Executive Summary: Rapid Path to Market: A Case Study of Accelerated Biopharmaceutical Development
This white paper details a landmark project undertaken jointly at Rentschler Biopharma’s Milford, Massachusetts and Laupheim, Germany, facilities, where the company successfully compressed the typical biopharmaceutical development timeline to achieve process performance qualification (PPQ) from good manufacturing practice (GMP) initiation in just 12 months — a process that conventionally takes 15 to 18 months. This achievement not only highlights Rentschler Biopharma's expertise in rapid biopharmaceutical development but also underscores its strategic capability to meet aggressive market demands, and is further notable given that this was the first PPQ project undertaken at the new Milford facility.
Facing direct competition, a client needed to expedite the development and approval of a groundbreaking therapy. The urgency to be first to market required a development and manufacturing partner that could navigate complex regulatory landscapes efficiently while maintaining the highest standards of quality and compliance. Rentschler Biopharma, with its dual-site capabilities spanning the United States and Europe, was uniquely positioned to rise to this challenge.
The project showcased innovative approaches to several key processes:
Process optimization: Rapid adaptation and optimization of chromatography processes, crucial for ensuring product purity and scalability.
Global collaboration: Leveraging expertise from both the Milford and Laupheim sites, Rentschler Biopharma demonstrated exceptional inter-site collaboration, aligning global resources to enhance process efficiencies and expedite development.
Regulatory excellence: The project adhered to stringent FDA guidelines from inception through completion, with the PPQ phase meticulously validating the production process to ensure consistent, high-quality outputs.
Key outcomes of the project included:
Market leadership: The client was the first to market, significantly impacting patient care and capturing a critical competitive edge.
Operational insights: The project yielded profound operational insights, particularly in terms of process scalability and inter-site collaboration, setting a new operational precedent for future projects.
Strategic growth: The success of this project has further positioned Rentschler Biopharma as a leader in fast-track biopharmaceutical development, demonstrating its capability to support similar ambitious projects.
Here, we explore the strategies employed, challenges overcome, and the technical and operational innovations that characterized this remarkable project.
Accelerated Development in a Competitive Market
The pharmaceutical landscape has grown fiercely competitive, compelling companies to significantly accelerate their development timelines and reduce costs. Achieving first-to-market status with cost-effective, differentiated therapeutics is not just advantageous — it's increasingly critical for commercial success.
One of Rentschler Biopharma's clients faced direct competition in developing a therapy analogous to one in development at a rival pharmaceutical company. The urgency to outpace the competitor and be the first to reach the market necessitated a contract development and manufacturing organization (CDMO) capable of adhering to an exceptionally aggressive timeline. Rentschler Biopharma, with its strategic locations in the United States and Europe and a rich history in fast-tracking biopharmaceutical commercialization, was perfectly positioned for this challenge. Despite the Milford, Massachusetts site being new to implementing such programs, Rentschler Biopharma successfully expedited the project from the initial good manufacturing practice (cGMP) manufacturing run through to process performance qualification (PPQ) in a record 12 months, showcasing their capability to meet and exceed the demanding industry standards.
The biopharmaceutical sector is characterized by intense competition and high regulatory standards, where the race to bring new therapies to market can dictate a company's success or failure. Innovations in medical science are rapidly expanding treatment possibilities, placing pressure on pharmaceutical companies to not only innovate therapeutically but also to streamline development processes. The first-mover advantage in this sector is particularly significant, as early market entrants can establish brand recognition, optimize market share, and maximize the period of patent exclusivity. However, accelerating development cycles must be balanced with the stringent requirements imposed by regulatory bodies such as the U.S. Food and Drug Administration (FDA), which mandate rigorous validation of all processes to ensure patient safety and product efficacy.
In response to these challenges, Rentschler Biopharma, a seasoned contract development and manufacturing organization (CDMO) with a rich legacy in biopharmaceutical commercialization, took on a task set by a client competing to be the first to market with a novel therapeutic drug, amid fierce competition from another company developing a similar therapy. This white paper chronicles Rentschler Biopharma's approach to this challenge, showcasing their dual-site capabilities across the United States and Europe and their adeptness at navigating the complexities of accelerated development timelines.
The project was initiated at Rentschler Biopharma's Milford, Massachusetts facility, marking the first time a PPQ would be implemented at this location. The Milford team successfully leveraged the CDMO’s global resources and expertise to not only meet but exceed the project's ambitious goals. This involved critical early-stage process development, innovative optimization strategies during scale-up, and seamless inter-site collaboration, particularly with the Laupheim, Germany facility, known for its extensive experience in late-stage development.
Ensuring Drug Consistency Through Process Performance Qualification
Process performance qualification (PPQ) is a pivotal component of drug production, ensuring that every batch of the product is robust, reliable, consistent, and meets stringent quality standards. PPQ is the second phase in the three-stage life cycle approach to process validation recommended by the U.S. Food and Drug Administration (FDA). This life cycle begins with process design, followed by PPQ, and concludes with continued process verification (CPV), which monitors the process’s consistency throughout its operational life span (Figure 1).
Figure 1.
During the PPQ phase, manufacturing-scale batches are meticulously produced and analyzed to verify both the process and its monitoring/control strategies. This stage is crucial for confirming that the production system can consistently deliver a product that meets predefined quality specifications. The rigorous testing during PPQ includes assessing the robustness and reliability of the production process and ensuring that the drug substance, key intermediates, or final drug product consistently exhibits high quality from batch to batch.
The importance of PPQ in biomanufacturing cannot be overstated. It not only confirms the process capability but also ensures regulatory compliance and patient safety by rigorously evaluating the efficiency and precision of the entire manufacturing process. By thoroughly validating the process during PPQ, manufacturers can identify potential variability in the production process and implement necessary controls to mitigate risks, thereby safeguarding the quality of the pharmaceuticals produced.
Global Collaboration: Harnessing Cross-Continental Expertise
Rentschler Biopharma's strategic integration of its facilities across the United States, Germany, and the United Kingdom reflects a unified operational philosophy dubbed "One Rentschler." This philosophy is underpinned by globally standardized management systems, encompassing quality management, risk assessment, and validation activities, ensuring consistency and excellence across all sites. The project's early development and initial GMP run were skillfully executed at the U.S. site in Milford, leveraging the facility's modern infrastructure and technological capabilities. Following this phase, the project was seamlessly transitioned to the Laupheim, Germany, facility renowned for its nearly half-century of expertise in late-stage development.
At Laupheim, the project underwent crucial late-stage development, process characterization studies, and analytical method validation. This strategic move not only utilized the deep-rooted experience of the Laupheim site to complete all necessary documentation, pre-validation work, and stability studies but also prepared the Milford facility for the next phases of development by allowing it to focus on additional early-stage programs. The final phase of the project, encompassing PPQ execution, was transferred back to Milford, marking a significant milestone as it was the site's first execution of such a critical stage.
Acquired from Shire in 2019, the Milford site has been transformed into a cutting-edge, multi-product facility that stands as a pivotal element of Rentschler Biopharma's expansion into the U.S. market. Located in Boston’s vibrant biotech hub, the facility is designed to leverage single-use technologies to support a range from clinical development to commercial-scale manufacturing, offering versatile production capacities ranging from 500 L to 2,000 L. A recent addition of 22,000 square feet of manufacturing cleanroom space (Line 3) effectively doubled the global cGMP capacity of Rentschler Biopharma, underscoring its commitment to scalability and flexibility.
The synergistic relationship between the Milford and Laupheim sites facilitated a robust preparation for Milford’s inaugural PPQ. This collaboration was instrumental in addressing and overcoming supply chain challenges, establishing alternative sourcing strategies for critical components, such as filters, and ensuring continuity in production quality. Additionally, the execution of three GMP runs at Milford provided the local team with invaluable experience and insight, enabling them to generate the necessary documentation and understand the process intricacies thoroughly.
Managing the Unexpected
Familiarity with the biotherapeutic type was a critical factor in the rapid advancement of this project at Rentschler Biopharma. However, the path to development is seldom without its hurdles, and this project was no exception. The unpredictable nature of biologics during scale-up processes presents unique challenges that must be adeptly managed to maintain project timelines and quality standards.
During the scale-up of downstream processes, it became apparent that the existing chromatography method could not be practically scaled based on the initial molecular structure analysis alone. This realization came after thorough characterization studies and extensive testing of various buffer combinations, highlighting a fundamental aspect of biopharmaceutical development: the need for flexibility and adaptability in the face of unforeseen challenges.
The necessary redevelopment of the chromatography processes involved a detailed investigation into alternative buffer formulations, loading conditions, and peak cut criteria to ensure robust removal of impurities and gradient modifications to achieve a scalable solution (Figure 2). This phase of redevelopment was critical and required a strategic revision of the existing methods to ensure the project remained on track. Despite these complexities, Rentschler Biopharma’s expertise and proactive management enabled the completion of this project within the established timeframe, underscoring their ability to handle the unexpected with precision and efficiency.
Figure 2.
Team Synergy Driving Successful PPQ Execution
The successful execution of PPQ runs at Rentschler Biopharma exemplifies the power of collaborative teamwork and diverse expertise. For the featured project, dedicated teams across both the Milford and Laupheim sites engaged deeply in lab-scale process development work. The manufacturing, science, and technology (MSAT) teams at these sites were instrumental in managing the scale-up from laboratory to commercial production and were responsible for authoring the essential protocols for the PPQ campaign. Furthermore, the long-standing experience regarding process validation within the Laupheim MSAT team was an integral success factor in achieving the PPQ and market authorization.
Given that this project marked the inaugural PPQ at the Milford site, the integration and synchronization of efforts were particularly critical. The quality control (QC) teams from both the U.S. and German sites played key roles in co-validating the methods, ensuring that the processes adhered to stringent regulatory standards. Meanwhile, the quality assurance (QA) teams oversaw the final documentation and maintained general oversight, ensuring that all aspects of the project met the highest quality benchmarks.
The addition of substantial resources from the Laupheim site was a decisive factor in accelerating the project timeline. Notably, the lead from the process characterization team at Laupheim provided invaluable on-site support in Milford once the process was transferred back to the United States, facilitating a seamless PPQ implementation.
These teams didn't operate in isolation; they were united under Rentschler Biopharma’s global policies that promote regular communication and synchronization of efforts. Weekly or biweekly meetings among the process science teams, and similar coordination within the QC and other departments, ensured a harmonious approach to tackling challenges and aligning on development activities. This structured yet flexible collaboration framework was critical in enabling the successful and timely completion of Milford's first PPQ.
Strategic Growth: Milford’s Successful Execution of Its First PPQ
Rentschler Biopharma’s Milford site successfully completed its inaugural PPQ, demonstrating the site’s readiness and robust operational capabilities. This milestone reflected the team's expertise, as well as its proactive approach to optimizing processes and ensuring seamless execution from the outset.
Leveraging the insights gained during this process, the Milford manufacturing team has further strengthened its operations by expanding both in size and expertise. Strategic investments have been made to enhance the site’s capabilities, ensuring even greater efficiency and precision in future projects. The focus on harmonizing operations with Rentschler Biopharma’s Laupheim site has also been a priority, aligning facility designs and equipment to deliver streamlined, high-quality outcomes.
The completion of this PPQ is a testament to Milford’s ability to drive innovation, accelerate development timelines, and maintain uncompromising standards of quality. This achievement underscores Rentschler Biopharma’s leadership in biopharmaceutical manufacturing and its commitment to delivering excellence for clients worldwide.
Realizing Rapid PPQ Completion and Market Entry
The timeline for this project at Rentschler Biopharma was a testament to operational efficiency, reducing the typical process from GMP1 to successful PPQ completion to just 12 months (Figure 3). Normally, process characterization alone can take nine to ten months, followed by a four- to five-month period for preparation prior to executing the PPQ campaign. Additional months are often required between the completion of GMP1 and the start of process characterization activities, extending the full timeline to as many as 18 months. The requirement for process optimization, such as the preoptimization of the chromatography step undertaken in this project, typically further extends these timelines.
Figure 3.
However, through strategic planning and rigorous execution, Rentschler Biopharma achieved this ambitious goal within the accelerated timeline, marking a significant accomplishment. This rapid progression not only enabled the client to advance its new biologic but also facilitated securing FDA approval in the year following the PPQ’s completion. The team’s dedicated efforts in preparing the biologics license application and conducting preparations for the FDA’s pre-approval inspection were crucial in achieving this milestone.
This success reflects the “One Rentschler” philosophy, where all team members across sites unite under a common goal, demonstrating the company’s commitment to fostering true partnerships with its clients. Rentschler Biopharma leverages its size for greater agility and responsiveness in project management. The successful completion of the first PPQ at the Milford site — with a highly accelerated fast-track to BLA timeline — illustrates Rentschler Biopharma’s dedication to going the extra mile to ensure client success and market impact.
Looking Ahead: Driving Innovation and Growth
The accelerated PPQ project at Rentschler Biopharma's Milford facility not only showcased the company's ability to meet stringent regulatory standards and aggressive timelines but also set a precedent for operational efficiency and strategic growth in biopharmaceutical development. This experience underscores the potential for more efficient future projects, emphasizing the importance of agile responses to market and regulatory demands. The successful integration of expertise across Rentschler Biopharma’s sites highlights the benefits of global collaboration, enhancing the company's flexibility and capacity to deliver tailored solutions. By continuing to invest in cutting-edge technologies and methodologies, Rentschler Biopharma remains at the forefront of biopharmaceutical innovation. Moreover, the project reinforced the value of a proactive regulatory strategy and a strong client-centric approach, which are essential for sustaining long-term relationships and ensuring project success. As the company expands its capabilities, the insights and successes from this project will serve as a foundation for future growth, ensuring continued excellence in delivering reliable solutions that drive client success.
