The Role of Filtration in the Biopharmaceutical Industry

 

Filtration holds immense importance in the biopharmaceutical industry, where it plays a crucial role in removing contaminants from desired products and ensuring their sterility. Since pharmaceutical products are highly sensitive, not all sterilization methods can be employed, making filtration an indispensable process.

This article aims to delve into the significance of liquid filtration in the biopharmaceutical industry. By understanding the critical role of filtration, it becomes possible for future innovators to contemplate its advantages and limitations while seeking solutions to overcome challenges. This article will explore various aspects of pharmaceutical filtration, including the types of filters used, and delve into topics such as bioprocess filtration and biopharma filtration.

What is pharmaceutical filtration?

Pharmaceutical filtration is an umbrella term that includes different types of filtration techniques used in various aspects of the pharmaceutical industry. These filtration techniques are used to either purify or separate substances. According to the size of the substance that needs to be filtered and the nature of the different constituents of the mixture, various techniques are used across the industry. Some of the common pharmaceutical filtration techniques used include surface filtration, ultrafiltration and depth filtration. The entire process of filtration can be divided into five stages:

Pre-Filtration: It is the first stage in the filtration process, which is used to remove larger debris. The pre-filtration reduces the load on the downstream filters, thereby increasing the efficiency of the filtration process.

Clarification: At this stage, the solution already has fewer solid particles due to pre-filtration. This stage further removes cell debris and bulk cellular materials from the liquid.

Bioburden Reduction: This filtration stage involves reducing the population of microbes such as bacteria or viruses. It utilizes ultrafilters to eliminate the microbes.

Sterilizing Filtration: This is the last stage in the filtration process and is utilized in situations such as sterilizing the fluid through a filter or during fill-and-finish operations.

Nonfiltration Separation: This filtration stage is highly important because it effectively reduces or removes contaminants and unwanted substances, resulting in a cleaner and better- quality product.

There are two types of filtration based on the involved mechanisms. The types of filtration are:

Surface Filtration: This type of filtration, where contaminants are trapped at the surface of the membrane, is typically employed when the main objective is to remove larger particles or contaminants from a fluid or gas stream. It is effective when the particle size is relatively larger compared to the pore size of the membrane. Surface filtration is commonly used in applications such as pre-filtration to protect downstream filters, removal of coarse particulate matter, and clarification of fluids with visible impurities.

Depth Filtration: On the other hand, depth filtration, which entangles contaminants or solid particles within the entire depth of the membrane, is used when the goal is to capture particles of various sizes, including both larger and smaller particles. It is particularly useful in situations where the mixture contains a wide range of particle sizes. Depth filtration finds applications in fine particle removal, microbial control, purification of fluids with submicron particles and removal of colloidal impurities.

Therefore, the choice between surface filtration and depth filtration depends on factors such as the size and nature of the particles or contaminants, the desired filtration efficiency, the flow rate and the specific objectives of the filtration process. Understanding these factors will aid in determining the most suitable filtration method for a given application.

Filtration in pharmaceutical industry

Pharmaceutical industries employ various filtration techniques with the respective filters to meet different requirements. The important types of filtration used in the pharmaceutical industry are charged filtration, bag filtration, self-cleaning filtration and ultrafiltration.

These filtration techniques provide the pharmaceutical industry with efficient and reliable means of purifying and separating substances. They also contribute to maintaining product integrity and meeting regulatory requirements, ensuring the production of high-quality pharmaceutical products.

Ultrafiltration

Ultrafiltration is a highly significant filtration technique extensively employed in the pharmaceutical industry. It operates through pressure-driven transport, where the suspension is passed across a membrane. This process is utilized both in laboratory settings and on an industrial scale. Ultrafiltration membranes typically have a retention limit ranging from 1 to 1,000 nm, with different membranes having specific molecular weight cut-off limits. Inorganic membranes employ inorganic colloids and porous supports, while organic membranes are made from synthetic polymers.

This process plays an important role in pharmaceutical applications where the separation and concentration of macromolecules are required. It is commonly used for the purification of proteins, enzymes, antibodies and other biomolecules. Ultrafiltration helps remove contaminants such as aggregates, impurities and smaller molecules while retaining the desired macromolecules based on their size or molecular weight. This technique aids in achieving high product purity and concentration, which are essential for the production of pharmaceuticals with precise and consistent quality.

Magnetic Filtration

Magnetic filtration is another important filtration method utilized in specific pharmaceutical applications. It employs magnetic filters containing neodymium magnets to separate iron particles from suspensions. This technique efficiently removes even microscopic iron particles as small as 10 microns. Magnetic filtration doesn’t affect the filtration rate, even when contaminants accumulate, as it does not significantly impact the pressure drop.

Magnetic filtration finds utility in pharmaceutical processes where the removal of iron particles is crucial to ensure product quality and safety. For example, in the production of injectable medications or biopharmaceuticals, magnetic filtration can be employed to remove iron contaminants that might arise from equipment or raw materials. Iron particles can catalyze oxidative reactions and cause degradation of pharmaceutical products, affecting their stability and efficacy.

Bag Filtration

Bag filtration is a valuable filtration method widely employed in the pharmaceutical industry for the purification of fluids and air. It utilizes bags made of various types of fabric as the filter media. In liquid bag filtration, the fluid suspension passes through the bag, and the fabric’s pores act as a filter, entrapping larger particles. Over time, the accumulation of oversized particles leads to the formation of a filter cake, which further enhances filtration by reducing the effective pore size.

Bag filtration can help in pharmaceutical applications where the removal of solid impurities or particles from liquids is necessary to achieve desired product quality. It is commonly used in processes such as pre-filtration of raw materials, clarification of solutions and removal of particulate matter during the production of pharmaceutical formulations. Bag filtration helps maintain the cleanliness and purity of fluids, ensuring that the final pharmaceutical products meet stringent quality standards.

Self-Cleaning Filtration

Self-cleaning filtration is an advanced filtration method that offers automatic removal of accumulated contaminants from the filter membrane. There are different mechanisms used for self-cleaning filtration, including direct flushing, back flushing and automatic self-cleaning.

It is particularly important in pharmaceutical processes where continuous filtration is required without frequent interruptions for manual cleaning or replacement of filter media. It helps maintain consistent filtration performance and reduces the downtime associated with filter maintenance. Self-cleaning filtration finds application in various pharmaceutical processes, including the filtration of process fluids, solvents, suspensions and formulations. It is commonly used in pharmaceutical manufacturing operations such as active pharmaceutical ingredient (API) production, formulation processing and sterile filtration of pharmaceutical preparations.

What is liquid filtration

Liquid filtration is a fundamental process used to remove solid particles, contaminants or impurities from a fluid stream. The concept behind liquid filtration is straightforward: the mixture of liquid and solid particles flows through a permeable membrane that captures and retains the solid particles, preventing their further movement. This filtration process relies on a membrane with pores of varying sizes, through which smaller particles can pass while larger particles are obstructed.

During liquid filtration, two distinct components are formed. The first component is the filtrate, which refers to the filtered liquid that successfully passes through the membrane. The second component is the filter cake or residue, which comprises the accumulated solid particles that gather on one side of the membrane over time. The filter cake can develop a significant thickness and can impede the flow of the fluid stream by creating resistance. Liquid filtration can be operated in two methods.

• Constant Rate Filtration

In this method, the rate at which the filtrate gets collected remains constant. This results in a gradual increase in the pressure drop across the membrane. To achieve a constant rate during filtration, the suspension is fed into the filter by using a reciprocating pump. The increase in the pressure differential across the filter types is, in turn, used to maintain the constant flow rate, as the depth of the filter cake increases with the increasing time, which in turn provides more resistance. Constant rate filtration is used in industries where a predictable and constant flow rate is required, as in water treatment facilities and wastewater treatment industries.

• Constant Pressure Filtration

In this method, the pressure drop developed across the filter membrane remains constant, which results in a decrease in the filtration rate. The constant pressure difference across the membrane is maintained by keeping the suspension above the filter medium under constant positive pressure by a pump, and the region below the filter can be left at a lower pressure than above. As a result of constant pressure differential, the rate of filtration gradually decreases with time due to an increase in the filter cake thickness and the resistance it produces. Constant pressure filtration is used in industries where, even under varying types of suspension feed conditions, the outgoing filtrate should be at a desired pressure, such as in pharmaceutical and chemical industries.

The liquid filtration theory is explained by a modified Kozeny-Carman equation. This equation establishes a relationship among the pressure drop experienced by the fluid during filtration, the thickness of the filter cake formed and the resistance offered by the accumulated solids. It serves as a valuable tool in understanding and analyzing the dynamics of liquid filtration processes.

Where to use liquid filtration in the pharmaceutical process

The pharmaceutical industry uses liquid filtration in several different aspects for different purposes. It is employed in several key areas throughout the industry. By utilizing liquid filtration techniques in these critical areas, the pharmaceutical industry can maintain product quality, improve process efficiency and meet regulatory requirements.

Obtaining Sterile Water

Sterile water is a crucial requirement in various pharmaceutical techniques, particularly in the bioreactor. Different levels of sterile water quality are achieved by utilizing specific types of filters. For example, when obtaining sterile water for injection, ultrafiltration or microfiltration methods are employed, typically utilizing filters with pore sizes ranging from 0.001 to 0.1 micron. Sterile water is also essential for blending different raw materials to create the substrate used in the bioreactor.

Production of Active Pharmaceutical Ingredients

Active Pharmaceutical Ingredients (APIs) are chemically active substances that provide therapeutic effects. During the isolation of these substances, various solvents are used, which need to be separated for further purification. Filter media are employed to remove contaminants, allowing the isolation of the desired API in the obtained filtrate. This filtrate can then undergo further concentration to isolate the API.

Bioburden Reduction

After the fermentation process, the substrate containing cellular debris, live cells and organic matter is processed in downstream stages. To reduce the bioburden before the substrate reaches the separation and purification stages, it undergoes filtration using ultrafilters or similar filters to remove cellular debris and bacteria.

Clarification and Pre-Filtration

To ensure the synthesis of pharmaceutical products is free from contamination, every aspect of production needs to be carefully controlled. This includes ensuring the raw materials are free from contaminants. Therefore, clarification and pre-filtration processes are employed when using liquid raw materials such as water or other fluids in the production process. Pre-filtration involves removing larger cellular or noncellular debris from the fluid. Once pre-filtration is complete, the fluid undergoes clarification to remove smaller solid debris like cell debris or bulk cellular materials. These stages help prevent contamination of the raw materials.

Sterile Filtration of Finished Product

Before the finished product is packaged and released to the market, it undergoes a series of filtration steps. The final stage of this filtration process is sterile filtration, which ensures the absolute sterility of the finished product. This type of liquid filtration employs membrane-based filters such as nanofilters to remove any microbes or viruses. The filters used are carefully selected to maintain the stability of the finished product and prevent any binding to the filtered components.

What is bioprocess filtration?

Bioprocess filtration involves the use of filtration techniques to purify and separate biological substances during the production of biologics, vaccines and other biopharmaceutical products. It plays a vital role in ensuring the safety, efficacy and quality of these products.

The filtration type encompasses a range of filtration methods specifically designed for handling sensitive biological materials. These techniques are employed at various stages of the bioprocess, including cell culture, harvest, clarification, purification and final product formulation. The goal is to remove impurities, such as cells, cell debris, aggregates, contaminants and other particulate matter, from the desired product.

Different types of filters are utilized in bioprocess filtration, including membrane filters, depth filters and chromatography columns, each designed to cater to specific requirements. Membrane filters with precise pore sizes are commonly used to separate particles based on size, while depth filters with a complex matrix structure are effective in retaining particles throughout their depth.

The bioprocess filtration steps may involve microfiltration, ultrafiltration, diafiltration and sterile filtration, depending on the specific needs of the bioprocessing operation. These filtration techniques aid in achieving desired product purity, concentration and formulation stability, while also contributing to the removal of potential contaminants, such as endotoxins and viruses.

What is biopharma filtration?

Biopharma filtration involves specialized filtration methods that are specifically employed in the pharmaceutical industry. It encompasses a range of filtration techniques used in downstream biopharmaceutical production that ensures the desired quality and purity of the products. Unlike general filtration methods that may be used in various industries, biopharma filtration is tailored to meet the unique requirements of biopharmaceutical products. Some of these filtration methods include sterile filtration, virus filtration and chromatography.

• Sterile Filtration

The sterile filtration in the pharmaceutical industry ensures that absolute sterility of the fluid or the final product is maintained. It mostly uses either ultrafiltration or nanofiltration to remove microbes and other host cell remains from the product. The filters used in the sterile filtration are also customized according to the product to ensure maximum sterilization while not adversely affecting the product stream.

• Virus Filtration

Virus filtration is the removal of viruses from the product stream using filtration techniques during the downstream process. Viral filtration can be done at different locations in the downstream processing, such as after pH inactivation steps and the intermediate or final chromatography process. Virus filtration uses different types of filters with pore sizes in the nanometer range. However, different pharmaceutical industries use different pore-size membranes, similar to the size range of the viruses, as the desired product.

• Chromatography

Unlike conventional filtration techniques, chromatography does not separate molecules using pore size; instead, it separates different substances based on their surface adsorption capabilities to the substrate. The chromatography technique has an immobile phase and a mobile phase. The mobile phase carries the product stream, whereas different substances get adsorbed onto the immobile phase based on their adsorption tendency and size. The mobile phase consists of different types of solvents, in which the components inside the product stream can dissolve differentially. By repeating this process, the substances can be separated. This is mostly used for separating large-size biomolecules or some impurities too.

If you want to learn more about the filtration process in biopharma production, explore VWR’s process filtration system products to gain in-depth knowledge and insights. From sterile filtration to virus removal, our comprehensive solutions cater to your specific filtration needs.

8 filter types for pharmaceuticals

The need for clean and sterile water in the pharmaceutical industry is paramount. Sterile water is required in almost every process, from culture preparation to downstream processing. Pharmaceutical companies rely on various filter types to ensure the production of high-quality pharmaceutical products by removing impurities, contaminants and microorganisms from liquids. The appropriate selection and implementation of these filters are vital to meet the industry’s stringent requirements for clean water and to ensure the safety and efficacy of pharmaceutical formulations. Here are eight types of filters in biopharma.

Nanofiltration Membranes

Nanofiltration membranes are a type of pressure-driven membrane that functions by passing water through them under pressure. These membranes have pore sizes ranging from 0.2 to 2 nm. They are commonly used to separate viruses or heavy metals from water. The surfaces of nanofiltration membranes are often negatively charged to enhance the filtration of dissolved ions. The mechanisms involved in nanofiltration membranes include a combination of solution-diffusion, the Donnan effect, electromigration and dielectric exclusion. These membranes offer effective separation capabilities, making them valuable in various applications requiring precise filtration and separation of specific substances.

Magnetic Filters

Magnetic filters utilize powerful permanent magnets to eliminate iron particles as contaminants in fluids, including water. These filters typically employ neodymium magnets encased within stainless steel pipes and attached to the filter using screws. Thanks to neodymium magnets, magnetic filters can effectively remove iron particles, even as small as 10 microns. One of the advantages of magnetic filters is their ease of manual cleaning. This feature allows for convenient maintenance and ensures consistent filtration performance over time.

Reverse Osmosis Systems

Reverse osmosis systems employ a filtration process to remove contaminants from water by applying pressure to force it through a filter membrane. In these systems, water moves from low-concentration to higher-concentration regions. Contaminated water is subjected to pressure and passed through these membranes, allowing only water molecules to pass through while retaining contaminants on the other side. The pressure drop across the membrane in reverse osmosis systems ranges from 2 to 82 psi, depending on the treated water. These systems are highly effective in purifying water and removing many contaminants.

Ultraviolet Purification Systems

Ultraviolet purification systems utilize ultraviolet light with a wavelength range of 250 to 270 nm for disinfecting water. Unlike traditional filtration processes, ultraviolet purification disrupts the genetic material of microbes in the water. Ultraviolet light causes irreparable damage to the genetic material, leading to the eradication of the microbe population. This method is effective against various common microbes, including salmonella, mycobacterium, streptococcus and E. coli. Ultraviolet purification systems utilize UV lamps filled with mercury vapors, enclosed in a glass quartz structure to prevent contact between the water and the vapors or filament. These systems provide reliable and chemical-free water disinfection.

Bag Filters

The bag filter serves as a mechanical device utilized across various industries, including the biopharmaceutical sector, to purify both air and water used in these operations.

In water filtration, the bag filter allows the water or other fluids to pass through filter bags composed of different fabric types, depending on the specific water being treated. These fabric bags have varying pore sizes for filtration purposes. As the water flows through the bags, contaminants larger than the pore size are trapped within the fabric, gradually filling up the bag. Subsequently, the bag can be removed and the accumulated contaminants disposed of.

In the pharmaceutical industry, both the air required for various processes and the air released from these operations contain high levels of dust, posing health risks and contributing to air pollution. To address this, the bag filter is employed. It is a large metal vessel with bags made from different fabric materials attached in an inverted position. The open ends of the bags extend into a hopper below. Dirty air enters the upper part of the metal vessel, while a carrier gas is introduced from the bottom region under pressure. As a result, dust particles adhere to the surface of the bags due to forces such as inertial or electrostatic attraction, interception and Brownian movement.

ANFDs

The Agitated Nutsche Filter Dryer (ANFD) is a liquid filtration device designed to separate solid substances from liquid suspensions while facilitating the drying and washing of the solids. It consists of a metal vessel with a perforated metal plate covered by a filter media. An agitator is used to ensure continuous agitation of the suspension. The agitated suspension or slurry undergoes filtration, separating the liquid portion and retaining the solid substances inside the vessel. The presence of the agitator prevents larger solid particles from settling.

After the filtration process, the solid residue can be dried using the ANFD’s drying system. Indirect heating is employed by heating the external jacket of the ANFD. A vacuum system that lowers the boiling point further enhances the drying process, expediting the drying phase.

Additionally, if required, the solid substance can undergo a washing process. The washing liquid is mixed with the solid substance and agitated. Subsequently, the washing liquid is separated, leaving the solid behind, which can then be extracted from the top of the filter.

Ceramic Filters

Ceramic filters are a type of solid filter media used in the pharmaceutical industry to filtrate water or other fluids. These filters consist of a filter membrane made out of ceramic with pre-designed pore sizes. The ceramic filters are mostly used to remove larger contaminants, as the pore size is not small enough to trap microbes or smaller contaminants. However, some ceramic filters have colloidal silver infused in them, which provides antimicrobial action to some extent. Mostly ceramic filters are not used as a stand-alone unit for water filtration; rather, they are used in coherence with other filter membranes for maximum efficiency. The main advantage of the ceramic filters is that they are relatively low-cost.

Self-Cleaning Filters

Different types of filter membranes suffer from one common problem: the accumulation of the contaminant either on the filter membrane or inside it. This decreases the filter efficiency. As a workaround for this problem, the self-cleaning filters are used. Self-cleaning filters work in different ways according to the filter design. However, some common ways by which the self-cleaning filter works are:

• Direct Flushing

In self-cleaning filters, a cleaning fluid, such as water, is directly applied to the accumulated contamination on the filter that effectively washes away these contaminants.

• Back Flushing

In such self-cleaning filters, the fluid flow through the filter is reversed, which helps remove the contaminants from the other side of the filter membrane.

• Automatic Self-Cleaning Filters

Such self-cleaning filters detect the change in the pressure drop across the filter membrane due to the accumulation of the contaminant layer over the filter. When such a change in pressure drop is detected, an automatic scraper fitted in the gap between the filter membrane and the exterior pipe housing is moved, which scrapes away all the accumulated contaminants.

What to consider when selecting a filter

When selecting a filter in the biopharmaceutical industry, there are several important factors to consider. These factors include filter material compatibility with the product, pore size selection based on particle retention requirements, validation and regulatory considerations, filter performance characteristics, including flow rate and capacity, and cost-effectiveness.

Filter Material Compatibility

The filter material used should be compatible with the specific product being processed. Different filter materials can have varying interactions with the product, which may result in adsorption or leaching of substances that could potentially impact the quality or safety of the final product. To ensure compatibility, it is suggested to conduct thorough compatibility testing and evaluate any potential interactions between the filter material and the product. This helps select the filter material that is chemically compatible and minimizes any risks associated with interactions.

Pore Size Selection

It is important to select an appropriate pore size to achieve the desired level of particle retention during filtration. The pore size should be determined based on the size of particles that need to be removed or retained. Factors such as the nature of the product, particle size distribution and regulatory requirements should be considered when determining the optimal pore size. By choosing the correct pore size, the filter can effectively remove contaminants while allowing the desired components of the product to pass through.

Validation and Regulatory Considerations

Filters used in the biopharmaceutical industry must meet regulatory requirements and be part of a validated filtration process. It is important to source filters from reputable manufacturers who provide comprehensive validation data and regulatory documentation. Regulatory agencies, such as the FDA or EMA, often have specific guidelines and requirements for filter selection and validation. Adhering to these guidelines ensures compliance and helps guarantee the safety, efficacy and quality of the biopharmaceutical products.

Filter Performance Characteristics

The performance characteristics of the filter, including flow rate and capacity, play a significant role in the filtration process. The flow rate refers to the rate at which the product passes through the filter. It is essential to optimize the flow rate to ensure efficient processing without compromising filtration performance. The capacity of the filter pertains to its ability to retain particles over a specified period. Selecting filters with appropriate flow rates and capacities ensures that the process requirements are met while maintaining the desired level of particle retention and product quality.

Cost-Effectiveness

Evaluating the cost-effectiveness of filters involves considering various factors. The initial cost of the filter, the frequency of filter replacement and the overall impact on process economics must be assessed. While ensuring high-quality filtration is paramount, it is necessary to strike a balance with the cost implications. By weighing the cost of the filter against its performance and durability, biopharmaceutical companies can make informed decisions that maximize the efficiency and profitability of their filtration processes while maintaining product integrity.