Quality management is not, however, a one-size-fits-all endeavour. Products at different stages of the drug development cycle require specific control strategies, which manufacturers need to understand and know how to implement.
In this interview, Michael Marini, Senior Director of Quality for Lonza’s Small Molecules Division, tells Dr Kevin Robinson how contract development and manufacturing organisations (CDMOs) can help customers to holistically address quality management challenges, incorporating the needs of both early and late-phase projects simultaneously.
Specifically, he explores how a phase-appropriate approach can reduce time to clinic and lower overall programme costs in early phase clinical development.
KSR: What are customers asking for when it comes to quality management?
MM: It goes without saying that compliance is a condition of doing business in the CDMO space. All customers want assurance that work will be executed in a compliant manner that is defendable to industry regulators.
Mike Marini
What they don’t want is a quality approach that obscures the objective, especially in the early phase of clinical development. That’s why a phase-appropriate quality management system is a must to ensure the application of the right amount of rigor while ensuring optimal speed of supply to meet customer dosing timelines.
KSR: How does Lonza envision a quality management system (QMS)?
MM: At Lonza, we’re in the process of re-evaluating our quality management system to adopt risk-based and fit-for-purpose practices that enable agility while still maintaining compliance.
The QMS is an integral component of any service offering and we want to ensure alignment across all our services; being phase-appropriate enables us to accelerate timelines and better meet customer needs.
An example of this is our focus on an early phase QMS within the Small Molecules Division. Historically, Lonza has largely exercised a conservative and standardised “one-size-fits-all” approach to compliance, modelled around late-phase expectations.
Although perhaps a bit cumbersome in the early phases, it ensured that compliance expectations were met and that an appropriate control strategy was in place at the time of submission for marketing approval.
However, we recognise that this approach can be problematic and cause undue delays in the early phases when processes are not well established or robust … and process understanding is nascent.
These avoidable delays can be detrimental to the success of early stage programmes, especially those sponsored by smaller companies. These companies now own the vast majority of early stage molecules and are often dependent on external funding to reach IND/IMPD.
Additionally, the rigour in establishing a late-phase-style control strategy for a Phase I dosage form can be misplaced as the dosage form may change during the course of development. Oftentimes a client simply wants to get the quickest possible read on the safety of their compound, so a “preliminary” dosage form such as our active pharmaceutical ingredient (API) in capsule is selected.
As development progresses, a custom formulation that maximises the performance of the compound and meets commercial objectives can be devised. This pairing of a quality approach with dosage form selection in the early phase is a key component of the regulatory strategy offering as we strive to deliver on the value proposition of “speed to clinic.”
KSR: How can phase-appropriate QMS support accelerated development?
MM: Early phase processes are not well established … and the control strategy needs be modified accordingly.
For instance, an early phase batch record should serve more as a roadmap in terms of how the resultant product was achieved and reflect the process understanding gathered along the way, which will drive future process refinements, rather than a rigidly structured document wherein any excursion shall prompt the need for a thorough investigation.
These unnecessary investigations in the early phase may unduly delay the release of product for use in clinical trials.
These delays can impact adherence to dosing dates which, in turn, can impact clinical subject recruitment, further delaying programme timelines and, potentially, the realisation of a much-needed therapy.
Batch records are but one opportunity and we are working on several additional improvements, including material/supplier qualification and fit-for-purpose methods, amongst others. All these initiatives hold the promise of not only reducing time to clinic by weeks to months, but also reducing overall programme costs.
KSR: So, what has changed and why now?
MM: Prevailing regulations for both active pharmaceutical ingredients and finished drug products have long acknowledged the necessity of disparate control strategies for early and late-phase development products. The challenge has been the implementation of these two strategies within a common facility that services both early and late-phase projects.
Typically in these instances, the control strategy defaults to the higher level of control to avoid confusion amongst the operational staff. This is why, for our early phase efforts, we are focusing implementation on dedicated early phase assets with dedicated staff.
We see this differentiated approach to Operations as a “must” to realise our desire to be a partner-of-choice for early stage development and clinical manufacturing, as well as late-stage clinical, commercialisation and overall product lifecycle.
KSR: What does the future hold?
MM: We are currently piloting our early phase QMS concept at our Bend (OR, US) particle engineering and drug product facility with the expectation of extending its implementation to our Tampa (FL, US) drug product facility later this year.
A similar rollout is set to occur at our API facilities in Visp, Switzerland, in early 2022, and Nansha in China.
Moving forward, we will continue to refine our early phase control strategy based on practical experience, regulatory monitoring, industry benchmarking and client feedback.
Additional complementary initiatives, such as Lean Lab and implementation of laboratory automation, will further enable predictable, optimised release times through the application of standardised ways of working in our quality control laboratories.
