Kristin Brooks, Managing Editor, Contract Pharma03.04.20
Pharmaceutical and biopharmaceutical manufacturing requires innovative equipment for compliance, efficiency, and to accommodate today’s complex novel drugs and dosage forms, along with advanced processing and packaging capabilities.
The major pharma and biopharma trends impacting this industry include: personalized medicine and low volume production, single use technologies, continuous manufacturing, big data for preventative and predictive measures, and digital technologies. Top suppliers provide insight into the manufacturing equipment market looking at these trends, advances and opportunities and future prospects in the manufacturing equipment space.
Low Volume Production
The growth of personalized medicine and low volume production is one of the more significant trends impacting the industry, requiring the utmost flexibility from equipment. “We are currently witnessing ground-breaking changes in the pharmaceutical industry in terms of both technologies and treatment. New gene therapies, biologics and personalized medicines are increasing the demand for low volume production and, consequently, for highly flexible equipment optimized for fast changeovers between batches with the lowest possible time and product loss,” said Dr. Andreas Mattern, director product management pharma, Syntegon Technology.
For example, Syntegon Technology (formerly Bosch Packaging Technology) equips its high-shear mixers for oral solid dosage (OSD) processing with its Gentlewing mixing tool, a Z-shaped mixer designed to ensure thorough emptying of the product container and a high yield without manual intervention. The GKF 720 HiProTect was specifically developed for containment capsule filling and features a washable high containment concept with reduced water requirement up to OEB5.
Often these therapies contain active pharmaceutical ingredients that have been assigned an occupational exposure band (OEB) rating, the most severe of which is 5, including low doses that are highly potent, have significant adverse effects, or may be genotoxic, carcinogenic, or have reproductive effects. Controlling exposure to OEB 5 compounds requires the highest level of containment, (such as isolators) with no open handling, closed transfers through validated systems (such as high-containment values), and highly skilled operators.
“In parallel to these new, often highly potent substances, the need for safe, contained technologies is rising to protect products, operators and patients. Yet, apart from flexibility and safety, the industry has a third major requirement: efficiency,” Mattern added.
The trend of flexibility continues, specifically, the increased demand for filling solutions for biologics. Jan Deininger, editor, OPTIMA packaging group GmbH said, “Highly specialized products in small quantities and different drug delivery systems continue to present a challenge for pharmaceutical companies. As a result, the demands on the flexibility of systems are increasing. Smaller batch sizes have to be mastered and different containers such as syringes, vials and cartridges, have to be filled on a single line.” To accommodate small batch sizes and diverse container types, Optima Pharma offers a MultiUse platform.
Single Use Technologies
The highly complex process of biomanufacturing requires more time and expense than small molecules and single-use manufacturing processes and equipment have helped to reduce production time, contamination risk, and cost. Single-use technologies are becoming increasingly more refined, upstream and downstream.
“Single use is a key technology for the required fast changeover times. This underlines the growing demand, both on the API processing side (where single-use bioreactors are now more or less standard for new projects) and for fill-finish equipment. Single-use components made of polymers have become essential to the production of biopharmaceutical medications. Yet they are still comparatively new in the context of aseptic filling, as the hygiene and safety standards for fill-finish are extremely high,” said Mattern of Syntegon. “Precisely here, standardized single-use systems offer essential advantages. They can be implemented quickly and affordably while reducing complexity.”
To help address these stringent requirements, Syntegon’s PreVAS, is a pre-Validated, pre-Assembled and pre-Sterilized single-use filling system for clinical production and commercial manufacturing.
Continuous Manufacturing
In an effort to bring more efficiency into the global supply of drug products, continuous manufacturing is now being explored by several large pharma companies, such as J&J and Lilly, among others. This production method, used to manufacture and process materials without interruption from raw materials to final products, offers huge potential, with greater speed and flexibility over the industry’s traditional batch production.
According to Frederick Murray, president of KORSCH America Inc., “Continuous manufacturing continues to be an emerging technology offering advantages from a process development and scalability perspective. Current technology permits a fully integrated system where the tablet press receives a product recipe from the central SCADA, and various aspects of the tablet press control are governed directly by the SCADA system, based on in-process physical testing of tablet parameters, and NIR sensors in the incoming blend. In some cases, product is diverted from the tablet press based on upstream NIR measurements of the blend.” SCADA, which stands for supervisory control and data acquisition, is a computer system for gathering and analyzing real time data.
“Similarly, the SCADA system can cause all tablets to be rejected based on near-infrared (NIR) measurements in the feed frame. The key to success is an open and seamless interface which permits the central line SCADA system to obtain data from the tablet press and reach into the tablet press control system directly to make process adjustments as required. The capital investment and validation requirements associated with continuous manufacturing remain the key obstacles to entry.”
While widely used in many other industries, continuous manufacturing presents several pharma-specific challenges. With initial investments upward of $50 million for facilities and equipment, based on estimates by The Association for Accessible Medicines (AAM), it can be cost prohibitive. Furthermore, potential issues include long technology integration times to switch from batch to a continuous manufacturing process, and regulatory obstacles, such as process analytical technology (PAT).
“In continuous manufacturing, the major growth that was predicted five years ago has not yet materialized, according to Mattern of Syntegon. “Although many companies are investing in new solutions, they are mainly still in the testing phase. Continuous manufacturing is highly complex regarding the required PAT and the precise, fully continuous dosing of APIs.”
The Pharma/Biopharma industry is heavily regulated, and therefore, inherently more complex. Further regulatory support and guidance is needed to develop and implement continuous manufacturing processes and overcome the adoption hurdles associated with new technology. The FDA’s draft guidance, Quality Considerations for Continuous Manufacturing, issued February 2019, aims to specify key quality considerations and provide recommendations to address technical and regulatory considerations, however concerns over harmonization and process validation remain.
Digital Technologies and Big Data
When it comes to digitization, the pharmaceutical industry is often perceived as slow and conservative. According to Mattern, there’s a good reason for this. “Every change in the production processes must be validated. This leads to great effort and costs. And still, digitization is moving forward at a good pace. Especially larger companies are digitizing their production processes and electronic batch records, pushing and enabling a QBD (quality by design) approach and paving the way for a new digital era,” Mattern said.
He noted that digitization is not limited to large companies. For example, the Syntegon Pharma i4.0 Solution Platform with Starter Edition was developed to improve transparency in pharmaceutical processes without having to implement a companywide MES with its corresponding complexity. The system can be validated and provides plant operators with essential data on their OEE (overall equipment effectiveness), for condition monitoring of plant status or processes, and on events like alarms or downtimes, in real time.
When it comes to leveraging Big Data for preventative and predictive measures, the potential for streamlining operations and optimizing processes is substantial. Shankar Gupta, president & COO, ACG Engineering, said, “Today’s pharma facilities rely on metrics-based data-to-dashboard setups that provide operations teams with real-time mobile access production KPIs (key performance indicator). The result has been more efficient means of streamlining manufacturing processes, enhancing efficiencies and eliminating waste. The engineering teams can better plan maintenance, avoid potential breakdowns, ensure critical component and spare parts availability and prevent the accumulation of unnecessary inventory and equipment. Not only will Big Data and Industrial Internet of Things (IIoT) enable preventive and predictive measures, but will usher in the most productive and efficient processes that pharma manufacturing has ever experienced. The supply chain can be optimized, and several other efficiencies can finally see the light of day.”
Challenges & Opportunities
Therapeutic advances such as cell and gene therapies and cytotoxic drugs, and leveraging Big Data and digitization, place specific demands on manufacturing equipment solutions, and while significant advances have been made, challenges remain.
“Personalized medicine, especially gene and cell therapies, are still mainly developed on manual lab equipment with processes which are difficult to scale up for commercial GMP production. Two technological advances will help overcome this challenge: on the one hand, the development of lab equipment that is suited for GMP production from the start through automation, data integrity and closed, connected processes; on the other hand, production equipment is being scaled down to suit low volume production and hence becomes more flexible, also for use in the lab,” said Mattern.
To address high containment requirements, Optima Pharma has put a focus on the development of robotics and transport systems to further improve system flexibility. According to Jan Deininger of OPTIMA, “The increased demand for high-potent pharmaceuticals could successfully be answered with room, pressure and waste water concepts since room and machine are only a totally functional system when they interact correctly. This includes barrier technologies, especially different filter concepts. In addition, cleaning and decontamination are significant.”
Mattern of Syntegon added, “Flexible, small-scale pilot and production lines will be shifting to the center of attention in liquid fill-finish operations. Increasingly they will be equipped with containment systems and use robotic technology to increase automation and reduce manual handling to a minimum. As far as continuous manufacturing goes, we are certain that we will soon witness a breakthrough of new technologies, while the equipment matures, and new options become available.”
The pharmaceutical industry is just beginning to witness the potential of digitization and artificial intelligence and leveraging these tools is becoming more and more realistic. According to Mattern, “In the area of digitization, new developments like smart machine features will make it possible to retrofit brownfield applications and significantly improve efficiency and yields.”
Another hot topic is the application of AI to pharmaceutical inspection processes. Mattern said, “The required software and algorithms are already used in many domains, so that machine manufacturers can apply their pharmaceutical process and validation expertise to existing solutions with only moderate software modifications—something Syntegon Technology is currently implementing in several customer
pilot projects.
Keeping pace with the latest pharma/biopharma innovations is no simple task. The industry relies on equipment suppliers to help make the manufacture of medicines more efficient while complying with stringent regulatory requirements. Shankar Gupta of ACG Engineering, said, “Going by the growing demand for ACG’s customized equipment, we see that pharma manufacturing requires equipment manufacturers to think consistently on the edge of possibility and push further the innovation that has given rise to higher compliance, efficient manufacturing and most importantly, novel dosage delivery forms and patient focused development, processing and packaging.”
Just as science and technology continue to usher in never before seen innovation in the industry, expect to see manufacturing equipment solutions evolve to address todays’ most significant therapeutic challenges.
The major pharma and biopharma trends impacting this industry include: personalized medicine and low volume production, single use technologies, continuous manufacturing, big data for preventative and predictive measures, and digital technologies. Top suppliers provide insight into the manufacturing equipment market looking at these trends, advances and opportunities and future prospects in the manufacturing equipment space.
Low Volume Production
The growth of personalized medicine and low volume production is one of the more significant trends impacting the industry, requiring the utmost flexibility from equipment. “We are currently witnessing ground-breaking changes in the pharmaceutical industry in terms of both technologies and treatment. New gene therapies, biologics and personalized medicines are increasing the demand for low volume production and, consequently, for highly flexible equipment optimized for fast changeovers between batches with the lowest possible time and product loss,” said Dr. Andreas Mattern, director product management pharma, Syntegon Technology.
For example, Syntegon Technology (formerly Bosch Packaging Technology) equips its high-shear mixers for oral solid dosage (OSD) processing with its Gentlewing mixing tool, a Z-shaped mixer designed to ensure thorough emptying of the product container and a high yield without manual intervention. The GKF 720 HiProTect was specifically developed for containment capsule filling and features a washable high containment concept with reduced water requirement up to OEB5.
Often these therapies contain active pharmaceutical ingredients that have been assigned an occupational exposure band (OEB) rating, the most severe of which is 5, including low doses that are highly potent, have significant adverse effects, or may be genotoxic, carcinogenic, or have reproductive effects. Controlling exposure to OEB 5 compounds requires the highest level of containment, (such as isolators) with no open handling, closed transfers through validated systems (such as high-containment values), and highly skilled operators.
“In parallel to these new, often highly potent substances, the need for safe, contained technologies is rising to protect products, operators and patients. Yet, apart from flexibility and safety, the industry has a third major requirement: efficiency,” Mattern added.
The trend of flexibility continues, specifically, the increased demand for filling solutions for biologics. Jan Deininger, editor, OPTIMA packaging group GmbH said, “Highly specialized products in small quantities and different drug delivery systems continue to present a challenge for pharmaceutical companies. As a result, the demands on the flexibility of systems are increasing. Smaller batch sizes have to be mastered and different containers such as syringes, vials and cartridges, have to be filled on a single line.” To accommodate small batch sizes and diverse container types, Optima Pharma offers a MultiUse platform.
Single Use Technologies
The highly complex process of biomanufacturing requires more time and expense than small molecules and single-use manufacturing processes and equipment have helped to reduce production time, contamination risk, and cost. Single-use technologies are becoming increasingly more refined, upstream and downstream.
“Single use is a key technology for the required fast changeover times. This underlines the growing demand, both on the API processing side (where single-use bioreactors are now more or less standard for new projects) and for fill-finish equipment. Single-use components made of polymers have become essential to the production of biopharmaceutical medications. Yet they are still comparatively new in the context of aseptic filling, as the hygiene and safety standards for fill-finish are extremely high,” said Mattern of Syntegon. “Precisely here, standardized single-use systems offer essential advantages. They can be implemented quickly and affordably while reducing complexity.”
To help address these stringent requirements, Syntegon’s PreVAS, is a pre-Validated, pre-Assembled and pre-Sterilized single-use filling system for clinical production and commercial manufacturing.
Continuous Manufacturing
In an effort to bring more efficiency into the global supply of drug products, continuous manufacturing is now being explored by several large pharma companies, such as J&J and Lilly, among others. This production method, used to manufacture and process materials without interruption from raw materials to final products, offers huge potential, with greater speed and flexibility over the industry’s traditional batch production.
According to Frederick Murray, president of KORSCH America Inc., “Continuous manufacturing continues to be an emerging technology offering advantages from a process development and scalability perspective. Current technology permits a fully integrated system where the tablet press receives a product recipe from the central SCADA, and various aspects of the tablet press control are governed directly by the SCADA system, based on in-process physical testing of tablet parameters, and NIR sensors in the incoming blend. In some cases, product is diverted from the tablet press based on upstream NIR measurements of the blend.” SCADA, which stands for supervisory control and data acquisition, is a computer system for gathering and analyzing real time data.
“Similarly, the SCADA system can cause all tablets to be rejected based on near-infrared (NIR) measurements in the feed frame. The key to success is an open and seamless interface which permits the central line SCADA system to obtain data from the tablet press and reach into the tablet press control system directly to make process adjustments as required. The capital investment and validation requirements associated with continuous manufacturing remain the key obstacles to entry.”
While widely used in many other industries, continuous manufacturing presents several pharma-specific challenges. With initial investments upward of $50 million for facilities and equipment, based on estimates by The Association for Accessible Medicines (AAM), it can be cost prohibitive. Furthermore, potential issues include long technology integration times to switch from batch to a continuous manufacturing process, and regulatory obstacles, such as process analytical technology (PAT).
“In continuous manufacturing, the major growth that was predicted five years ago has not yet materialized, according to Mattern of Syntegon. “Although many companies are investing in new solutions, they are mainly still in the testing phase. Continuous manufacturing is highly complex regarding the required PAT and the precise, fully continuous dosing of APIs.”
The Pharma/Biopharma industry is heavily regulated, and therefore, inherently more complex. Further regulatory support and guidance is needed to develop and implement continuous manufacturing processes and overcome the adoption hurdles associated with new technology. The FDA’s draft guidance, Quality Considerations for Continuous Manufacturing, issued February 2019, aims to specify key quality considerations and provide recommendations to address technical and regulatory considerations, however concerns over harmonization and process validation remain.
Digital Technologies and Big Data
When it comes to digitization, the pharmaceutical industry is often perceived as slow and conservative. According to Mattern, there’s a good reason for this. “Every change in the production processes must be validated. This leads to great effort and costs. And still, digitization is moving forward at a good pace. Especially larger companies are digitizing their production processes and electronic batch records, pushing and enabling a QBD (quality by design) approach and paving the way for a new digital era,” Mattern said.
He noted that digitization is not limited to large companies. For example, the Syntegon Pharma i4.0 Solution Platform with Starter Edition was developed to improve transparency in pharmaceutical processes without having to implement a companywide MES with its corresponding complexity. The system can be validated and provides plant operators with essential data on their OEE (overall equipment effectiveness), for condition monitoring of plant status or processes, and on events like alarms or downtimes, in real time.
When it comes to leveraging Big Data for preventative and predictive measures, the potential for streamlining operations and optimizing processes is substantial. Shankar Gupta, president & COO, ACG Engineering, said, “Today’s pharma facilities rely on metrics-based data-to-dashboard setups that provide operations teams with real-time mobile access production KPIs (key performance indicator). The result has been more efficient means of streamlining manufacturing processes, enhancing efficiencies and eliminating waste. The engineering teams can better plan maintenance, avoid potential breakdowns, ensure critical component and spare parts availability and prevent the accumulation of unnecessary inventory and equipment. Not only will Big Data and Industrial Internet of Things (IIoT) enable preventive and predictive measures, but will usher in the most productive and efficient processes that pharma manufacturing has ever experienced. The supply chain can be optimized, and several other efficiencies can finally see the light of day.”
Challenges & Opportunities
Therapeutic advances such as cell and gene therapies and cytotoxic drugs, and leveraging Big Data and digitization, place specific demands on manufacturing equipment solutions, and while significant advances have been made, challenges remain.
“Personalized medicine, especially gene and cell therapies, are still mainly developed on manual lab equipment with processes which are difficult to scale up for commercial GMP production. Two technological advances will help overcome this challenge: on the one hand, the development of lab equipment that is suited for GMP production from the start through automation, data integrity and closed, connected processes; on the other hand, production equipment is being scaled down to suit low volume production and hence becomes more flexible, also for use in the lab,” said Mattern.
To address high containment requirements, Optima Pharma has put a focus on the development of robotics and transport systems to further improve system flexibility. According to Jan Deininger of OPTIMA, “The increased demand for high-potent pharmaceuticals could successfully be answered with room, pressure and waste water concepts since room and machine are only a totally functional system when they interact correctly. This includes barrier technologies, especially different filter concepts. In addition, cleaning and decontamination are significant.”
Mattern of Syntegon added, “Flexible, small-scale pilot and production lines will be shifting to the center of attention in liquid fill-finish operations. Increasingly they will be equipped with containment systems and use robotic technology to increase automation and reduce manual handling to a minimum. As far as continuous manufacturing goes, we are certain that we will soon witness a breakthrough of new technologies, while the equipment matures, and new options become available.”
The pharmaceutical industry is just beginning to witness the potential of digitization and artificial intelligence and leveraging these tools is becoming more and more realistic. According to Mattern, “In the area of digitization, new developments like smart machine features will make it possible to retrofit brownfield applications and significantly improve efficiency and yields.”
Another hot topic is the application of AI to pharmaceutical inspection processes. Mattern said, “The required software and algorithms are already used in many domains, so that machine manufacturers can apply their pharmaceutical process and validation expertise to existing solutions with only moderate software modifications—something Syntegon Technology is currently implementing in several customer
pilot projects.
Keeping pace with the latest pharma/biopharma innovations is no simple task. The industry relies on equipment suppliers to help make the manufacture of medicines more efficient while complying with stringent regulatory requirements. Shankar Gupta of ACG Engineering, said, “Going by the growing demand for ACG’s customized equipment, we see that pharma manufacturing requires equipment manufacturers to think consistently on the edge of possibility and push further the innovation that has given rise to higher compliance, efficient manufacturing and most importantly, novel dosage delivery forms and patient focused development, processing and packaging.”
Just as science and technology continue to usher in never before seen innovation in the industry, expect to see manufacturing equipment solutions evolve to address todays’ most significant therapeutic challenges.
