(Original title: Continuous manufacturing, subverting new technologies in the future pharmaceutical industry?)
[China Pharmaceutical Network Technology News] "The pharmaceutical industry's acceptance of new technologies is very slow and has been decades later than other industries." FDA former director Margaret Hamburg said during a visit to the Vertex Pharmaceuticals plant. It is reported that continuous manufacturing technology, also known as the advanced manufacturing technology of the pharmaceutical industry, may subvert the future pharmaceutical industry, which is becoming a new focus of the future technological competition and industrial protection of the pharmaceutical industry, and has the opportunity to become the key to the new era. Academics, industry and regulators are conducting large-scale research, experimentation, practice and thinking on this new technology topic.
"Continuous" is no longer new
As early as 1900, before the Industrial Revolution, the earliest continuous manufacturing prototype appeared, which was used in the smelting of pig iron. The ore, fuel and flux are continuously filled into the blast furnace, continuously contacting the molten pig iron and slag, removing the chemical reaction of silicon and silicon oxidation while continuously occurring in the furnace. With the development of modern technology, the manufacturing industry has realized continuous manufacturing in various forms. Currently, common continuous processes include: petroleum refining, basic chemicals, synthetic fibers, fertilizer processing, pulp and paper, metallurgical refining, natural gas processing, and water treatment. , float glass, etc. Involving processing technology and industrial investment structure, the pharmaceutical industry and chemical oil have great differences, but in recent years, with the advancement of control technology, the “neighbor industry†food industry has gradually moved toward the stage of continuous manufacturing, and the pharmaceutical industry has its product characteristics. And the uniqueness of the regulatory environment, but in contrast, in the processing and control technology, the pharmaceutical industry is still slightly inferior to other manufacturing industries.
The pharmaceutical industry's exploration of continuous manufacturing has never stopped. In the early 1990s, in order to circumvent the problems brought about by the process, Germany had registered patents for continuous granulation and continuous drying, and tried to put into production. At that time, the continuous synthesis technology in the chemical plant also led to the “semi-continuous†processing process of many raw material pharmaceutical factories. Around 2000, online cleaning and online sterilization technologies continued the transition of pharmaceutical production to online. Around 2010, the embedded control and monitoring methods of online control and monitoring methods developed rapidly. The QbD concept also allowed the modeling and forecasting and experimental design methods to better integrate the regional pharmaceutical production process. Today, it is no accident that the FDA to the Wall Street Journal, from the industry to the academic world, to mention the "continuous manufacturing" of drugs.
From "Batch" to "Flow"
Taking tablet production as an example, the basic unit operation of the traditional production method is shown in Figure 1. The outstanding features are:
The material/product is collected after each unit operation and transferred to the next unit operation (in fact, some equipments are currently capable of semi-continuous manufacturing of certain unit operations, such as partial granulation and tableting operations).
The final formulation was tested in an off-line laboratory after all operations were completed.
Actual production time (per batch) = several days to several weeks
1) Material/product continues to flow between each unit operation
2) Real-time monitoring during production
3) Fine tuning of the entire process based on online test results and evaluation
4) Actual production time = several minutes to several hours
Current research and practice progress
Although the enthusiasm for continuous manufacturing in Europe and the United States has been burning for a long time, there are only a handful of companies that have made real progress.
1) Vertex:
Vertex is the first company to declare a continuous manufacturing formulation, spending $30 million in the Boston area to build a 4,000-square-foot (372-square-meter) continuous manufacturing facility to support this continuous manufacturing process. Application for the treatment of cystic fibrosis drugs.
2) Novartis- MIT:
Novartis has signed a 10-year, $65 million investment with MIT, a top-notch engineer, to combine the experience of Novartis scientists in production with the help of MIT laboratory doctoral, postdoctoral, researcher, and professors. Joint development and research in engineering, process and control. At present, MIT's pilot laboratory has completed its mission, and Novartis has built a “tennis court size†continuous manufacturing facility in Switzerland for the development and production of fully continuous end-to-end tablets from starting materials to preparations. .
ICT CMAC (ICT CMAC, Intelligent Decision Support and Control Technologies for Continuous Manufacturing and Crystallisation of Pharmaceuticals and Fine Chemicals) was established in 2011, sponsored by 13 scholars from 7 research institutions including Cambridge. Training and experimentation in post-doctoral, doctoral, and master's programs in chemistry, engineering, and control, and continuous manufacturing and continuous crystallization research in the pharmaceutical and fine chemical industries. In 2014, the research workshop was prepared and cooperated with a number of multinational pharmaceutical companies.
4) GSK:
Singapore's $29 million continuous manufacturing plant is scheduled to go live in 2016 and is currently focusing more on continuous or semi-continuous manufacturing of APIs, targeting the Asian market.
5) J&J:
The Johnson & Johnson facility in Puerto Rico is also in full swing for research and development and preparation for production to prepare for the FDA to issue the continuously manufactured HIV drug Prezista.
In addition, companies such as Genzyme and Amgen are also preparing to build factories and research and development.
Domestic progress: Hisun Pharmaceutical's continuous manufacturing research on immediate release tablets and Dongfulong's research on the potential of continuous production of spray freeze dryers in the aseptic core area is China's pioneer in the development of continuous manufacturing.
Potential innovation space
1. Shorten the supply chain:
This may be the topic of greatest concern to US regulators (including other US government agencies). Shortening the supply chain means not only greatly reducing the safety risks, shortage risks and regulatory burdens brought by the supply and transportation of raw materials, reducing the uncertainty and extra cost brought by the long supply chain, but also the return of the pharmaceutical industry. And the resulting return of capital.
2. Swift and flexible:
Production is fast. Significantly reduce production time and shorten production cycle. According to the estimates of the Novartis continuous manufacturing team, according to the previous order volume, (theoretically) 2-3 weeks can produce the products required for one year of orders. Of course, this advantage is tailor-made for the original drug. For the generic drug industry with large orders and instability, the inventory and consumption value brought by the rapid production in advance is also a factor that must be considered.
No process amplification is required. As the amount of products increases, there is no need to consider the various problems caused by amplification, especially when breakthrough therapies and clinically urgently needed products have market demand, they can quickly meet clinical needs, and are more likely to cope with drug shortages and outbreaks. The response is also time-consuming for companies to shorten the time to market.
The dosage form is flexible in design. It is possible to offer a wider range of dosage form innovations, especially for combination products, where the scope of control is more precise, and the corresponding reduction in validation and verification can make the use of the combined formulation more convenient.
3. Quality and cost
More likely to guarantee uniform quality with minimal waste
Provide more meaningful statistics and more timely and stable process control
Real-time controllable systems and effective data reduce over-regulation and focus regulatory resources on higher-risk areas
Reduce inventory, shorten lead times, improve service levels, and ease environmental pollution
Disputes and challenges that cannot be ignored
For the generics industry: Regardless of the engineering design, implementation or product development and process control, the early stage investment is huge, and the generic drug industry, which is profitable at low cost, has not found a reasonable profit model and sustainable in continuous manufacturing. Development momentum. The narrowing process used in the declaration of new drugs has made the imitation difficulty more and more, and the profitable varieties in the generic drug industry have decreased.
Technical and regulatory docking: definition of “lot†(batch), definition of shelf life, degree of completeness of material traceability system, control of flow rate for one of the most important parameters in “flowprocessingâ€, for residence time ( Residencetime), the choice of the amount of product that is selectively disposed of after the interruption/failure, the method of sampling and release
Social and industry development: The industrial restructuring that may be brought about by technological innovation may gradually shift to the equipment industry, possible closure of large-scale factories and layoffs, lack of relevant talents, and potential impact on drug prices. The domestic situation seems to be more complicated than the United States, and the contradiction between international technology and the domestic market remains to be resolved.
[China Pharmaceutical Network Technology News] "The pharmaceutical industry's acceptance of new technologies is very slow and has been decades later than other industries." FDA former director Margaret Hamburg said during a visit to the Vertex Pharmaceuticals plant. It is reported that continuous manufacturing technology, also known as the advanced manufacturing technology of the pharmaceutical industry, may subvert the future pharmaceutical industry, which is becoming a new focus of the future technological competition and industrial protection of the pharmaceutical industry, and has the opportunity to become the key to the new era. Academics, industry and regulators are conducting large-scale research, experimentation, practice and thinking on this new technology topic.
"Continuous" is no longer new
As early as 1900, before the Industrial Revolution, the earliest continuous manufacturing prototype appeared, which was used in the smelting of pig iron. The ore, fuel and flux are continuously filled into the blast furnace, continuously contacting the molten pig iron and slag, removing the chemical reaction of silicon and silicon oxidation while continuously occurring in the furnace. With the development of modern technology, the manufacturing industry has realized continuous manufacturing in various forms. Currently, common continuous processes include: petroleum refining, basic chemicals, synthetic fibers, fertilizer processing, pulp and paper, metallurgical refining, natural gas processing, and water treatment. , float glass, etc. Involving processing technology and industrial investment structure, the pharmaceutical industry and chemical oil have great differences, but in recent years, with the advancement of control technology, the “neighbor industry†food industry has gradually moved toward the stage of continuous manufacturing, and the pharmaceutical industry has its product characteristics. And the uniqueness of the regulatory environment, but in contrast, in the processing and control technology, the pharmaceutical industry is still slightly inferior to other manufacturing industries.
The pharmaceutical industry's exploration of continuous manufacturing has never stopped. In the early 1990s, in order to circumvent the problems brought about by the process, Germany had registered patents for continuous granulation and continuous drying, and tried to put into production. At that time, the continuous synthesis technology in the chemical plant also led to the “semi-continuous†processing process of many raw material pharmaceutical factories. Around 2000, online cleaning and online sterilization technologies continued the transition of pharmaceutical production to online. Around 2010, the embedded control and monitoring methods of online control and monitoring methods developed rapidly. The QbD concept also allowed the modeling and forecasting and experimental design methods to better integrate the regional pharmaceutical production process. Today, it is no accident that the FDA to the Wall Street Journal, from the industry to the academic world, to mention the "continuous manufacturing" of drugs.
From "Batch" to "Flow"
Taking tablet production as an example, the basic unit operation of the traditional production method is shown in Figure 1. The outstanding features are:
The material/product is collected after each unit operation and transferred to the next unit operation (in fact, some equipments are currently capable of semi-continuous manufacturing of certain unit operations, such as partial granulation and tableting operations).
The final formulation was tested in an off-line laboratory after all operations were completed.
Actual production time (per batch) = several days to several weeks
　 Traditional tablet production unit operation example
Tablets requiring the same operation are continuously manufactured, and the concept of continuous manufacturing is as shown in FIG. The same operations of mixing, granulating, tableting and coating are designed through the equipment and control system so that the material/product passes between each unit operation without interruption. In the case of the tablet, real-time monitoring and control of the particle size distribution measured after the granulation operation, the multi-component content uniformity measured after the final mixing operation, and the tablet weight and hardness measured after the tableting operation constitute a real-time linkage The feedback control system, combined with the physical and chemical properties of the material, generates a solubility model that simulates the release and performs a real-time release test of the coated formulation. The outstanding features are: 1) Material/product continues to flow between each unit operation
2) Real-time monitoring during production
3) Fine tuning of the entire process based on online test results and evaluation
4) Actual production time = several minutes to several hours
Tablet manufacturing as an example of continuous manufacturing
Current research and practice progress
Although the enthusiasm for continuous manufacturing in Europe and the United States has been burning for a long time, there are only a handful of companies that have made real progress.
1) Vertex:
Vertex is the first company to declare a continuous manufacturing formulation, spending $30 million in the Boston area to build a 4,000-square-foot (372-square-meter) continuous manufacturing facility to support this continuous manufacturing process. Application for the treatment of cystic fibrosis drugs.
2) Novartis- MIT:
Novartis has signed a 10-year, $65 million investment with MIT, a top-notch engineer, to combine the experience of Novartis scientists in production with the help of MIT laboratory doctoral, postdoctoral, researcher, and professors. Joint development and research in engineering, process and control. At present, MIT's pilot laboratory has completed its mission, and Novartis has built a “tennis court size†continuous manufacturing facility in Switzerland for the development and production of fully continuous end-to-end tablets from starting materials to preparations. .
Novartis-MIT continuous manufacturing center laboratory equipment (left), Novartis new continuous manufacturing workshop (right)
3) ICT CMAC: ICT CMAC (ICT CMAC, Intelligent Decision Support and Control Technologies for Continuous Manufacturing and Crystallisation of Pharmaceuticals and Fine Chemicals) was established in 2011, sponsored by 13 scholars from 7 research institutions including Cambridge. Training and experimentation in post-doctoral, doctoral, and master's programs in chemistry, engineering, and control, and continuous manufacturing and continuous crystallization research in the pharmaceutical and fine chemical industries. In 2014, the research workshop was prepared and cooperated with a number of multinational pharmaceutical companies.
4) GSK:
Singapore's $29 million continuous manufacturing plant is scheduled to go live in 2016 and is currently focusing more on continuous or semi-continuous manufacturing of APIs, targeting the Asian market.
GSK API continuous manufacturing pilot workshop
5) J&J:
The Johnson & Johnson facility in Puerto Rico is also in full swing for research and development and preparation for production to prepare for the FDA to issue the continuously manufactured HIV drug Prezista.
In addition, companies such as Genzyme and Amgen are also preparing to build factories and research and development.
Domestic progress: Hisun Pharmaceutical's continuous manufacturing research on immediate release tablets and Dongfulong's research on the potential of continuous production of spray freeze dryers in the aseptic core area is China's pioneer in the development of continuous manufacturing.
Potential innovation space
1. Shorten the supply chain:
This may be the topic of greatest concern to US regulators (including other US government agencies). Shortening the supply chain means not only greatly reducing the safety risks, shortage risks and regulatory burdens brought by the supply and transportation of raw materials, reducing the uncertainty and extra cost brought by the long supply chain, but also the return of the pharmaceutical industry. And the resulting return of capital.
2. Swift and flexible:
Production is fast. Significantly reduce production time and shorten production cycle. According to the estimates of the Novartis continuous manufacturing team, according to the previous order volume, (theoretically) 2-3 weeks can produce the products required for one year of orders. Of course, this advantage is tailor-made for the original drug. For the generic drug industry with large orders and instability, the inventory and consumption value brought by the rapid production in advance is also a factor that must be considered.
No process amplification is required. As the amount of products increases, there is no need to consider the various problems caused by amplification, especially when breakthrough therapies and clinically urgently needed products have market demand, they can quickly meet clinical needs, and are more likely to cope with drug shortages and outbreaks. The response is also time-consuming for companies to shorten the time to market.
The dosage form is flexible in design. It is possible to offer a wider range of dosage form innovations, especially for combination products, where the scope of control is more precise, and the corresponding reduction in validation and verification can make the use of the combined formulation more convenient.
3. Quality and cost
More likely to guarantee uniform quality with minimal waste
Provide more meaningful statistics and more timely and stable process control
Real-time controllable systems and effective data reduce over-regulation and focus regulatory resources on higher-risk areas
Reduce inventory, shorten lead times, improve service levels, and ease environmental pollution
Disputes and challenges that cannot be ignored
For the generics industry: Regardless of the engineering design, implementation or product development and process control, the early stage investment is huge, and the generic drug industry, which is profitable at low cost, has not found a reasonable profit model and sustainable in continuous manufacturing. Development momentum. The narrowing process used in the declaration of new drugs has made the imitation difficulty more and more, and the profitable varieties in the generic drug industry have decreased.
Technical and regulatory docking: definition of “lot†(batch), definition of shelf life, degree of completeness of material traceability system, control of flow rate for one of the most important parameters in “flowprocessingâ€, for residence time ( Residencetime), the choice of the amount of product that is selectively disposed of after the interruption/failure, the method of sampling and release
Social and industry development: The industrial restructuring that may be brought about by technological innovation may gradually shift to the equipment industry, possible closure of large-scale factories and layoffs, lack of relevant talents, and potential impact on drug prices. The domestic situation seems to be more complicated than the United States, and the contradiction between international technology and the domestic market remains to be resolved.
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