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Introduction to the Manufacturing of Biologics Introduction to the Manufacturing of Biologics

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Introduction to the Manufacturing of Biologics Introduction to the Manufacturing of Biologics HEALTHCARE TRENDS Introduction to the manufacturing of biologics Introduction to the manufacturing of biologics Ditte Funding, Blue Latitude Health The last decade has seen the rapid growth of biologics in the pharmaceutical market, making them a key sector to watch in the coming years. Biopharma made up 22% of big pharma companies’ sales in 2013, with this number being expected to rise to 32% of sales by 2023. With the growing popularity of these products, it’s important to understand the opportunities and threats they present to pharma companies. Associate Consultant Ditte Funding takes us “Biologics present great value as they are through how biologics are made, what makes highly specific molecules that tend to them unique, and what it all means for pharma target more difficult to treat populations; companies. it seems that biologics may become What is a biologic? a primary tool for targeting hitherto Before looking at how to manufacture them, it’s untreatable diseases.” important to first understand what a biologic is. However, in order for biologics to be widely The definition of a biologic isn’t always clear, used treatments in the future, they must be and what’s considered a biologic is constantly manufactured at the right cost and the right scale. being updated and tweaked as new products are introduced to market. However, the broad Introduction to the manufacturing process: why definition of a biologic is they are created by either is it unique and complex? a microorganism or a mammalian cell, and are Biologics are much harder to manufacture than large, complex molecules; the majority of which chemical drugs as they are extremely sensitive. are proteins or polypeptides. Examples of biologics Their immunogenicity, adverse events, and efficacy include blood or blood products, gene therapies, can all by affected by even the slightest process vaccines, and cell therapies. change because a biologic is defined by its process. There is a significant distinction that As such, the manufacturing process has to be needs to be made between traditional small carefully designed and closely monitored at every molecule pharmaceuticals (such as aspirin), step in order to ensure correct product identity. and biopharmaceuticals. Biologics differ from This makes it extremely expensive. For example, small molecule drugs in their cost, production, it costs $200 – 500 million to build a large-scale administration, and clinical efficacy. Small molecule biotech facility versus $30 – 100 million to build drugs are usually chemically synthesised, simple, a small molecule facility. and have a very well-defined structure. Whereas To highlight the complexity of manufacturing biologics, or large molecule drugs, are difficult to even further, there are key metrics that the process define and characterise. must meet. Is the end purity high enough? If the 2 bluelatitude.com product is going into a human, it needs to be 99.9% The manufacturing of biologics is highly specific. pure at the end. Is the process robust? Meaning, It requires a lot of very skilled technicians defining do you get the same output when you run it the process steps with very precise parameters and first time as the hundredth time? Is the process operating expensive equipment. However, economically viable? the complexity of the process also gives pharma The process engineer designing the process companies some security as it is extremely difficult will often have to design it very early in the for competitors to recreate the process and development stages. They work under a tight impossible for them to manufacture an identical time frame with a lot of uncertainty in order to biologic. [see page 4] get to market as soon as possible. Under these What does this mean for pharma companies? circumstances, the process often ends up being The complexity of the manufacturing process the first workable solution, rather than the has a significant impact on pharma companies perfect solution. developing biologics. With biopharma growing Once a process has been decided, it is extremely at 8% per year, double that of conventional pharma, difficult and costly to change. This introduces yet it is now a significant area of growth for most another complexity unique to the manufacturing of pharma companies. biologics: it’s extremely difficult to scale up or scale The manufacturing process affects our clients’ out. This means that it’s challenging to change the competitive advantage, impacting the selling price, volume of product produced once the process has profit margin, and time to market. As illustrated in been designed and the manufacturing plant built. the diagram below, manufacturing influences the This makes accurately predicting the market share whole development process of a biologic from early on incredibly important - it is expensive to pre-clinical to market. have equipment sitting idle, but you also don’t want to have a supply shortage. Preclinical Phase I Phase II Phase III Market Manufacturing and logistics Decisions Constraints Uncertainties • Portfolio size • In-house vs. • Budget • Time • Clinical • Market and structure third party • Manufacturing • Regulatory performance performance • Timing of • Process capacity requirements • Technical activitities design • Personnel performance The impact on marketing and the BLH approach determining the most successful marketing strategy. BLH has worked on biologics across therapy The complexity of the manufacturing process areas. Our understanding of process engineers is both one of the largest competitive advantages developing workable yet limited solutions has for our clients, as it is difficult for competitors tailored our approach to biologics. to replicate a process, as well as one of the When working with a biologic, it’s impossible biggest challenges. Remembering to consider to ignore the manufacturing process. It feeds into manufacturing when developing brand strategies determining the launch strategy, understanding for biologics ensures the creation of more robust the competitive market, and the threats posed to and bespoke plans. For more on how we can help established products. An awareness of the strengths your brand tackle these challenges, get in touch and weaknesses the process presents is essential when with us at [email protected]. ■ 3 bluelatitude.com Manufacturing of Biologics An overview of a typical process WORKING CELL BANK MASTER CELL BANK 1. Fermentation increase in cell biomass and mAB expression upstream processing CENTRIFUGE PROTEIN A CEX CHROMATOGRAPHY CHROMATOGRAPHY FILTER 2. Primary recovery 3. Capture 4. Polishing removal of cells and cell debris highly purified product removal of product/process prior to chromatography in one step related impurities FORMULATION AEX CHROMATOGRAPHY FILTER 5. Formulation downstream preparing final, formulated processing bulk drug substance Key process impurities Constant process considerations • Host cell protein • Flow rate • Aggregates • pH • DNA • Temperature • Cell Debris • Media • Good manufacturing processes is a regulatory requirement • Cleaning of the of equipment after each batch yield • Purity - contaminants 4 bluelatitude.com.
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