Tom Chang, President, Bora Pharmaceutical Laboratory Co. Ltd.11.17.20
The demand for the services of contract development and manufacturing organizations (CDMOs) has never been higher, with approximately 28% of the world’s prescription and non-prescription drugs being manufactured by an outsourcing partner.1
The growing use of CDMOs is being driven by the logical need of the industry: large pharma companies can divest non-core manufacturing facilities and focus capital instead on core products, while smaller companies often require the specialist services CDMOs offer to produce increasingly complex drugs cost effectively. For both small and large companies, partnering also allows for the reduction of risk, the management of costs, and ensuring the quality of the manufactured product.
The importance of the right partnership
The outsourcing partnership is one based on trust and begins with the technology transfer. When the pharmaceutical company transfers the required IP, the partner receives crucial technical and scientific information, which will allow for the manufacture of a product at a new manufacturing site. The formulation, manufacturing process, analytics, and packaging IP, as well as additional relevant documentation, knowledge, and professional expertise change hands in the process.
If the technology transfer is handled badly, issues and risks can be introduced all the way through the process. There can be problems with the initial batches, analytical testing, packaging, and potentially patient safety. As a result, it is essential that extra time and effort is taken to outline all relevant parameters, so that product quality does not become an issue and, if it does, that there are adequate warnings. In this article we outline the key parameters and considerations to take into account, to ensure a successful technology transfer.
Robust risk assessment
First, it’s critical to conduct a thorough feasibility evaluation at the outset of the technology transfer. A risk assessment should cover all activities included in the technology transfer, where the contracted partner challenges assumptions, offers practical solutions and offers a range of value-based options to address and mitigate potential issues. A good outsourcing partner can identify problems from formulation issues during scale up to spotting regulatory incompatibilities early into the process.
The more rigorously a process is challenged in the feasibility stage, the more robust that process will be during the scale up, validation, and commercial production phases. The technology transfer may not always be a smooth transition, especially when working with complex oral solid dose drugs, for example, but robust risk assessment is one way to ensure a quality end product.
Communication is key
When a technology transfer is executed successfully, both partners stand to gain in terms of time saved and costs minimized, while product quality is improved and performance risk is reduced. Communication to ensure this happens is central to the working relationship.
Technology transfer is a person-to-person, system-to-system knowledge transfer. In line with this, the better the exchange and communication of information, the greater the likelihood of successfully fulfilling the program’s financial and commercial goals. It is important for sponsors to provide all relevant information, including ‘tribal’ knowledge, in a secure, defined space where the respective organizations can collaborate to develop practical solutions and ensure a robust technical transfer package.
Three questions
When choosing an outsourcing partner, it’s worth considering the following questions first:
Critical Quality Attributes (CQA)
The technical transfer package is not complete until it provides Product Quality Attributes: Critical Quality Attributes (CQAs) and material attributes. A CQA appraisal will include an overview of processes, including unit operations, a control strategy, manufacturing process parameters, continuous improvement ideas and plans, historical deviations lists, and equipment and analytical technology lists.
SUPAC
Changes are often made to the manufacturing process after a drug is approved, from the equipment involved to the location of the site itself, or even the composition of the product. These are known as Scale-Up and Post Approval Changes (SUPAC). Any changes made can have an impact on the raw materials involved, manufacturing process, equipment train, manufacturing site, and the batch size. In turn, this can affect the CQAs of a drug or a finished product.
It is, therefore, necessary to consider in advance the impact of any changes on the quality of a drug or finished product.
SUPAC guidances provide those sponsors of new drug applications (NDAs) and abbreviated new drug applications (ANDAs) recommendations on the following: post-approval changes to components or compositions; the site of manufacture; the scale up/scale down of manufacture; and the manufacturing (process and equipment) of an immediate release oral formulation.
All in the analytics
The manufacturing process requires precise controls to ensure the quality of a drug throughout its lifecycle.
For example, at Bora Pharmaceuticals we utilize a wide range of analytical tools to support product quality, which is especially important to ensure commercial products meet the requirements of regulators and the patients themselves. This involves using Design of Experiments (DoE), risk assessment platforms, and Process Analytical Technologies. Through the utilization of such tools, a design space can be created between partners where the CQA can meet predetermined specifications during technology transfer and scale up activity.
Through analytical tools and when a sponsor provides reliable process knowledge, the contract manufacturing partner can establish a Normal Operating Range during technology transfer or a scale up activity.
Engineering runs
Before the scale up process, engineering (or demonstration) runs are the proving ground for the process and the equipment used during production. A successful engineering run is invaluable to ensure quality in subsequent current good manufacturing practice (cGMP) and packaging runs.
The engineering run is carried out on the commercial equipment train to gather data (including stability) and perform filling and packaging line trials. It also provides the processing data that can then be used in the scale up and validation steps to follow.
Since collecting this data is critical, at least one engineering run should be completed, with the risk of additional costs and delays if this step is neglected.
Scale up
Scale up is the process by which batch sizes are increased from feasibility or engineering batch scale to commercial scale, usually representing a 5-10x increase in volume.
Knowledge should be gained on two factors during this process: acquiring the chemistry and process knowledge to be able to effectively manage the formulation at commercial scale and developing a strategy to manage production and material costs.
Project and program management
An experienced project and program management team is an essential element in ensuring that challenges at the later stages of the process can be managed. Working together with sponsors has allowed our team at Bora to navigate hurdles that have arisen once a product has been submitted for approval to regulators.
In one example, Bora worked with a long-standing client on a complex modified-release capsule product with several different components. Once the product was submitted to the U.S. FDA for approval, an issue arose regarding capsule filling equipment not being able to measure individual component weights, which was deemed by the agency to be a necessary control parameter. The team at Bora organized a joint project group with the partner to develop potential solutions, resulting in a change to a more suitable capsule filling machine. The FDA agreed to the changes and the product was successfully approved and commercialized.
Key takeaways
We’ve provided a lot of information, but ultimately the three takeaway points to ensure a successful tech transfer are:
References
Tom Chang is the President of Bora Pharmaceuticals Laboratory Co. Ltd. and oversees two manufacturing sites for Bora Pharmaceuticals. He has over 27 years’ experience in the pharmaceutical industry and over 14 years’ experience as a site general manager for multinational companies including Wyeth, Pfizer, and Impax. He has extensive knowledge and experience in global supply chain and operational management. Tom has outstanding leadership and professional skills and seeks to provide the highest quality products for his customers. He is a critical part of the leadership team at Bora Pharmaceuticals, a premier international CGMP CDMO specializing in oral solid dosage, liquids (solutions, suspensions, and nasal sprays), and semi-solids (creams and gels) pharmaceutical Rx and OTC products for late-phase clinical through commercial manufacturing and packaging. For more information visit: info@bora-corp.com
The growing use of CDMOs is being driven by the logical need of the industry: large pharma companies can divest non-core manufacturing facilities and focus capital instead on core products, while smaller companies often require the specialist services CDMOs offer to produce increasingly complex drugs cost effectively. For both small and large companies, partnering also allows for the reduction of risk, the management of costs, and ensuring the quality of the manufactured product.
The importance of the right partnership
The outsourcing partnership is one based on trust and begins with the technology transfer. When the pharmaceutical company transfers the required IP, the partner receives crucial technical and scientific information, which will allow for the manufacture of a product at a new manufacturing site. The formulation, manufacturing process, analytics, and packaging IP, as well as additional relevant documentation, knowledge, and professional expertise change hands in the process.
If the technology transfer is handled badly, issues and risks can be introduced all the way through the process. There can be problems with the initial batches, analytical testing, packaging, and potentially patient safety. As a result, it is essential that extra time and effort is taken to outline all relevant parameters, so that product quality does not become an issue and, if it does, that there are adequate warnings. In this article we outline the key parameters and considerations to take into account, to ensure a successful technology transfer.
Robust risk assessment
First, it’s critical to conduct a thorough feasibility evaluation at the outset of the technology transfer. A risk assessment should cover all activities included in the technology transfer, where the contracted partner challenges assumptions, offers practical solutions and offers a range of value-based options to address and mitigate potential issues. A good outsourcing partner can identify problems from formulation issues during scale up to spotting regulatory incompatibilities early into the process.
The more rigorously a process is challenged in the feasibility stage, the more robust that process will be during the scale up, validation, and commercial production phases. The technology transfer may not always be a smooth transition, especially when working with complex oral solid dose drugs, for example, but robust risk assessment is one way to ensure a quality end product.
Communication is key
When a technology transfer is executed successfully, both partners stand to gain in terms of time saved and costs minimized, while product quality is improved and performance risk is reduced. Communication to ensure this happens is central to the working relationship.
Technology transfer is a person-to-person, system-to-system knowledge transfer. In line with this, the better the exchange and communication of information, the greater the likelihood of successfully fulfilling the program’s financial and commercial goals. It is important for sponsors to provide all relevant information, including ‘tribal’ knowledge, in a secure, defined space where the respective organizations can collaborate to develop practical solutions and ensure a robust technical transfer package.
Three questions
When choosing an outsourcing partner, it’s worth considering the following questions first:
- Do they have a similar experience in scaling up similar processes?
- Are they capable of exploring the design space of parameters and identifying the critical process parameters before scaling up?
- Can they offer appropriate equipment to scale up and do they have the appropriate knowledge to scale up?
Critical Quality Attributes (CQA)
The technical transfer package is not complete until it provides Product Quality Attributes: Critical Quality Attributes (CQAs) and material attributes. A CQA appraisal will include an overview of processes, including unit operations, a control strategy, manufacturing process parameters, continuous improvement ideas and plans, historical deviations lists, and equipment and analytical technology lists.
SUPAC
Changes are often made to the manufacturing process after a drug is approved, from the equipment involved to the location of the site itself, or even the composition of the product. These are known as Scale-Up and Post Approval Changes (SUPAC). Any changes made can have an impact on the raw materials involved, manufacturing process, equipment train, manufacturing site, and the batch size. In turn, this can affect the CQAs of a drug or a finished product.
It is, therefore, necessary to consider in advance the impact of any changes on the quality of a drug or finished product.
SUPAC guidances provide those sponsors of new drug applications (NDAs) and abbreviated new drug applications (ANDAs) recommendations on the following: post-approval changes to components or compositions; the site of manufacture; the scale up/scale down of manufacture; and the manufacturing (process and equipment) of an immediate release oral formulation.
All in the analytics
The manufacturing process requires precise controls to ensure the quality of a drug throughout its lifecycle.
For example, at Bora Pharmaceuticals we utilize a wide range of analytical tools to support product quality, which is especially important to ensure commercial products meet the requirements of regulators and the patients themselves. This involves using Design of Experiments (DoE), risk assessment platforms, and Process Analytical Technologies. Through the utilization of such tools, a design space can be created between partners where the CQA can meet predetermined specifications during technology transfer and scale up activity.
Through analytical tools and when a sponsor provides reliable process knowledge, the contract manufacturing partner can establish a Normal Operating Range during technology transfer or a scale up activity.
Engineering runs
Before the scale up process, engineering (or demonstration) runs are the proving ground for the process and the equipment used during production. A successful engineering run is invaluable to ensure quality in subsequent current good manufacturing practice (cGMP) and packaging runs.
The engineering run is carried out on the commercial equipment train to gather data (including stability) and perform filling and packaging line trials. It also provides the processing data that can then be used in the scale up and validation steps to follow.
Since collecting this data is critical, at least one engineering run should be completed, with the risk of additional costs and delays if this step is neglected.
Scale up
Scale up is the process by which batch sizes are increased from feasibility or engineering batch scale to commercial scale, usually representing a 5-10x increase in volume.
Knowledge should be gained on two factors during this process: acquiring the chemistry and process knowledge to be able to effectively manage the formulation at commercial scale and developing a strategy to manage production and material costs.
Project and program management
An experienced project and program management team is an essential element in ensuring that challenges at the later stages of the process can be managed. Working together with sponsors has allowed our team at Bora to navigate hurdles that have arisen once a product has been submitted for approval to regulators.
In one example, Bora worked with a long-standing client on a complex modified-release capsule product with several different components. Once the product was submitted to the U.S. FDA for approval, an issue arose regarding capsule filling equipment not being able to measure individual component weights, which was deemed by the agency to be a necessary control parameter. The team at Bora organized a joint project group with the partner to develop potential solutions, resulting in a change to a more suitable capsule filling machine. The FDA agreed to the changes and the product was successfully approved and commercialized.
Key takeaways
We’ve provided a lot of information, but ultimately the three takeaway points to ensure a successful tech transfer are:
- Communicate openly and frequently from the outset through planned meetings with solid record keeping
- Establish working processes and take time with the initial planning stages
- Maintain a partnership based on trust and respect to ensure success with each transfer and program
References
Tom Chang is the President of Bora Pharmaceuticals Laboratory Co. Ltd. and oversees two manufacturing sites for Bora Pharmaceuticals. He has over 27 years’ experience in the pharmaceutical industry and over 14 years’ experience as a site general manager for multinational companies including Wyeth, Pfizer, and Impax. He has extensive knowledge and experience in global supply chain and operational management. Tom has outstanding leadership and professional skills and seeks to provide the highest quality products for his customers. He is a critical part of the leadership team at Bora Pharmaceuticals, a premier international CGMP CDMO specializing in oral solid dosage, liquids (solutions, suspensions, and nasal sprays), and semi-solids (creams and gels) pharmaceutical Rx and OTC products for late-phase clinical through commercial manufacturing and packaging. For more information visit: info@bora-corp.com
