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Bioengineering: The Various Forms And Types Of Impurities That Need To Be Isolated In Downstream Processing

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Abstract

Removal of impurities is a key aspect of downstream processing. While the newly produced target protein must be harvested and purified from the culture, a variety of impurities, including endotoxins, HCPs, viruses and cells must be removed. This study examines each of these impurities and the impact they may have on patient safety and/or drug efficacy. Various removal techniques were investigated for each impurity, with the aim of designing an effective overall clearance strategy for a bioprocess. The report proposes a strategy whereby multiple impurities can be removed efficiently, and suggests some areas where improvements may be made in the future.

Introduction

Downstream processing is currently the most expensive stage of production of biopharmaceuticals, as a result of high protein yields from the upstream process and the need to ensure impurities are removed from the harvest in order to produce a drug safe and effective for humans (Goey, Alhuthali and Kontoravdi, 2018). Downstream processing begins with the harvest or “capture” of the protein product, which has been produced during the upstream processing stages and continues with a number of stages including protein purification, product polishing and viral clearance. As modern biopharmaceuticals, predominantly monoclonal antibodies (mAbs), are produced using cells as expression systems, a crucial step in downstream processing is the separation of the protein product, referred to as “Bulk Drug Substance” (BDS) at this point, from the cells, cellular debris, waste products, and culture media. The most commonly used method for this separation is centrifugation, although ultrafiltration and chromatography are also used, amongst others (Gronemeyer, Ditz and Strube, 2014). These approaches to cell separation will be investigated and compared as part of this project.

After BDS harvest, there may still be a variety of impurities present in the solution, including process chemicals, endotoxins, host cell proteins (HCPs), host cell DNA, viruses, bacteria and mycoplasma. The presence of these impurities is undesirable for the final drug product, as they may affect the stability and efficacy of the drug and also pose a risk for drug safety. For example, the presence of endotoxins, which are a major component of the outer membrane of gram-negative bacteria, can cause severe side effects in patients. Even very low concentrations of endotoxins can result in fever, septic shock and potentially death (Mack et al., 2014). HCPs are proteins other than the desired protein product produced by the host cells in culture, and have the potential to induce an immune response in patients if not removed (Li, 2017). HCPs can also have an impact on the quality of the drug, as they have been demonstrated to lead to aggregation of the desired therapeutic protein and also to affect the stability of the drug (Robert et al., 2009). Insufficient removal of impurities can have a major impact on patient safety and also implications for the company. For example, viral contamination forced the closure of a Genzyme plant in 2009 (Bethencourt, 2009). Therefore the removal of these and other impurities from the harvest solution is extremely important and as such strict regulations are in place to ensure high levels of protein purity in biopharmaceutical products.

This project investigates viruses, HCPs, and other impurities and their potential impacts on drug safety and efficacy. As these impurities all pose problems to the final drug product, their removal is of utmost importance to the biopharmaceutical industry and so a wide range of techniques have been developed. This project will examine the different techniques utilized for removal of process impurities, such as depth filtration, affinity chromatography, ion-exchange chromatography and detergent-mediated inactivation, amongst others (Van Reis and Zydney, 2001; Goey, Alhuthali and Kontoravdi, 2018). The project discusses which techniques are best suited to removal of each of the impurities and proposes a strategy for effective removal impurities in a downstream processing plant.

Aims

The aim of this project is to investigate the effects of the various impurities that can be found in a downstream processing system and to research the best techniques for removal of these impurities. The project aims to propose an optimal clearance plan for a bioprocessing plant and suggest areas where improvements may be made in the future. The project also aims to examine the impact of protein purification on the overall cost of the bioprocess.

Methods

Databases such as Pubmed, EMBASE, BioPharm International and ScienceDirect were searched for relevant literature, selecting the most recent and appropriate publications where possible. I will also consult ICH and FDA legislation for appropriate guidelines for protein purification standards. Impurity removal techniques will be compared on the basis of cost, efficacy and specificity.

Discussion

Harvest and Clarification

Downstream processing usually begins with harvest of the product and the removal of cells and cellular debris from the harvest solution (Kalyanpur, 2003). Although the cells were an essential part of the upstream process, and used to produce the protein product, they must now be removed before further product clarification. Chinese Hamster Ovary (CHO) cells are the most commonly utilized cell line in the biopharmaceutical industry, as they are well characterized and undergo post-translational modifications such as glycosylation (Butler and Spearman, 2014). These cell cultures are observed carefully at all times for several parameters including cell density, nutrient concentration, pH and dissolved oxygen (DO) content. CHO cells being used today originated from parent cells which were isolated in 1957, before being immortalized and subsequently generated into many CHO clones (Beckmann et al., 2012). Generation of a new cell line commences with an initial sample of tissue, which is cultured and typically immortalized. For production of biopharmaceuticals, a cell line will often be genetically engineered in order to produce a therapeutic, before generation of the Master Cell Bank (MCB). If the culture is successful, the group will publish an “establishing paper”, and the cell line can be shared or sold on to other groups (Horbach and Halffman, 2017). Ideally, authenticated cell lines should be purchased from a reputable source, for example The American Type Culture Collection (ATCC), to minimise risk of contamination with mycoplasma (Nübling et al., 2015) .

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Cells and cellular debris must be removed from the solution in order for the product to be subsequently captured using chromatography (Shukla and Kandula, 2008). The most common strategy is cell removal using centrifugation, followed by clarification using filtration. Centrifugation is a technique based on the fact that heavier particles will be deflected further than lighter, less dense particles, after subjection to centrifugal force. Disk-stack centrifugation is the most commonly used method of centrifugation for the removal of cells in the biopharmaceutical industry, and takes advantage of the fact that the cells and cell debris are far heavier than the desired protein. Disk-stack centrifuges allow for continuous operation and low operating costs when compared to filtration and chromatography (Majekodunmi, 2015). Careful optimisation of process steps, such as rotation speed and flow rate, are required for optimal separation. A longer residence time in the centrifuge bowl generally leads to better separation, but will have a negative impact on process run time. A further consideration is the nature of the “flush fluid” which is used before discharge of contents from the bowl – if there is a significant osmotic difference between this fluid and the culture broth, it may result in cell lysis, releasing HCPs, cell debris or proteases, all of which can have a negative impact on product quality (Shukla and Kandula, 2008). Downstream processes commonly include a depth filtration (DF) step following centrifugation, as centrifugation is unable to efficiently remove all particles (Singh et al., 2013). DF uses a porous medium which can retain particles from the mobile phase all through its matrix, as opposed to just on its surface, allowing them to remove particles with high efficiency.

Tangential flow microfiltration can also be used to separate cells from the culture broth. Tangential flow filtration (TFF) is a form of filtration where the flow stream passes parallel to the membrane, while the permeate passes through the membrane, and the retentate is recirculated back into the feed stream (Grzenia, Carlson and Wickramasinghe, 2008). TFF has the advantage over centrifugation of efficiently removing all cells and particles from the solution and thus eliminating the need for addition of a depth filtration step. However filter blocking is a common problem, resulting from layers of polarised particles on the membrane surface, as is the issue of membrane “fouling” or decline in flux through the membrane (Bhave, 2014). As a result, filters must be regularly replaced or cleaning, meaning that this method is significantly more expensive and time consuming than centrifugation, and may be more suited to small scale operations. Cleaning and cleaning validation of disk-stack centrifuges is also more straightforward and cost efficient, as TFF systems’ flow paths allow for the possibility of dead legs, which could harbour bacteria and growth of biofilms (Yavorsky et al., 2003). Therefore, I believe that the strategy of using a centrifugation step followed by DF is more suitable for removal of cells from the BDS than TFF.

Host cell proteins (HCPs)

As mentioned above, biotherapeutics are produced using host cells, with CHO cells being the most common expression system for mAbs, which make up the majority of biopharmaceuticals. These cells are crucial for production of the therapeutic protein, however they also express a variety of their own proteins, known as HCPs (Li, 2017). HCPs comprise a large class of process-related impurities that need to be removed during purification. Even a low level of HCP contamination can affect the safety and efficacy of biopharmaceuticals and so regulations recommend a final purity of 4.6 and should be included where possible in viral reduction strategies. Some therapeutic products are unable to tolerate low pH conditions, and in these cases inactivation by solvent/detergent is employed (Shukla and Aranha, 2015). Commonly used solvents and detergents include Triton X100, Tween 80 or tri-n-butyl phosphate (TNBP). These chemicals must subsequently be removed from the protein solution, and so this step should be performed at the early stages of downstream processing, so further steps will be able to clear the solvents and detergents (Hellstern and Solheim, 2011). These chemicals may also interfere with some subsequent steps, however methods such as IEX and Protein A chromatography are quite resistant to interference from solvents and detergents, and so are good choices for further viral reduction steps

Endotoxins: Properties and removal

As mentioned previously, even minute concentrations of endotoxins can have severe risks for patient health, and so their removal from biotherapeutic products is critical. Endotoxins or lipopolysaccharide (LPS) make up a major portion of gram-negative bacteria’s cell walls (Beutler and Rietschel, 2003). Endotoxins are composed of an O-antigen, a non-polar lipid component (Lipid A), and a core oligosaccharide, as shown in Figure 2. Lipid A has been shown to be responsible for the pathogenic activities of endotoxins, including shock, fever, hypotension and sepsis (Mack et al., 2014). Sepsis is a systemic immune response to LPS which activates a range of pro-inflammatory cytokines, including TNFα, IL-1β and IL-6. A major issue with the removal of endotoxins from harvest solutions is their stability. Endotoxins can withstand high temperatures (180-250OC required to destroy endotoxin) and harsh pH, which would not be tolerated by the target protein (Petsch and Anspach, 2000). Therefore, alternative removal strategies must be implemented for endotoxins.

A variety of techniques are employed for endotoxin removal, including AEX chromatography and filtration, which would be beneficial for a mAb producing bioprocess, as these techniques can also remove other impurities such as HCPs and viruses as discussed previously. The use of detergents coupled with affinity chromatography and phase separation is another common method for endotoxin removal. The properties of the individual therapeutic protein must be considered when deciding on an effective endotoxin removal strategy. While ultrafiltration is an effective method for removing endotoxin from water, it may not be suitable for purifying protein solutions which are sensitive to physical force (Pyo et al., 2001). Two-phase micellar systems have been demonstrated to be effective at endotoxin removal (de Oliveira Magalhães et al., 2007). These systems involve an aqueous surfactant solution, for example, Triton X, which will spontaneously separate into two distinct and immiscible liquid phases (TANI, KAMIDATE and WATANABE, 2005). One of the liquid phases has a higher micelle concentration than the other, and this physiochemical difference allows for the basis of a separation technique. The separation is based on excluded-volume interactions between molecules (endotoxins in this case), and non-ionic surfactant micelles. The micelle-rich phase has stronger excluded-volume interactions between its micelles and the endotoxin molecules, resulting in the endotoxins being driven into the micelle-poor phase (Petsch and Anspach, 2000). Endotoxin molecules can be taken into the micelles via non-polar interactions of Lipid A alkyl chains, and the tail groups of the detergent, allowing for separation by centrifugation, making this a useful method for endotoxin removal.

Conclusions

Removal of impurities is one of the major goals of downstream processing. It is critical to ensure that any impurity, which may impact on product quality or patient safety, is efficiently removed from the final product. This project examined the effects and removal strategies for cells, HCPs, viruses and endotoxins. Other impurities, such as media components, cell waste products and mycoplasma, must also be considered when designing a downstream process, as well as detection methods for each impurity. A proposed workflow for a downstream process to efficiently remove the impurities discussed in this report is provided in Figure 3. Some steps, such as Protein A affinity chromatography, can be used to remove several impurities, providing a cost-efficient solution for bioprocessing.

Although recent advancements in filtration and chromatographic techniques have allowed for better removal of impurities, improvements are still required. Further advancements in genetic engineering may give rise to new impurities in the harvest solution, or alterations to existing ones which may require alternative removal strategies. Newly introduced viruses may have different properties that are not captured by current methods, and the same may occur with mutations in bacteria or HCPs. At present there is a drive towards implementing “quality by design” (QbD) in the biopharmaceutical industry. QbD involves building quality control into the manufacturing process as opposed to subsequent testing (Goey, Alhuthali and Kontoravdi, 2018). The QbD process identifies and characterizes critical quality attributes (CQAs) for each product/process. Mathematical modelling and Design of Experiments (DoE) are used to produce a “design space” which can offset variability from inputs (ICH Expert Working Group, 2008). It may be advantageous to implement QbD for impurity removal systems in the biopharmaceutical industry, and prevention of introduction of impurities.

As the biopharmaceutical industry continues to grow, and improvements in upstream processing continue to be made, it is vital to continue efforts to improve efficiency of downstream processing to deal with this increased load, and reduce “bottlenecks” at the downstream stage, while also ensuring maximal removal of impurities from the therapeutic protein.

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