The Application of Membrane Separation Technology in the Pharmaceutical Industry

With the advancement in membrane technology, membrane separation technology has been found increasingly widespread applications in the pharmaceutical industry. It is utilized in drug separation and purification, wastewater treatment, and the recycling of wastewater resources. This study summarizes the application history of membrane technology in the pharmaceutical industry, presents practical engineering examples of its applications, analyzes the various types of membrane technologies employed in the pharmaceutical sector, and finally, highlights the application cases of renowned international and Chinese membrane technology companies in the pharmaceutical field.


Introduction
Membrane technology has undergone a long, historical development in laboratory research and achieved its first major industrial application in the 1960s [1].Membrane is a kind of material with a selective separation function, and can transfer one component and restrict others because of the special properties of the components [2].The main membrane technologies include microfiltration, ultrafiltration, nanofiltration, reverse osmosis, pervaporation, electrodialysis, and membrane bioreactors [3].Membrane separation technology has unique advantages such as a high efficiency, wide applicability, and minimal environmental impact [2].With a rapid development over the past few decades, membrane separation technology has become one of the emerging technologies and has been used in numerous industrial sectors.
With the rapid development of membrane technology, the application of membrane separation technology in the pharmaceutical industry is becoming increasingly widespread.Researchers have found extensive applications in pharmaceutical processes such as drug purification, wastewater treatment, and wastewater resource utilization [4,5].The scientific and reasonable applications of membrane separation technology in the pharmaceutical field can improve production efficiency, ensure the progressiveness of pharmaceutical processes, reduce pollution, and promote the pharmaceutical industry's development towards a greener, environmentally friendly, and highly efficient direction.
This study presents a comprehensive review on the application of membrane separation technology in the pharmaceutical industry.The application history of membrane technology in the pharmaceutical industry is summarized, and the practical engineering cases are presented.The various types of membrane technologies employed in the pharmaceutical sector are analyzed.The application cases of renowned domestic and international membrane technology companies in the pharmaceutical field are introduced.Conclusively, existing challenges and prospects of membrane separation technology within the field of pharmaceutical industry are identified.

History of Membrane Technology Application in the Pharmaceutical Industry
The application of membrane technology in the pharmaceutical field originated with the preparation of pharmaceutical-grade water.In 1972, GOW from the UK used cellulose acetate reverse osmosis membranes to produce pyrogen-free water [6].Following this, in 1974, the U.S. pharmaceutical company Upjohn employed Dupont-produced, aromatic polyamide hollow fiber, reverse osmosis membrane modules to manufacture injectable water, meeting regulatory standards for injection water [7].The 19th edition of the U.S. Pharmacopeia in 1975 introduced membrane methods for injectable water production, challenging the traditional belief in the reliability of distillation alone [8].In the 1980s, membrane technology gradually extended to the purification and production of pharmaceuticals.Millipore, in the early 1980s, applied a combination of membrane filtration techniques to separate and refine cephalosporin C from fermentation broth [9].In 1983, an ultrafiltration system developed by Japan's Asahi Chemical Industry was reported, which used hollow fiber membranes for drug purification [10].Subsequently, membrane materials like hollow fiber, ultrafiltration, and reverse osmosis membranes were applied for the extraction of antibiotics, vitamins, and proteases [11][12][13][14].
Since entering the 21st century, membrane separation technology has been gradually used in pharmaceutical wastewater treatment.A sewage treatment plant in Queensland used microfiltration and reverse osmosis technology to treat eleven kinds of drugs and two kinds of endocrine disruptors from different treatment categories.The results showed that the microfiltration and reverse osmosis systems can reduce the concentration of pollutants by an order of magnitude, and the overall removal efficiency of the circulating water is higher than 97% [15].In addition, researchers proposed combining membrane separation technology with biological treatment units for pharmaceutical wastewater treatment [16][17][18].After 2011, membrane technology in the pharmaceutical industry underwent a rapid development, with a surge in applications post-2016, notably focusing on the removal of pharmaceuticals, hormones, endocrine disruptors, and antibiotic resistance genes from wastewater [19].An overview of the international application history of membrane technology in the pharmaceutical industry is depicted in Figure 1.In the 1970s, membrane technology was primarily employed for pharmaceutical-grade water preparation.Moving into the 1980s and 1990s, this transitioned towards drug purification and production.After entering the 21st century, there was a notable shift towards utilizing membrane technology for pharmaceutical wastewater treatment.
Membranes 2024, 14, x FOR PEER REVIEW 3 of 14 to concentrate the decolorization solution of streptomycin sulfate [9].In 1994, the NFB series plate-type reverse osmosis device from the Penglai reverse osmosis equipment factory was successfully applied in streptomycin production at Jining Antibiotic Factory, demonstrating an improved quality, higher yield, and reduced energy and material consumption [24].In 1999, Santar Membrane achieved a breakthrough in the crucial technology for cephalosporin production, developing a membrane separation-based process for 7-ACA production [25].In 2000, Northeast Pharmaceutical General Factory utilized Ultra-Flo ultrafiltration membrane systems for the removal of impurities in a vitamin C fermentation broth, showing the potential of the membrane separation technology in shortening production processes, reducing costs, and increasing yields [26].Subsequently, the application of membrane separation technology expanded to the production of other antibiotics like erythromycin and penicillin [27,28].After entering the 21st century, with the rapid development of membrane technology, membrane separation techniques were further applied to the treatment of pharmaceutical wastewater.Since 2010, membrane bioreactor technology has been widely employed for pharmaceutical wastewater treatment, realizing multiple engineering applications as indicated in Table 1.
The Chinese journey of membrane technology in the pharmaceutical industry, as illustrated in Figure 2, shows its evolution from the 1960s to 1970s primarily in pharmaceutical-grade water preparation to its gradual application in traditional Chinese medicine extraction in the 1980s, antibiotic production in the 1990s, and eventually, wastewater treatment in the 21st century.In China, the application of membrane technology in the pharmaceutical industry could be traced back to the 1960s.The Institute of Health Devices of the Academy of Military Medical Sciences (IHDAMMS) developed electrodialysis pure water equipment that uses multistage processes combined with pretreatment technologies of raw water to directly treat Tianjin tap water into injection water that meets pharmacopoeia standards [20].In the late 1970s, with the advancement of membrane technology, the IHDAMMS began researching the use of reverse osmosis to produce pharmaceutical-grade water [21].By the 1980s, membrane separation technology was also applied to the extraction of traditional Chinese medicines.In 1979, the pharmacy bureau of the PLA Air Force Beijing Hospital utilized membrane separation technology for the extraction of effective components from traditional Chinese medicines, demonstrating the efficacy of ultrafiltration in removing impurities while retaining the main constituents [22].In 1981, they further utilized this method to prepare traditional Chinese medicine injections [23].In the late 1990s, membrane technology found its application in antibiotic production.In 1989, Dalian Pharmaceutical Factory introduced Danish DDS sanitary reverse osmosis membrane equipment to concentrate the decolorization solution of streptomycin sulfate [9].In 1994, the NFB series plate-type reverse osmosis device from the Penglai reverse osmosis equipment factory was successfully applied in streptomycin production at Jining Antibiotic Factory, demonstrating an improved quality, higher yield, and reduced energy and material consumption [24].In 1999, Santar Membrane achieved a breakthrough in the crucial technology for cephalosporin production, developing a membrane separation-based process for 7-ACA production [25].In 2000, Northeast Pharmaceutical General Factory utilized Ultra-Flo ultrafiltration membrane systems for the removal of impurities in a vitamin C fermentation broth, showing the potential of the membrane separation technology in shortening production processes, reducing costs, and increasing yields [26].Subsequently, the application of membrane separation technology expanded to the production of other antibiotics like erythromycin and penicillin [27,28].After entering the 21st century, with the rapid development of membrane technology, membrane separation techniques were further applied to the treatment of pharmaceutical wastewater.Since 2010, membrane bioreactor technology has been widely employed for pharmaceutical wastewater treatment, realizing multiple engineering applications as indicated in Table 1.The Chinese journey of membrane technology in the pharmaceutical industry, as illustrated in Figure 2, shows its evolution from the 1960s to 1970s primarily in pharmaceuticalgrade water preparation to its gradual application in traditional Chinese medicine extraction in the 1980s, antibiotic production in the 1990s, and eventually, wastewater treatment in the 21st century.

Application of Membrane Technology in the Pharmaceutical Industry
The application of membrane technology in the pharmaceutical industry primarily encompasses microfiltration, ultrafiltration, nanofiltration, reverse osmosis, membrane bioreactors, electrodialysis, osmosis, osmotic vaporization, and combined processes.These membrane technologies are mainly used for pharmaceutical production, wastewater treatment, and wastewater product recovery, as shown in Table 2.
Microfiltration is the earliest membrane technology.The separation mechanism of microfiltration is sieving with a membrane pore size of 0.01-1 µm, which can allow macromolecular organic compounds and dissolved solids to pass through [2].It is mainly used to intercept particles, bacteria, and pollutants from the liquid or gas phase to achieve the purposes of purification and bacteria removal [48].In the pharmaceutical industry, microfiltration is mainly used for sterilization filtration, clarification of pharmaceutical solutions, removal of particles and viruses, purification of medical water, and pretreatment of ultrafiltration and reverse osmosis processes [49].Among them, a microfiltration membrane with a pore size of 0.6-0.8µm can be used for the removal of bacteria and the filtration of gases.A microfiltration membrane with a pore size of 0.45 µm is the most commonly used, often used for the purification of liquid material and water, and a microfiltration membrane with a pore size of 0.2 µm can be used for the sterilization filtration of liquid medicine [49].
Ultrafiltration is a kind of membrane filtration method with a molecular level membrane having a pore size of 10-100 nm.It uses the pressure difference on both sides of the membrane to selectively separate solutes with different molecular weights.In the pharmaceutical industry, ultrafiltration can not only be used to remove bacteria, viruses, and particles, but also pyrogens, hyphae, and proteins.It is often used for the fractionation and desalting concentration of macromolecular substances, the purification of small molecular substances, and the depyrogenation of pharmaceutical and biochemical preparations [50].
Nanofiltration is a membrane separation process between ultrafiltration and reverse osmosis, with a membrane pore size of 1-10 nm.The separation mechanism of nanofiltration is adsorption-diffusion.In the pharmaceutical industry, nanofiltration can be used for clarification, sterilization, filtration, protein removal, and the separation and purification of fermentation broths such as those for antibiotics, vitamins, amino acids, and enzymes [51].It can also be used for the desalination and concentration of 6-APA, 7-ACA, 7-ADCA, and other semisynthetic antibiotics [49].
Reverse osmosis is also a membrane filtration process driven by pressure.The pore size of a reverse osmosis membrane is less than 1 nm, and its function is to intercept ionic substances that only pass through the solvent.The organic and inorganic molecules are separated from the feed solution through a solution diffusion process [52].In the pharmaceutical industry, reverse osmosis is mainly used for drug concentration, purification and separation, desalination, preparation of water for preparation, water for injection, dialysis water, and sterile water [50].
Membrane bioreactor is a new wastewater treatment technology that combines membrane separation technology with biological treatment [53].This technology adopts an immersion membrane component with a unique structure that is placed in an aeration tank.After aerobic aeration and biological treatment, the wastewater is pumped through a filter membrane and then pumped out [54].In the pharmaceutical industry, membrane bioreactors are often combined with other technologies for the treatment of pharmaceutical wastewater [55].Pall Life Sciences comprises three divisions: biopharmaceutical, medical, and food and beverage.The biopharmaceutical department provides equipment and consumables for the entire process, from laboratory research and development to pilot testing and large-scale production.It is the only company in the world with a full line of pharmaceutical process fluid technologies.Pall first introduced the P grade (pharmaceutical grade) standard into the production of pharmaceutical filters, which has been widely adopted by the pharmaceutical industry.At the same time, Pall is the preferred filter supplier of GSK, Baxter, Frensenius, and other well-known pharmaceutical companies in the world.

Novasep (France)
Novasep is a company dedicated to the downstream separation and purification process solutions for the life science industry.Based on its core technologies such as the high-performance chromatography separation technology and crossflow membrane filtration technology, Novasep has developed a series of new production processes with low operating costs and environmental protection in the fields of medicine, food, bioengineering, dairy products, and starch deep processing.It has been used by thousands of companies in more than 50 countries around the world.
Novasep offers a wide range of services to the pharmaceutical industry.The company can provide competitive development and manufacturing solutions for the synthesis and purification of APIs, highly active APIs, and intermediates through a variety of flexible equipment, technical expertise, and advanced process capabilities.Novasep is a premium supplier in specific fields such as hazardous reactions, cytotoxic compounds, highly active pharmaceutical ingredients, low-temperature reactions, coupled reactions, etc.It can also carry out the production of various nonpatented pharmaceutical ingredients and intermediates such as nitroglycerin, paclitaxel, and omega-3.

Millipore (USA)
Millipore was founded in 1954 and mainly produces filter membrane and membrane filtration products.Milipore's products can be divided into four major categories based on their application scope: laboratory pure water, life sciences, membrane technology, and bioengineering and pharmaceuticals.In the field of bioengineering and pharmaceuticals, Millipore can provide pharmaceutical companies with various specifications for filtration, ultrafiltration, reverse osmosis systems, chromatography systems, chromatography columns, and chromatography fillers for the clarification, separation, purification, and concentration of pharmaceutical and biological products and the removal of bacteria, pyrogens, and viruses from the final product.In July 2010, the German Merck Group successfully acquired the American company Millipore and established a new division: Merck Millipore.Merck Millipore is a new division of the Merck Group and is dedicated to the field of life science, with more than 40,000 kinds of products, basically covering all aspects of life science research, drug development, and production.Merck Millipore has thus become one of the three major suppliers of life science products in the world.

Santar Membrane
Santar Membrane (Xiamen, China) is a pioneer in the field of membrane technology development and application in China.As early as the 1990s, Santar Membrane began to engage in the development of advanced membrane separation application technology in China and introduced foreign advanced membrane technology into China and carried out large-scale industrial applications.In 1998, Santar Membrane successfully developed a vitamin C production process based on membrane separation, realizing the dream of China's leading position in vitamin C production technology.In 1999, Suntar Membrane broke through the major key technology of cephalosporin production, and successfully developed the production process of 7-ACA based on the membrane separation process.Santar Membrane is one of the first enterprises to promote the application of nanofiltration technology in the pharmaceutical industry in China and is also one of the first enterprises to apply ultrafiltration, nanofiltration, and continuous separation technologies to the production of vitamin C, penicillin, and 7-ACA in China.At present, Santar Membrane is widely used in the production of vitamins, antibiotics, traditional Chinese medicines, and biological products.Typical engineering cases for the application of Santar Membrane in the pharmaceutical industry are shown in Table 3. Jiangsu Jiuwu High-tech Co., Ltd.(Nanjing, China) is the main pioneer of the ceramic film industry in China.Focusing on the development and application of membrane materials such as ceramic membranes and membrane separation technology, it is a wellknown membrane industry enterprise with independent intellectual property rights.In the pharmaceutical field, Jiangsu Jiuwu High-tech Co., Ltd. has rich application experience in the separation and purification of antibiotics and the extraction of traditional Chinese medicines.In 2000, Jiangsu Jiuwu High-tech Co., Ltd.successfully applied the first set of threonine extractions in theindustry in China.In 2004, this company successfully applied the first set of ceramic membrane in the cephalosporin antibiotic extractions in China.Subsequently, Jiangsu Jiuwu High-tech Co., Ltd.successfully applied ceramic membranes to antibiotic production enterprises such as cephalosporins, erythromycin, and vancomycin, as well as to enzyme and pharmaceutical intermediate production enterprises.At the same time, this company has also successfully applied the ceramic membrane to the extraction of traditional Chinese medicines such as Rhodiola, Isatis indigotica, Salvia miltiorrhiza, and Pueraria lobata.The typical engineering cases of Jiangsu Jiuwu High-tech Co., Ltd. in the pharmaceutical industry are shown in Table 4. Hangzhou Qiushi Membrane Technology Co., Ltd.(Hangzhou, China) is one of the largest suppliers of membrane products in China, specializing in the research and development, production, sales, and technical services of all kinds of ultrafiltration membrane, and is one of the largest manufacturers of PVDF membrane and PP membrane in China.The applications of Hangzhou Qiushi Membrane Technology Co., Ltd. in the pharmaceutical industry mainly include the separation of fermentation liquid and the treatment of phar-maceutical wastewater.The typical engineering cases of this company's applications in the pharmaceutical industry are shown in Table 5.

Conclusions and Prospect
Membrane technology provides a feasible alternative to conventional separations, purification, and wastewater treatment in pharmaceutical processing.It has been widely used in drug production, pharmaceutical wastewater treatment, and wastewater recycling.The high efficiency of membrane technology provides an alternative for pharmaceutical production.The economic feasibility and advancement of MBR technology provide a better option for the treatment of pharmaceutical wastewater over the traditional methods [4].However, the application of membrane technology is still limited with the main drawback of membrane fouling [4].With the continuous progress of membrane technology, it will inevitably become more advanced and perfect.The pharmaceutical industry should continuously introduce the most advanced membrane separation technology and develop its new applications, so as to maximize its advantages in the pharmaceutical field and promote the sustainable development of the pharmaceutical industry.

Figure 1 .
Figure 1.International application history of membrane technology in the pharmaceutical industry.Figure 1.International application history of membrane technology in the pharmaceutical industry.

Figure 1 .
Figure 1.International application history of membrane technology in the pharmaceutical industry.Figure 1.International application history of membrane technology in the pharmaceutical industry.

Figure 1 .
Figure 1.International application history of membrane technology in the pharmaceutical industry.

Figure 2 .
Figure 2. Chinese application history of membrane technology in the pharmaceutical industry.Figure 2. Chinese application history of membrane technology in the pharmaceutical industry.

Figure 2 .
Figure 2. Chinese application history of membrane technology in the pharmaceutical industry.Figure 2. Chinese application history of membrane technology in the pharmaceutical industry.

4 .
Development of Membrane Technology and Its Application in the Pharmaceutical Industry by International Membrane Technology Enterprises 4.1.Pall Corporation (USA) Pall Corporation was founded in New York in 1946.It specializes in the research of fluid purification and separation technologies and the production of filtration systems.Pall Corporation is the world leader in fluid filtration technology.Pall's products are widely used in water treatment, and in biomedical, aerospace, petrochemical, food and beverage, metallurgical power, and microelectronics industries.Pall is the world's largest filtration, separation, and purification company, involving the most extensive fields.

Table 1 .
Engineering cases of membrane technology applications in the pharmaceutical industry.

Table 2 .
Application of different process types in the pharmaceutical industry.

Table 3 .
Typical engineering cases of Santar Membrane in the pharmaceutical industry.

Table 4 .
Typical engineering cases of Jiangsu Jiuwu High-tech Co., Ltd. in the pharmaceutical industry.

Table 5 .
Typical engineering cases of Hangzhou Qiushi Membrane Technology Co., Ltd. in the pharmaceutical industry.