Tim Wright, Editor, Contract Pharma05.13.24
The contract manufacturing landscape is constantly evolving, influenced by advancing technologies, changing customer demands, and progressing patient needs. The most significant trend the pharmaceutical industry continues to undergo is the seismic shift toward biotechnology, with sales of biotech-based products expected to triple by 2028.
In recent years, according to Peter Soelkner, managing director, Vetter Pharma International, there has been a noticeable transition of focus away from requests for the development and manufacturing of blockbuster drugs, to small-batch sized drugs. “At the same time,” he says, “there is a growing emphasis on orphan drugs in the global research and development (R&D) pipeline. This dual trend requires a high degree of flexibility for innovative companies and their partners.”
To support customers looking for outsourcing in these growing market areas, contract development and manufacturing organizations (CDMOs) must continuously adapt to the unique requirements of sensitive biotech-based products and the requirements associated with their development and manufacturing.
“Our industry is moving more and more towards developing large-molecule biologics for which specialized manufacturing processes are required,” says Soelkner. “This has led to the exploration of advanced facilities, flexible equipment, and specialized expertise, often unavailable in-house for many drug developers.”
In addition, among the many dynamics driving growth in the outsourcing of sterile injectable development and manufacturing services, injectable drugs are adopting patient-friendly delivery systems to enhance patient convenience and reduce clinic-based management. This includes a transition towards self-administration at home.
This shift towards more complex delivery of therapeutics bodes well for CDMOs as it requires specialized manufacturing equipment and processes, according to Jane Meyer, director, CDMO business development, August Bioservices. “The capital investment combined with the highly technical requirement to manufacture parenteral medications supports outsourcing as a more cost-efficient option in many cases,” she says. “There is also an increasing presence of complex formulations within the R&D pipeline, which benefit from access to development and manufacturing expertise that is most efficiently leveraged through outsourcing.”
At the same time, the variety of therapeutics has increased dramatically in the last decade. “The time when small molecules and limited large molecule therapies dominated is long gone,” says Colleen Dixon, vice president of program management, Selkirk. “Monoclonal antibody therapies have come into their own and are putting pressure on the demand for injectables manufacturing capacity. mRNA, oliogs and gene therapy are emerging as the latest modalities, while a wide variety of other modalities are in development. It is a much more complex market than it used to be.”
The companies engaged in development have diversified too, Dixon says, with many more small biotech companies pursuing these new approaches and creating opportunities for contract manufacturing organizations (CMOs) to provide rapid, efficient clinical supply services.
While biologics were initially limited to some specific disease categories, drug developers are expanding the impact of these therapies into many other disease areas other than just oncology and rare diseases, creating the potential for blockbuster drugs as we have seen in a few cases already, according to Selkirk’s Dixon.
“The success of mRNA COVID vaccines has led to investment in the development of many more mRNA vaccines, and these products have very rapid development cycles creating the potential for many new vaccines entering the market—each needing manufacturing capacity,” she says. “This diversification of therapies means that CMOs have to keep pace with the latest therapies and understand the needs of drug developers more than ever while they build capacity to handle all the new demands.”
While treatments for oncology, diabetes, and heart disease, as well as vaccines, are experiencing increased demand, Mary Lou Glotzbach, senior business development manager at Grand River Aseptic Manufacturing (GRAM), says it’s the hurdles to sterile manufacturing of each disease state that has led to more reliance on contract manufacturing.
“For example,” she says, “with oncology, you have cytotoxins or highly potent compounds that need the advances in containment and safety standards that CDMOs specialize in.”
At the same time, while vaccine production is a constant source of revenue, according to Glotzbach, the parenteral drug delivery and manufacturing market is shifting from vaccines to an incredible focus on GLP-1. “Producing GLP-1s allows CDMOs to enhance their service offering and meets the growing demand that Big Pharma cannot currently support,” she says.
“Service providers that develop expertise in cutting-edge technology for these sensitive substances can gain a competitive edge by providing those specialized technical solutions for their whole customer base,” he says. “The integration of autonomous robotics and machine learning supports precise and consistent manufacturing processes, minimizing room for errors. At the same time, AI contributes to data analysis, quality control, and process optimization to support decision making while meeting regulatory standards.
Vetter is investing roughly €230 million in a new commercial production building at its headquarters in Ravensburg, Germany. This facility is part of a €1.5 billion investment roadmap over the next decade and will house several new commercial filling lines to boost aseptic manufacturing capacity. Additional investments include expanding lab space for analytical services, increasing filling capacity, expanding cool storage, and optimizing infrastructure.
The basic needs of CMO clients haven’t changed over the years, offers Selkirk’s Dixon. According to her, clients want a quality-minded company with an excellent regulatory record, experienced knowledgeable staff who will take care of their product, and a reliable supply chain that delivers their product on time. “What’s changed,” she says, “is that drug developers present in a greater variety than they used to, from tiny virtual companies, to start-up biotech firms, to traditional big 50 pharma.”
CMOs must be more adaptable to the needs of this diverse client base and diverse product portfolio. “Using the latest filling technologies can help provide exquisite flexibility for clients seeking drug product capacity,” Dixon says. “Integrated system approaches can bring Pharma 4.0 to life and ensure more rapid tech transfers, more efficient production, and quicker batch disposition times. There are more regulatory observations issued for data integrity than any other single cause, and an elegant Pharma 4.0 strategy and computer system assurance (CSA) approach is essential to ensure data integrity.”
In February 2024 Selkirk announced the Aseptic Process Simulation (APS) qualification of its sterile manufacturing facility and newly available fill-finish capacity. The purpose-built aseptic manufacturing facility operates with leading-edge technology, including unidirectional material and personnel flow, single-use systems, SKAN isolator technology, and Bausch and Strobel VarioSys advanced dose filling systems.
There are several technological innovations that are helping to advance the efficiency of outsourcing providers across the manufacturing services continuum, according to August Bio’s Meyer. “Isolated lines using robotics minimize human intervention during the aseptic filling process,” she says. “Equipment dosing technology has advanced to enable more accurate filling of smaller containers with precise fill volumes. Automation of visual inspection and finishing of sterile injectable products has evolved to support increased throughput and enhanced quality and the adoption of electronic batch records and software systems, moving away from more cumbersome paper-based systems, yields more efficient traceability.”
August Bioservices has made recent investments in state-of-the-art equipment and new facilities in anticipation of the growing need for fill-finish development and manufacturing capacity. The investments made over the last 4 years include 7 filling lines, for a wide range of container types, that range from small-scale for precision medications to large-scale, high-speed filling for commercial manufacturing.
Moving forward, technology innovation around new delivery systems for biologics will allow more patient flexibility in the administration of their therapy.
There is an increasing number of options for drug delivery in development,” says Grand River’s Glotzbach, but, she asks, “How much risk do you take in the hope that something new will be successful?”
“There will always be vials,” she says, “but the patient will soon receive options, and if you are only in a vial, you may be left behind. That goes for both the development company and the manufacturer. It is a time of decisions, and there is an increasing number of options for drug delivery in development, specifically as it relates to on-body delivery systems. You have a cartridge versus a syringe for auto-injectors, and will patients tolerate larger volume injections? Drug developers and manufacturers must decide whether they will invest now or later.”
Grand River Aseptic Manufacturing’s recent finishing and warehouse center expansion added 90,000 sq. ft. to the existing 110,000 sq. ft., totaling 200,000 sq. ft. of sophisticated inspection, packaging, testing, and warehouse capabilities. The expansion of additional capabilities and systems supports an industry-wide need for syringe, cartridge, and vial filling and finishing, as well as the growth in advanced drug delivery systems.
In conclusion, Glotzbach says, “The CDMO with a robust business plan and proper recognition of its employees should be around for the long term. Commitment to the business through investing in new technology and the appropriate personnel will separate the weak CDMO from the strong CDMO.”
Side Bar
When deciding on the contract development and manufacturing organization (CDMO) to trust with your drug product, look for these key traits of a CDMO experienced in Annex 1 compliance.
To start, the CDMO incorporates draft, current, and anticipated requirements of Annex 1 into constructing their filling and finishing facilities. Essential design elements that reduce the risk of contamination include unidirectional flow and airlocks that separate personnel and material flow into and out of formulation, Bag-In/Bag-Out high-efficiency filtration systems that capture airborne contaminants, and wide corridors that allow easy movement. Dedicated customer office space, large viewing windows into formulation suites, and camera feed inside equipment help to reinforce transparency and communication during manufacturing.
CDMOs implementing Annex 1 guidelines include flexible systems and advanced aseptic manufacturing technology. Their filling lines utilize isolator technology, which is the safest method for maintaining high sterility levels and reducing the risk of impurity.
Advanced isolator decontamination systems provide an environment free of contamination and increase efficiency by reducing process time. Automated lyophilizer loader/unloader within isolator technology reduces the need for operator interventions and minimizes contamination risks. Single-use-based systems and PUPSIT are available and determined based on client preferences and product-specific needs.
The CDMO performs a thorough gap analysis to identify system, process, or documentation gaps. Department heads are assigned to each section to address identified gaps, and a formal assessment report is prepared and reflected upon with the client to ensure alignment. Continuous improvement is imperative, and a contamination control strategy (CCS) is established and built into the CDMO’s systems and policies. The CCS is updated and assessed regularly and includes the multi-product facility risk assessment to identify and mitigate potential risks.
A CDMO focused on quality that stays current with GMP regulations and Annex 1 guidelines is built to last. It undergoes regular client audits to challenge its processes and ensure it meets high compliance standards. Training is developed to ensure its personnel understand current requirements and that its compliance history reflects the high standards. CDMOs built to last adapt quickly to changes in regulations with minimal impact on operations. Resiliency is critical when deciding on your next manufacturing partner.
In recent years, according to Peter Soelkner, managing director, Vetter Pharma International, there has been a noticeable transition of focus away from requests for the development and manufacturing of blockbuster drugs, to small-batch sized drugs. “At the same time,” he says, “there is a growing emphasis on orphan drugs in the global research and development (R&D) pipeline. This dual trend requires a high degree of flexibility for innovative companies and their partners.”
To support customers looking for outsourcing in these growing market areas, contract development and manufacturing organizations (CDMOs) must continuously adapt to the unique requirements of sensitive biotech-based products and the requirements associated with their development and manufacturing.
“Our industry is moving more and more towards developing large-molecule biologics for which specialized manufacturing processes are required,” says Soelkner. “This has led to the exploration of advanced facilities, flexible equipment, and specialized expertise, often unavailable in-house for many drug developers.”
In addition, among the many dynamics driving growth in the outsourcing of sterile injectable development and manufacturing services, injectable drugs are adopting patient-friendly delivery systems to enhance patient convenience and reduce clinic-based management. This includes a transition towards self-administration at home.
This shift towards more complex delivery of therapeutics bodes well for CDMOs as it requires specialized manufacturing equipment and processes, according to Jane Meyer, director, CDMO business development, August Bioservices. “The capital investment combined with the highly technical requirement to manufacture parenteral medications supports outsourcing as a more cost-efficient option in many cases,” she says. “There is also an increasing presence of complex formulations within the R&D pipeline, which benefit from access to development and manufacturing expertise that is most efficiently leveraged through outsourcing.”
At the same time, the variety of therapeutics has increased dramatically in the last decade. “The time when small molecules and limited large molecule therapies dominated is long gone,” says Colleen Dixon, vice president of program management, Selkirk. “Monoclonal antibody therapies have come into their own and are putting pressure on the demand for injectables manufacturing capacity. mRNA, oliogs and gene therapy are emerging as the latest modalities, while a wide variety of other modalities are in development. It is a much more complex market than it used to be.”
The companies engaged in development have diversified too, Dixon says, with many more small biotech companies pursuing these new approaches and creating opportunities for contract manufacturing organizations (CMOs) to provide rapid, efficient clinical supply services.
Biologics continue to gain therapeutic ground
The pharmaceutical outsourcing landscape is witnessing increased demand in specific therapeutic areas such as GLP-1 and various oncology treatments, driven by the rising prevalence of diabetes and cancer, and, more recently, the surge in demand for weight loss drugs to treat obesity.While biologics were initially limited to some specific disease categories, drug developers are expanding the impact of these therapies into many other disease areas other than just oncology and rare diseases, creating the potential for blockbuster drugs as we have seen in a few cases already, according to Selkirk’s Dixon.
“The success of mRNA COVID vaccines has led to investment in the development of many more mRNA vaccines, and these products have very rapid development cycles creating the potential for many new vaccines entering the market—each needing manufacturing capacity,” she says. “This diversification of therapies means that CMOs have to keep pace with the latest therapies and understand the needs of drug developers more than ever while they build capacity to handle all the new demands.”
While treatments for oncology, diabetes, and heart disease, as well as vaccines, are experiencing increased demand, Mary Lou Glotzbach, senior business development manager at Grand River Aseptic Manufacturing (GRAM), says it’s the hurdles to sterile manufacturing of each disease state that has led to more reliance on contract manufacturing.
“For example,” she says, “with oncology, you have cytotoxins or highly potent compounds that need the advances in containment and safety standards that CDMOs specialize in.”
At the same time, while vaccine production is a constant source of revenue, according to Glotzbach, the parenteral drug delivery and manufacturing market is shifting from vaccines to an incredible focus on GLP-1. “Producing GLP-1s allows CDMOs to enhance their service offering and meets the growing demand that Big Pharma cannot currently support,” she says.
Technology innovations pave the way to the future
Advances in technology are reshaping the outsourcing landscape in the pharmaceutical industry, particularly in the handling of biologics. According to Vetter’s Soelkner, technological innovations are significantly improving the efficiency and capabilities of development and manufacturing outsourcing services by creating a balance between necessary speed and regulatory compliance.“Service providers that develop expertise in cutting-edge technology for these sensitive substances can gain a competitive edge by providing those specialized technical solutions for their whole customer base,” he says. “The integration of autonomous robotics and machine learning supports precise and consistent manufacturing processes, minimizing room for errors. At the same time, AI contributes to data analysis, quality control, and process optimization to support decision making while meeting regulatory standards.
Vetter is investing roughly €230 million in a new commercial production building at its headquarters in Ravensburg, Germany. This facility is part of a €1.5 billion investment roadmap over the next decade and will house several new commercial filling lines to boost aseptic manufacturing capacity. Additional investments include expanding lab space for analytical services, increasing filling capacity, expanding cool storage, and optimizing infrastructure.
The basic needs of CMO clients haven’t changed over the years, offers Selkirk’s Dixon. According to her, clients want a quality-minded company with an excellent regulatory record, experienced knowledgeable staff who will take care of their product, and a reliable supply chain that delivers their product on time. “What’s changed,” she says, “is that drug developers present in a greater variety than they used to, from tiny virtual companies, to start-up biotech firms, to traditional big 50 pharma.”
CMOs must be more adaptable to the needs of this diverse client base and diverse product portfolio. “Using the latest filling technologies can help provide exquisite flexibility for clients seeking drug product capacity,” Dixon says. “Integrated system approaches can bring Pharma 4.0 to life and ensure more rapid tech transfers, more efficient production, and quicker batch disposition times. There are more regulatory observations issued for data integrity than any other single cause, and an elegant Pharma 4.0 strategy and computer system assurance (CSA) approach is essential to ensure data integrity.”
In February 2024 Selkirk announced the Aseptic Process Simulation (APS) qualification of its sterile manufacturing facility and newly available fill-finish capacity. The purpose-built aseptic manufacturing facility operates with leading-edge technology, including unidirectional material and personnel flow, single-use systems, SKAN isolator technology, and Bausch and Strobel VarioSys advanced dose filling systems.
There are several technological innovations that are helping to advance the efficiency of outsourcing providers across the manufacturing services continuum, according to August Bio’s Meyer. “Isolated lines using robotics minimize human intervention during the aseptic filling process,” she says. “Equipment dosing technology has advanced to enable more accurate filling of smaller containers with precise fill volumes. Automation of visual inspection and finishing of sterile injectable products has evolved to support increased throughput and enhanced quality and the adoption of electronic batch records and software systems, moving away from more cumbersome paper-based systems, yields more efficient traceability.”
August Bioservices has made recent investments in state-of-the-art equipment and new facilities in anticipation of the growing need for fill-finish development and manufacturing capacity. The investments made over the last 4 years include 7 filling lines, for a wide range of container types, that range from small-scale for precision medications to large-scale, high-speed filling for commercial manufacturing.
Moving forward, technology innovation around new delivery systems for biologics will allow more patient flexibility in the administration of their therapy.
There is an increasing number of options for drug delivery in development,” says Grand River’s Glotzbach, but, she asks, “How much risk do you take in the hope that something new will be successful?”
“There will always be vials,” she says, “but the patient will soon receive options, and if you are only in a vial, you may be left behind. That goes for both the development company and the manufacturer. It is a time of decisions, and there is an increasing number of options for drug delivery in development, specifically as it relates to on-body delivery systems. You have a cartridge versus a syringe for auto-injectors, and will patients tolerate larger volume injections? Drug developers and manufacturers must decide whether they will invest now or later.”
Grand River Aseptic Manufacturing’s recent finishing and warehouse center expansion added 90,000 sq. ft. to the existing 110,000 sq. ft., totaling 200,000 sq. ft. of sophisticated inspection, packaging, testing, and warehouse capabilities. The expansion of additional capabilities and systems supports an industry-wide need for syringe, cartridge, and vial filling and finishing, as well as the growth in advanced drug delivery systems.
In conclusion, Glotzbach says, “The CDMO with a robust business plan and proper recognition of its employees should be around for the long term. Commitment to the business through investing in new technology and the appropriate personnel will separate the weak CDMO from the strong CDMO.”
Side Bar
Telling Traits of a CDMO Experienced in Annex 1 Compliance
By Ryan Waldhart, Sr. Manager of Manufacturing, Science, and Technology, Grand River Aseptic ManufacturingWhen deciding on the contract development and manufacturing organization (CDMO) to trust with your drug product, look for these key traits of a CDMO experienced in Annex 1 compliance.
To start, the CDMO incorporates draft, current, and anticipated requirements of Annex 1 into constructing their filling and finishing facilities. Essential design elements that reduce the risk of contamination include unidirectional flow and airlocks that separate personnel and material flow into and out of formulation, Bag-In/Bag-Out high-efficiency filtration systems that capture airborne contaminants, and wide corridors that allow easy movement. Dedicated customer office space, large viewing windows into formulation suites, and camera feed inside equipment help to reinforce transparency and communication during manufacturing.
CDMOs implementing Annex 1 guidelines include flexible systems and advanced aseptic manufacturing technology. Their filling lines utilize isolator technology, which is the safest method for maintaining high sterility levels and reducing the risk of impurity.
Advanced isolator decontamination systems provide an environment free of contamination and increase efficiency by reducing process time. Automated lyophilizer loader/unloader within isolator technology reduces the need for operator interventions and minimizes contamination risks. Single-use-based systems and PUPSIT are available and determined based on client preferences and product-specific needs.
The CDMO performs a thorough gap analysis to identify system, process, or documentation gaps. Department heads are assigned to each section to address identified gaps, and a formal assessment report is prepared and reflected upon with the client to ensure alignment. Continuous improvement is imperative, and a contamination control strategy (CCS) is established and built into the CDMO’s systems and policies. The CCS is updated and assessed regularly and includes the multi-product facility risk assessment to identify and mitigate potential risks.
A CDMO focused on quality that stays current with GMP regulations and Annex 1 guidelines is built to last. It undergoes regular client audits to challenge its processes and ensure it meets high compliance standards. Training is developed to ensure its personnel understand current requirements and that its compliance history reflects the high standards. CDMOs built to last adapt quickly to changes in regulations with minimal impact on operations. Resiliency is critical when deciding on your next manufacturing partner.
