutic proteins.

Over the next five years, the biologics market is expected to generate significant revenue growth. Even companies traditionally focused on “small molecule” drugs have shifted their attention and pipelines toward biologics. 

It’s anticipated that the global biologics market could surge to reach upwards of $480 billion by 2024. In 2019, a remarkable 80% of best-selling prescription drugs were biologics, with market projections indicating a healthy 11% growth rate (CAGR) for biologic products. 

So how are these products manufactured? At the heart of biologics production, there are various steps and technologies involved. From the cultivation of living cells to the fine art of purification, we will unveil the science behind biologics manufacturing. Let’s get started!

The Process Of Manufacturing Biopharmaceuticals

Manufacturing a biological drug product involves the production of pharmaceuticals derived from living organisms or their components. These complex drugs include vaccines, monoclonal antibodies, and gene therapies.  The manufacturing process typically consists of several critical steps.

Cell Culture

Biologics manufacturing frequently begins with the essential process of cell culture. This step involves the careful cultivation of living cells, which can be either mammalian or microbial cells, depending on the type of biological being produced. 

The primary objective of cell culture is to harness the remarkable ability of these cells to produce specific therapeutic proteins or molecules that have the potential to treat various diseases. Cells can come from two 

Mammalian Cell Culture

In the case of biologics derived from mammalian cells, specialized cell lines are often used. These cell lines are carefully selected and genetically engineered to ensure consistent production of the desired therapeutic proteins. 

Mammalian cell culture is known for its ability to produce complex proteins with post-translational modifications that closely resemble those found in the human body. This makes it particularly suitable for manufacturing biologics like monoclonal antibodies and certain vaccines.

Microbial Cell Culture

On the other hand, when producing microbial biologics, such as certain vaccines or recombinant proteins, microbial cell cultures come into play. Microbial cells, such as bacteria or yeast, are cultivated in bioreactors under controlled conditions. 

These cells are typically genetically modified to express the target protein efficiently. Microbial cell culture is valued for its scalability and cost-effectiveness, making it a preferred choice for the production of certain biologics.

Fermentation

Fermentation is a critical step in biologics manufacturing, and its success hinges on precise control and monitoring of conditions within the bioreactors. The choice between mammalian and microbial cell culture, as well as the specific conditions used during fermentation, depends on the type of biologic being produced, cost considerations, and desired product characteristics.

Fermentation takes place within bioreactors, specialized vessels designed to provide an optimal environment for microbial cell growth and protein production. There are some key aspects of fermentation:

  • Optimized Growth Conditions: During fermentation, environmental factors such as temperature, pH, oxygen levels, and nutrient supply are carefully controlled to maximize the growth of microbial cells. These conditions ensure that the cells can produce the desired product efficiently.
  • Harvestation: As microbial cells grow and reproduce in the bioreactors, they simultaneously produce the therapeutic protein of interest. Once the cells reach an optimal density and the target protein has been synthesized, the culture is harvested.
  • Purification: The harvested culture contains the target protein along with other cellular components. This culture is then processed further to isolate and purify the protein from the rest of the cellular material.

Purification

As mentioned above, purification is the process where the harvested culture contains not only the desired target product but also a collection of other cellular components, debris, and impurities. The primary goal of purification is to separate and isolate the target biologic with a high degree of purity. 

Here’s a more detailed look at the purification process:

  • Chromatography: Chromatography plays a central role in purification. This technique exploits the differences in the chemical properties of molecules to separate them. In the context of biologics manufacturing, various types of chromatography, such as affinity chromatography, ion exchange chromatography, and size exclusion chromatography, are used to selectively capture and separate the target protein from the complex mixture.
  • Filtration: Filtration techniques, including depth filtration and sterile filtration, are used to remove larger particles and contaminants from the solution. These steps are critical for ensuring the purity and safety of the final product.
  • Concentration: After initial purification, the biological solution may undergo concentration steps to increase the protein concentration while reducing the volume. This is often achieved through methods like ultrafiltration and diafiltration.
  • Viral Clearance: Depending on the nature of the biologic, viral clearance steps are included to ensure that the final product is free from any potential viral contaminants. These steps are especially crucial for products derived from mammalian cell cultures.

Successful purification is a multi-step process that demands a deep understanding of the properties of the target biologic and the use of cutting-edge separation techniques. The result is a highly purified biologic ready for the next phase of manufacturing.

Formulation

Once the purified biologic is obtained, the formulation step comes into play. Formulation involves the careful design and preparation of the biologic for its final use as a drug product. The key objectives of the formulation are to enhance the stability, safety, and effectiveness of the biologic. 

The formulation process includes:

  • Stabilizers: Biologics are often sensitive to environmental factors such as temperature and pH. Stabilizers are added to the formulation to protect the biologic from degradation during storage and transportation. Common stabilizers include sugars, amino acids, and other excipients.
  • Preservatives: In some cases, preservatives are included to prevent microbial contamination in multi-dose biologic products, such as vaccines or antibody therapies. Preservatives like thimerosal or benzyl alcohol are just a few of many that are commonly used.
  • Buffering Agents: Maintaining the optimal pH level is crucial for the stability and activity of many biologics. Buffering agents are added to the formulation to control and maintain the desired pH.
  • Final Product Presentation: The purified biologic is formulated into its final presentation, which may include vials, syringes, or other delivery systems. Proper packaging and labeling are also essential for product identification and compliance with regulatory requirements.

Fill-Finish

Once the biologic has undergone purification and formulation, it needs to be transferred into its final packaging. This can include vials, syringes, or other appropriate containers. This process is crucial for several reasons:

  • Product Sterility: Maintaining sterility throughout this step is absolutely essential. Any contamination at this stage could jeopardize the safety and efficacy of the biological product. Cleanrooms and aseptic techniques are commonly employed to ensure sterility.
  • Dosing Accuracy: Having a precise dose is critical, especially in the case of therapeutic biologics. Patients rely on accurate and consistent dosages to achieve the desired therapeutic outcomes.
  • Packaging Integrity: The integrity of the packaging materials and containers is closely monitored. Proper sealing and closure systems are employed to prevent leakage or tampering.

Quality Control

Quality control is a continuous and rigorous aspect of biologics manufacturing. Throughout the entire process, from cell culture to fill-finish, strict measures are in place to ensure the safety, efficacy, and consistency of the product. 

Quality control includes:

  • In-Process Testing: Various tests and assays are performed at different stages of manufacturing to monitor the quality and characteristics of the biologic.
  • Final Product Testing: Prior to release, the final product undergoes comprehensive testing to verify its identity, purity, potency, and safety. This includes assays to ensure that it meets the required specifications.
  • Environmental Monitoring: Cleanroom environments and equipment are regularly monitored to prevent contamination during production.

Packaging

Often outsourced, this process prepares the biologic for distribution and use. It involves carefully packaging the finished product into labeled final containers. Labels that contain crucial information such as dosage instructions, expiration date, and batch number. Special attention is given to packaging materials to prevent any form of contamination or degradation during storage and transportation.

Regulatory Compliance

Biologics manufacturing is subject to strict regulatory oversight by health authorities, such as the FDA in the United States. Compliance with Good Manufacturing Practices (GMP) is essential to ensure the quality, safety, and efficacy of biological products. 

GMP guidelines are made up of every aspect of biologics manufacturing, including facility design, equipment calibration, personnel training, documentation, and quality control procedures. Failure to do so is not just a crime but also inhumane as people’s lives depend on it.

Cold Chain Management

Many biologics, especially vaccines and some antibodies, are highly temperature-sensitive. To maintain their potency, these products must be stored and transported within specific temperature ranges. 

Specialized logistics and temperature-controlled supply chains are collectively referred to as the Cold Chain. Cold chain management ensures that biologics remain effective from the moment they leave the manufacturing facility until they reach the patient.

Batch Records and Documentation

Detailed record-keeping is a big requirement in biologics manufacturing. Comprehensive batch records and documentation are maintained throughout the entire process. These records provide a traceable history of each product, documenting every step, test, and quality control measure taken. Proper documentation is crucial for regulatory compliance, product accountability, and continuous process improvement.

Conclusion

These critical steps in biologics manufacturing collectively ensure the production of safe, effective, and high-quality biologic products. Their adherence to strict standards and protocols is essential to meet regulatory requirements and, most importantly, to safeguard a patient’s health.

The world of biologics manufacturing is not merely about producing medicines; it’s about transforming lives. Each vial or syringe carries the promise of hope, the potential for healing, and the pursuit of better health. The industry’s commitment to precision, safety, and regulatory compliance ensures that the promise of biologics remains reliable in the coming future.

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