Many years ago I heard a QA executive say, “The only difference between two batches of a validated process should be their dates of manufacture.” The underlying message here is that the manufacturing process should be so well designed, so well understood and so well described that it is obvious when anything is wrong. The complexity of pharmaceutical active ingredient (API) processes allows opportunity for great variability. Current approaches to process design and development largely eliminate such variability, but the risk incurred by development investment prior to approval usually subverts the process designer’s better efforts. Many pharmaceutical companies identify their commercial supply chain during clinical development. Reconciling the benefit of early commercial supply chain development with risk of early process development is a constant challenge to the pharmaceutical manager. Yet the well-designed process is foundational to the development of a robust manufacturing supply chain: between a pharmaceutical company (hereafter referred to as “Pharma”) and the contract manufacturing organization (hereafter referred to as “CMO”) the best tool for success is a well designed, well described manufacturing process .
With an interest to continue the dialogue between Pharma and CMOs about supply chain development, the authors of this supplemental issue of Outsourcing have offered well-described articles and referenced papers covering four critical topics for the Pharma-to-CMO relationship: Quality by Design, continuous processing, particle engineering, and the evolution of regulations for API manufacturing.
Quality by Design
Since its introduction in 2003 , the impact of Quality by Design (QbD) has allowed regulatory bodies and the API manufacturing industry to evaluate process design and performance with an emphasis on risk understanding and mitigation. The design of processes with quality in mind allows the developer to achieve processes with much greater understanding and control; by providing well-designed operational reliability, QbD removes regulatory risk and lowers cost . The multiple perspectives on QbD in the API outsourcing industry offered by the article herein (Seibert, et. al.) will shed light on this important tool for process conformance and product quality in the dynamic interface between Pharma and CMOs.
Approved Active Pharmaceutical Ingredients used in solid oral dosage forms are comprised of particles matching critical quality attributes which enable a patient to realize therapeutic advantage from the formulated products. In cases where the desired product attributes cannot be achieved, formulators may look for modifications of the active ingredient to achieve the desired outcome. A classic example is to micronize the API to increase surface area, and potentially, dissolution rate. Many other examples of the need for particle control exist throughout pharmaceutical research. The API industry (especially Pharma manufacturers) have historically designed processes to grow large particles for ease of filtration and drying, followed by terminal milling of the dried material. Other milling technologies have enjoyed increased use in the last decade as well. Jarmer and Burcham (vide infra) have described emerging technologies in solid form process engineering which can have a dramatic impact on the consistency of an API, improve reliability of the crystallization process and yield materials that meet critical quality attributes without involving any downstream processing. These techniques are described here for APIs but can be applied to intermediates as well (for example, thermo cycling to improve impurity profile and particle form).
Chemical companies have long used continuous processes for production of large volumes of materials, in situations where the reaction conditions are best operated in a flow paradigm, and where process control can be achieved with in-line controls. The legacy approach to process design in the pharmaceutical industry has leveraged batch operations. Batch operations have provided a convenient model from lab to plant which enabled chemists to continue to define their synthesis routes during clinical supply campaigns. Further, the expense involved in designing an advanced process operation might make more sense after product launch. With their paper on continuous process design during clinical development, Scott May and Martin Johnson describe a number of platform technologies that allow pharmaceutical process design scientists to capitalize early on the inherent benefits of continuous processes while continuing to finalize syntheses prior to registration. These platforms will also enable Pharma companies and CMOs to partner directly on continuous process deployment for commercial and clinical supply of APIs.
Emerging Regulatory Realities for API Outsourcing
It is essential to engage source development at all stages of the API’s development. Between Pharma Companies and CMOs, the management of source development is strongly linked to the Pharma companies' appetite for investment risk, especially during the earliest stages of development when Pharma is looking for technology to enable early clinical supply. For all Pharma companies, there will be a point in the development and commercialization of an API process where investment in process intensification has clear benefits for the risks involved. In his paper, “Implementing New Technologies in a Regulated Environment” (vide infra), James Bruno outlines the supply management challenges presented through the evolving regulatory landscape for active ingredients.
Looking Forward –Thoughts about People Capabilities
Pharma Companies are quite concerned about the security of their supply chains for everything from GMP consumables to active ingredients to formulated products and packaging. As custom elements of that supply chain, the API, its intermediates and raw materials emerge from a substantial body of study during development to enable the API’s reliable commercial supply. A Pharma companie's best first strategy for a reliable API source is to match a well-designed manufacturing process  with a well-staffed manufacturing firm where such a process can be realized. Pharma companies leveraging emerging technologies and strategies during process design will need CMOs who provide the best opportunity for commercial supply that matches the design technology. Therefore CMOs should look to apply platform technologies and strategies – some of which are described in this supplement – to solidify their role in the API outsourcing industry. Importantly however, these technologies are normally not off-the-shelf, and always require subject matter experts who know when and how to use them. The reality is that this can often be overlooked by the aspiring Pharma or CMO during their engagement.
CMOs should also look to match their scientific disciplines to the Pharma companies’ process design needs. Within this industry, CMOs sometimes feature a one-sided technological capability for process chemistry. Engineering has always been present in our industry; however chemical engineers typically support unit operation design or plant production. Analytical chemistry is sometimes limited to the quality control lab. In cases where a CMO features a central analytical laboratory, this capability is wholly separate from the design effort. In fact some companies’ design labs pay for analytical development on a fee-for-service arrangement with their own central lab. The reality for full-service outsourcing companies in the API industry is that a high-performance development team must be balanced with process chemists, analytical chemists and chemical engineers all working on the process design itself. Companies who provide a balanced team approach will be valuable collaborators for development, registration and commercial supply.
Finally, Pharma companies and CMOs can benefit their collaboration through the employment of prescient project managers on each side of the relationship. Individuals with experience in commercial process design and material delivery will be able to foresee developing issues; knowledge of their own organization’s capabilities will allow the project manager to quickly resolve issues and redirect resources to critical needs. Experienced project leaders can also keep team morale on a positive track and leverage the strengths of various team members to achieve the desired outcome.
- FDA Guidance for Industry Contract Manufacturing Arrangements for Drugs: Quality Agreements, May 2013. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM353925.pdf
- Pharmaceutical Quality by Design: Product and Process Development, Understanding, and Control, Journal of Pharmaceutical Research, Vol. 25(4), pp 781-791, 2008
- Financial Justification for QbD and Cost of Regulation Compliance, Girish Malhotra, Pharmaceutical Processing, Analyst Blog, May 23, 2012. See: http://www.pharmpro.com/articles/2010/03/pharmaceutical-costs-technology-innovation-opportunities-reality
- Building a Sustainable API Supply Chain, Pharmaceutical Outsourcing, January 29, 2013.
Thomas M. Eckrich, Ph.D., is Advisor, Chemical Product Research and Development at Eli Lilly and Company. Tom received a BS in chemistry from Purdue University and a doctorate in chemistry from Harvard University. Tom has worked for Eli Lilly and Company since graduating from Harvard, starting out as a chemist working in the area of antibiotic research. Tom has held various leadership positions in chemical development, including the position of managing director of Lilly’s European Development Centre in Brussels, Belgium. Tom has published 10 scientific papers and holds three patents. Tom is currently a member of Lilly’s Small Molecule Design and Development leadership team with responsibility for small molecule outsourcing strategy.