Operational excellence in biopharmaceutical development and manufacturing
Having worked over the last 20 years in multiple companies ranging from start-up to large, multi-national biopharmaceutical companies in various functions in novel drug lead development, commercial manufacturing and Quality Assurance, has taught me that just pursuing the same objective is not enough to ensure success.
In addition to education, training and talent, thorough organization and coordination of all involved colleagues is a must differentiating between performance and excellence.
- The left picture shows a flock of birds traveling into the same direction in a loose formation. I have chosen this picture to display what I have often witnessed in work environments.
In such a situation, it is very difficult for colleagues to keep a holistic overview on the current status of a project or a tasks and to understand the importance of their contribution although knowing what the overall objective pursued is. Even worse, communication among colleagues is not efficient and scattered what requires a significant effort of the organization to ensure that all colleagues receive one truth communications in a timely way to support critical decision-making.
- The right picture of the header shows gooses flying in a well-organized formation enabling each bird to know the direction of the travel, where the other birds are and to share information efficiently. This model of organization enables safe, fast and efficient traveling in the case of the migration of gooses.
Transposing the messages from these pictures to our industry will equip us with the tools and ways-of-working to find the optimal balance between the different drivers ruling and impacting development of a novel drug lead and its later manufacturing and technical life-cycle management.
Establishment of a Product Development Value Stream
Development of a novel drug lead is a lengthy process that requires the coordinated collaboration of multiple colleagues with different functions and tasks ranging from research to manufacturing and business development to only mention a few.
Over the entire development cycle, several key decisions need to be taken such as investing into manufacturing capacity or progressing towards clinical trials. Both decision examples engage significant resources in a biopharmaceutical company. It is therefore of primary importance that decision-making is based on facts & data in order to mitigate risk exposure to the minimum necessary.
Working towards the same objective but not in a well-coordinated way (see the left picture of the header) however bears major risks that facts & data is not available to enable decision-making and risk mitigation at given moments in time in the development cycle.
The consequences of lacking facts & data can range from delays in development in the best case to continuing development for a novel drug lead that should be stopped in the worst case but for which data was not available at the moment of decision-making.
Having been exposed to such situations, it became obvious to me that integration of operational excellence approaches into novel drug lead development are necessary and will enable structuring the organization such that every colleague knows when what data is required to enable facts & data-base decision-making.
On two occasions, the first in a mid-sized and the second in an established multi-national biopharmaceutical company, I could prime and drive the development and establishment of a Product Development Value Stream which resulted in a deep impact on the quality of product development with regard to efficient coordination of multiple colleagues, speed, quality of scientific work conducted, and availability of all facts & data necessary to make decisions at a given moment in time.
Hallmark of the Product Development Value Stream is the structuring of the novel drug lead development cycle into clearly defined Stage Gates. For each Stage Gate a checklist has been prepared that outlines what data needs to be available to enable decision-making. This checklist has been prepared such that preparation of regulatory submissions are straight-forward with regard to CMC information.
The figure below shows how the Stage Gates of the Product Development Value Stream have been integrated into the End-to-End novel drug lead development cycle including product launch and handover to the Technical Life-Cycle team.
Product Development Value Stream showing the six Stage Gates structuring the novel drug lead development cycle
Selection of optimal technologies and platforms
The three pictures below show the evolution of bioreactors over the last 40 years. The left picture shows a bioreactor together with associated analogue controls in the early 1980's. In the center picture is shown a bioreactor operated using digital controls what enabled already a massive simplification of the support installations required for its operation. The right picture shows an example for a mobile stand-alone 2000-L single-use bioreactor being currently the highest level of integration and independence.
Evolution of bioreactor technology over the last 40 years
Major technological advances have taken place in the entire biopharmaceutical industry significantly changing product development and manufacturing. The advent of single-use technologies paired with increased productivity cell lines, better media, much better understanding of cell cultivation and purification make selection of the most appropriate clinical and commercial manufacturing technologies more complicated.
Today, various technology options exist from traditional stainless steel to fully single-use for upstream manufacturing and various purification technologies can be combined to achieve the desired scale, purity and process efficiency.
As outlined above, technology choices have to be taken early in the novel drug lead development cycle to supply clinical phase I and II material at a time when the risk of attrition is still very high.
Most of the times, the technology choices taken will only evolve slightly to enable scale-up of the manufacturing process to avoid the risks associated with changes in the manufacturing process architecture requiring potentially further clinical verification which would cost significant time.
It is therefore very important to think ahead of technologies that could be used as a platform enabling product development and commercial manufacturing not only of the drug which was priming technology selection and adoption.
Identifying the most appropriate technology should be based on science and performance on one and cost, supply security, compliance with regulatory requirements, longevity, and multipurpose capability on the other side of the equation.
Over the last 20 years, I have been exposed on various occasions to such decision-making. Driving building of a development and manufacturing platform has enabled a mid-sized biopharmaceutical company to streamline and increase process development and clinical manufacturing capacity to match an ambitious and continuously increasing novel drug lead pipeline.
Selection of facility type, design, start-up and operation
The evolution and improvement of technologies used in novel drug lead development and commercial manufacturing had also a significant impact on the facility architecture and ways of building. Today, facilities are still built in the traditional way meaning concrete and steel, but modular concepts offer significant advantages to balance depending on type and scale of novel drug lead being developed or commercially manufactured.
In the frame of selecting and adopting technologies, I have also been exposed to develop new or work-over existing facility concepts for producing therapeutic proteins, vaccines and cell & gene therapies. Selecting a novel manufacturing platform and adopting the associated facility concept in a mid-sized biopharmaceutical company has permitted to ramp-up process development and clinical manufacturing capacity within 18 months to match an ambitious and continuously increasing novel drug lead pipeline.
Ballroom concept production area integrating fully single-use based up-and downstream operations
Establishment of a Technical Life-Cycle Value Stream
Once development of a novel drug lead has been successfully completed with a regulatory approval for commercialization, two novel challenges start which can be best described as proactive and reactive activities to ensure supply continuity of the drug to patients in need.
The focus of the two activities are different:
The reactive activities can also be described as crisis management required when unforeseen issues pop up that require investigation, troubleshooting and problem-solving to recover and secure manufacturing operations, analytical testing, and the supply of raw materials as well as of intermediates and finished drug products.
The proactive activities can also be described as continuous improvement driven by the evolution of scientific knowledge, technologies available, regulatory requirements, market development, as well as commercial requirements and potential.
Having been responsible for Technical Life-Cycle Management in a large, multi-national biopharmaceutical company producing 30 marketed drugs requiring over 250 stock-keeping-units (SKUs) to ensure global supply, I was in the front seat to witness the consequences of vaguely coordinated reactive and proactive activities.
As for the Product Development Value Stream presented earlier, I could prime and drive the development and establishment of a Technical Life-Cycle Value Stream.
The result was deeply impacting the quality of proactive continuous improvement activities with regard to the selection of the most attractive projects and the efficient coordination of multiple colleagues to achieve speed, quality of scientific work conducted, and availability of all facts & data necessary to make the final decision for implementation given the strict regulatory framework of an approved drug.
On the other hand, the Technical Life-Cycle Value Stream enabled a structured approach towards crisis management resulting in faster identification, contextualization and framing of the issue(s) thanks to a structured communication and investigation sequence which is the basis for efficient troubleshooting and problem-solving.
The figure below shows how the Stage Gates of the Technical Life-Cycle Value Stream have been integrated into the End-to-End continuous improvement cycle for approved drugs together with the reactive troubleshooting and problem-solving activities.
Technical Life-Cycle Value Stream showing the Reactive and the Proactive pathways
Finding the right and if possible optimal balance
The probably most difficult task in novel drug lead development as well as drug manufacturing is to find the right balance between the different impacting factors.
The risk of under- and overreaching various requirements is real and its materialization has significant negative impacts in both cases.
With this in mind, the quote of Saint-Exupéry saying that "perfection is achieved not when there is nothing left to add but when there is nothing left to take away" holds true not only when crossing the South Atlantic with an Aeropostale plane in the 1930's when every kilo saved adds flight time, but is still a very potent guide for us in the biopharmaceutical industry due to the massive effort and cost development of a novel drug lead and its later manufacturing entails.
Building on this understanding, my objective is to take you beyond the Oracle of Delphi and to Get concrete solutions !