By Jani Yömaa and Andrés Guerrero, 3PBIOVIAN
Analytical services are critical to the development and manufacture of safe and effective biopharmaceuticals. These analytical services often are outsourced to third-party laboratories, and in some cases, more than one provider is used. However, leveraging separate vendors for development, manufacture, and analysis can sometimes lead to technical and regulatory challenges.
In response, biopharmaceutical sponsors are increasingly choosing to partner with CDMOs with extensive integrated analytical capabilities, which enables a more seamless and collaborative partnership from early development through commercialization. However, reaping the full benefit of a CDMO’s in-house analytical capabilities requires a full understanding of such benefits and how value can manifest. In addition, it is essential to understand how to differentiate one provider from another.
When Samples Exit The Building, Added Risk And Cost Can Enter
Outsourcing of analytical assays is necessary, to some extent, for nearly all projects, particularly in cases where establishing in-house capability does not make sense for a CDMO (e.g., adventitious virus analysis). However, some laboratory testing should or must take place in-house: for example, time- and safety sensitive samples related to microbiology, endotoxins, or even a product that simply is not stable could be compromised when testing is outsourced. The result could be loss of process control, quality challenges, increased costs, and extended project timelines.
Additionally, a CDMO that sends samples to one or more third parties for analysis must audit and qualify each vendor in advance. Next, the CDMO assumes the costs and risks associated with outsourcing that activity, including packaging the samples and shipping. Moreover, shipping to a dedicated analytical laboratory also adds to the project timeline and introduces the risk of damage to the samples.
Outsourcing analytical services to a third party also can rob a sponsor of visibility into the state of their molecule’s stability. For example, a sample could be shipped under supposedly optimal conditions, yet degradation or other unexpected effects occur during transport. Organizations can easily overlook these impacts if they rely solely on the lab’s reported results. But, if the results are somehow ambiguous, it is difficult, if not impossible, to determine the extent to which shipping impacted those results. In short, shipping samples introduces additional variables.
Also, the transfer of analytical methods from an analytical vendor to CDMO or sponsor presents a significant challenge. Due to differences in instrumentation, operator knowledge, and workflows, it is nearly impossible to generate the same results from two different laboratories. So, each transfer results in some loss of information or subtle changes in the way analyses must be performed.
Outsourcing analytical services to more than one laboratory also introduces the risk of performing overlapping studies, complicating the project supply chain and burdening the program manager with additional tasks, though these risks can be mitigated by establishing strong communication plans to avoid duplication of activities and keep the project under control.
Keep Your Process Close, and Your Product Closer
As CDMOs increase their analytical capabilities and expertise, production can be monitored more comprehensively, enabling fast-track process development and creating analytical knowledge of each API from its inception. This collected knowledge is invaluable as each project moves through clinical, IND, and commercial stages.
These CDMOs’ sponsor partners benefit from a more complete understanding of their drug substances and greater clarity regarding the analytical methods used to characterize each substance. Drug substance release methods are more thoroughly vetted and reliable when they are developed in-house, in parallel with the production activities; they also are more easily explained and justified when writing regulatory documents or responding to agency queries.
Regarding drug manufacture, close collaboration between analytical scientists, project management, and the production team helps establish logical points of control throughout the process. It also helps to identify retention points where it might be best to stop the process and await analytical results before proceeding. Such meticulousness would be extremely complex or impossible when outsourcing time-sensitive samples to a third party.
Having an array of alternative analytical methods to understand specific problems quickly empowers CDMO and sponsor teams to make important decisions quickly, without the risk of negative timeline impacts or lost information. Representatives from each critical team can be in the same room during discussions, versus constantly meeting with representatives from third parties and trying to tie their questions, suggestions, and findings together. This is particularly impactful when a project transitions to later phases, when critical quality attributes (CQAs) must be precisely defined and process validation accomplished.
Additionally, investigations and root cause analysis of out-of-specification (OOS) issues benefit from in-house analytical capability. Near-instant access to analytical scientists and instrumentation provides a clear advantage in terms of communication and timeline. Also, in-house knowledge of the specific protein or viral vector being produced and the manufacturing process constantly grow within the organization at a level unattainable when working with a third-party lab, simply returning results. Documentation is more consistent, easing data analysis by both the sponsor and regulatory authorities. This homogeneity — in communication, analytical execution and interpretation, and documentation — makes results simpler to understand and to report.
Experience Is A Key Differentiator
A common myth is that CDMOs with in-house analytical offerings are somehow inferior to dedicated, third-party analytical laboratories because they will operate principally as producers and only secondarily as analytical laboratories. This is counterintuitive, given the volumes of diverse projects and processes a CDMO is exposed to across its customer base, resulting in exposure to many different protein and product candidates analyzed over time. It also must be acknowledged that regulatory authorities inspect CDMO in-house analytical operations to the same standard they hold dedicated analytics shops.
As a result, a CDMO with inadequate analytical capabilities would be incapable of developing a manufacturing process, let alone optimizing processes specific to each customer and project. In this respect, experience is paramount. A CDMO that has partnered with sponsors across hundreds of projects eventually crafts platform processes designed to handle specific issues, from identifying risks to solving quality assurance (QA) issues and troubleshooting OOS results. Each problem represents an opportunity for the CDMO to learn and to refine its internal mechanisms to be more effective. This knowledge is leveraged for subsequent programs, benefiting sponsors. Additionally, a CDMO with strong quality systems is likely to be more adept in auditing and supervising the qualified CROs to whom it does outsource some testing, if and when necessary.
Also, the importance of accumulated knowledge within an organization cannot be overstated. It is one thing to be able to provide a menu of analytical services; it is another to have a wealth of experience in, for example, a specific stability study. An experienced individual or team can observe precipitation of the protein, or aggregation, and they can connect the dots between that event and potential causes and/or outcomes. Useful analytics not only produce an unambiguous result, but they also contextualize that data, relating it to problems that have been observed and pointing the way toward strategies to overcome any issues.
Find Analytical Certainty Under One Roof
In-house analytical capabilities within a CDMO contribute to improved efficiency, speed, and data integrity across the drug development life cycle. CDMOs that offer in-house analytical expertise can contribute to enhanced communication and better-informed decision-making throughout a project, as well as reduce turnaround times and mitigate risks compared to outsourced analytical services.
The key element of the value provided by in-house analytics isstreamlined process development. The fact is, development proceeds more slowly when in-house analytics are not available, since those critical tools are almost compulsory to monitor the manufacturing process, and each degree of separation between the sponsor and its analytical data adds time and cost.
While the dollars-and-hours benefit of avoiding the potential delays and extraneous costs associated with outsourced analytical services can be difficult to quantify, the outcomes that may otherwise occur, such as failed batch releases, are tangible. Losing a GMP batch is costly by any metric, and it can be caused by miscommunication, failure to integrate analytics with the production process, or any number of other risks associated with reasons related to outsourcing analytics to one or more third parties.
Accordingly, working with a CDMO that offers an in-house analytics department is now considered an industry best practice. This team reinforces QA and can quickly accommodate any compliance problems that emerge during development and production activities. Also, it is vital to carefully vet CDMOs to learn the extent of their analytical capability and the depth of their experience with similar compounds. This due diligence ensures the partner fully understands and is equipped to handle the sponsor’s project. To learn more, contact the authors and visit https://3pbiovian.com.
About The Authors
Jani Yömaa, M.Sc. Biochemistry – Director of Analytical Development, co-founder of 3PBIOVIAN (Turku site). Jani brings to 3PBIOVIAN 20+ years of experience in the biopharmaceutical industry. Earlier in his career, Jani worked as a Principal Protein Scientist responsible for process development, scale-up, protein purification, and protein characterization of clinical-grade therapeutic proteins. He had a central role in establishing collaborative working relationships between the Analytical Development, Research, and Quality Control departments both internally and at external CROs. He has a solid understanding of the fundamentals of ICH and other industry guidelines supporting drug development, analytical method development, and method validations. He also has extensive knowledge in the field of in-vitro diagnostics and taught Biochemistry graduate students at the University of Turku.
Andrés Guerrero, B.Sc. Biology, B.Sc. Biochemistry, PhD Chemistry – Analytical Development and Quality Control Director (Pamplona site). Dr. Guerrero joined 3PBIOVIAN in 2019 and is responsible for all analytical activities at the Pamplona Site, from early development to validation and GMP testing. He has more than 15 years of experience in R&D — both in academia and industry — evaluating, developing and using a wide range of techniques and concepts applied to the fields of medical science, pharmaceutical development, and food science. Before arriving at 3PBIOVIAN he worked as a postdoctoral researcher at the University of California developing tools for the high-throughput analysis of proteins, peptides, and glycans in large sample cohorts. He worked also at ProZyme and Agilent Technologies as R&D Manager, developing methods, standards and instrumentation for the analysis of proteins and carbohydrates.
About 3PBIOVIAN
3PBIOVIAN is a globally operating Contract Development and Manufacturing Organization (CDMO), delivering end-to-end services for biotech and pharma companies. Their service offerings include protein expression and production platforms based on microbial strains and mammalian cells, plasmid DNA, viral vectors for adenovirus and adeno-associated virus for gene therapy, and cell therapy products. Additionally, they provide fill and finish services for recombinant proteins and viral vectors. The company has manufacturing facilities in Pamplona-Noáin, Spain, and Turku, Finland, efficiently supporting the diverse needs of their clients, covering everything from preclinical and clinical supply to large-scale commercial manufacturing for drug substance and drug product.
