For contract development and manufacturing organizations (CDMOs) looking to scale-up processes throughout development phases and through to commercial scale, tech transferring of projects is a necessary skill. This may be an internal transfer from a development site or pilot plant to another facility, or taking on a new project from a customer site where the previous work has been undertaken by the customer or a third party. Either scenario has many challenges, which may bring about unforeseen consequences of scale-up, but to ensure a successful transfer to production sites, key process risks and analytical parameters must be identified to ensure that all critical information has been successfully incorporated.

External Transfers

A chemical process that a CDMO has never previously undertaken must be fully evaluated, based on the information shared by the customer before a CDMO bids on the project. The key areas that must be assessed are safety, the process needs in terms of the chemistry, and the analytical technical package.

Even with limited information, it is highly unusual for any chemistry development to be trialed prior to quoting on the project. The experience and expertise of the process chemists reviewing the proposal lies in their ability to identify the potential for risks when the process is carried out at the receiving site, and how it may be scaled up using available equipment. It is not uncommon that a route set to be scaled up may only have been carried out at laboratory scale using reagents that are uneconomical or unfeasible for larger scale manufacturing, and there may be issues surrounding the type of vessel, stirring, filtration and purification options available at the CDMO’s site. While the exact nature of how a process will behave at any given scale may be partially unknown until a campaign is initiated, development teams will often use predictive software to model how the process may fit into existing plant equipment.

In an ideal situation, the analytical characterization of the steps will have been fully completed and undertaken on instruments that are common to the new site. If not, then the evaluation of the project must take into account any additional work that may be necessary to validate the instruments at the scale-up facility to those that generated the original data.

In terms of safety, the route shared may involve reagents that are difficult to handle, and potentially hazardous steps. In some situations, it may be prescient for a company to undertake safety assessments or modelling to ensure that a project is suitable to be undertaken at the receiving site. This may have an impact on whether a CDMO bids for a project, or factors in some necessary changes and further work into a proposal to undertake a project—which would most likely lead to a higher cost. Receiving CDMOs must also fully understand the containment needs around any potentially highly potent intermediates or active pharmaceutical ingredients (APIs) as part of a project, and ensure that it has suitable equipment and capabilities.

Post-Transfer

When the proposal has been accepted and the process is transferred, the scale-up team will address any immediate concerns related to safety and the chemistry. The route would be reviewed in terms of bond connection and strategy/convergence, as well as if there are any poor yields on steps or operational efficiency related to throughput. The next step would be to run the process at laboratory scale to ensure equivalence. When trialing the chemistry ahead of manufacturing larger quantities, the process chemistry team should identify key parameters that may help with the process but will not lead to radical changes to the route. These could be temperature, pressure, molar equivalency, heating / cooling cycles and mixing characteristics in the larger vessels. Any potential changes must be discussed with the customer, and the leniency in terms of how much change is dependent upon cost, timelines, and what phase the process is at. For a late-phase project, any change to the route can lead to potential new impurities, which would result in having to undertake new toxicity testing, and may not be a viable option.

Open and honest conversations and collaboration between the CDMO and customer are vital to ensure no issues arise that may lead to unexpected costs and delays. Route changes in terms of bond-forming chemical steps and reagents are easier to be incorporated at the start of development rather than later on, and it could be the case that commercial launch of a drug may be undertaken with a route to the API that is then optimized post-launch with a new route that can improve costs and efficiency in a second-generation process.

The chemistry must be backed up by analytical methods. Analytical teams must take great care that all technical information is properly documented and communicated, especially in the areas of purity and impurity methods. Site-to-site comparative testing or validation exercises are necessary to ensure harmonization. This work varies depending on phase: at an early clinical site, methods will be qualified to support production; whereas for commercial production, more formal validation is required.

For transfers within a company, it is common practice for sites to have identical analytical equipment, to ensure minimal impact, but where the analytical work has been done on different instruments, comparative studies are necessary to ensure that no differences in the techniques are missed.

API manufacturing projects often come with specifications in terms of solid-state properties of the molecule. Depending on the advancement of the project, this means that investigative work must be carried out to help determine the ideal solid-state characteristics, or a polymorph/crystal form has already been identified as the most appropriate for formulation. When it is the latter, before scale-up can be commenced, trials must be carried out to ensure the solid form properties are consistently reproducible and the specification is achievable.

Another factor that should not be overlooked when transferring a process is the quality of incoming raw materials; if there are different vendors of reagents being used than those in the original technical package, studies must be completed to ensure that this material performs to desired specifications and that the purity profile of the final product is not changed. 

Although it is possible to undertake some modelling to observe potential effects of factors such as the reactor size, power output and stirring speed, sometimes the changes to the set up are so different that this is not possible at the engineering batch stage. It is unusual for vessel difference to lead to batch failure, but such an outcome is not impossible, so an engineering batch at the receiving site before production runs are initiated is imperative.

Potential Pitfalls

CDMOs undertake a large number of tech transfers routinely, and each must undergo the same theoretical process and use their experience and expertise to ensure risks are minimized. However, these risks can never be eliminated entirely, and in many cases have nothing to do with the chemical process itself not working. Here, real-life scenarios that have been witnessed by our team at Sterling Pharma Solutions over the years with customers’ programs highlight some unexpected challenges to tech transfer:

A filter dryer is a filter dryer is a filter dryer

Different drying equipment can lead to variation in the physical properties of a material, and one project highlighted that although two filter dryers can have the same dimensions, variation in agitator type and design of the heating system within them caused significant differences in the particle size distribution of the isolated product. Following an issue, Britest tools identified that as the product progressed through the drying process, agglomerates formed before breaking down. One filter dryer had a lower thermal input, which resulted in a longer product residence time in the dryer, and in turn increased the opportunity for agglomeration to occur. The reduced mechanical energy from the agitator was not sufficient to break these down, resulting in a higher proportion of larger particles and the product being out of specification.

Downstream equipment such as filters and dryers have less effect on the product, but should be chosen to ensuring handling and isolations can be carried out efficiently as subtle differences in equipment can lead to significant differences in performance or API form.

When is specification not a specification?

A multi-kilogram campaign of an API was undertaken based on a customer specification generated from data obtained from the previous development, conducted at another CDMO. A significant list of theoretical impurities was provided to demonstrate the complexity of the chemistry and synthesis, but no analytical references had been prepared, because of the difficulty in synthesizing the impurities and ambiguity around their exact identity. There were no defined limits for these specific impurities at the intermediate release steps as no formal fate and purge work had been completed, and none had been requested for this campaign. The project aimed to meet the Phase II specification used by the previous CDMO and gather important impurity data for future progression into Phase III.

A cGMP manufacturing campaign was instigated against a tight delivery deadline; however, the customer tightened the Phase III API specification midway through production, introducing levels of tolerance outside of all previous batches.

A clear objective for a manufacturing campaign from a customer is vital when initiating a program with a CDMO, else there is the potential risk of serious cost and time overruns, or even project failure.

It’s just a tech transfer

A customer with rights to an API wanted commercial manufacturing undertaken. The chemistry looked challenging, with several competing reaction pathways possible, but no information on development work was available. The customer was confident that the process was robust, as it had been successfully manufactured on a similar scale prior to transfer.

Laboratory-scale familiarization showed no concerns, and the first batch manufactured on plant proceeded as expected, albeit with slightly reduced yield. The second batch required the rapid development of a rework process due to the presence of a named impurity well above specification.

Investigations to understand the reaction profile were carried out in the absence of previous development work details. These showed that the order, and rate of addition of reagents was crucial to the process to avoid side reactions and impurities, and highlighted the risks when there is a lack of knowledge on previous process development.

Changing regulatory requirements with time

A process was transferred and manufacturing initiated of a known commercial drug substance, where the customer was targeting a new indication and formulation. This took place prior to the creation of ICH M7,¹ which established regulations around potentially genotoxic impurities (PGIs).

In the process, the starting material and one of the downstream intermediates are genotoxic impurities, which can then convert and/or degrade to various impurities downstream, resulting in multiple PGIs. in accordance with ICH M7, these must be controlled. Changing the route was not an option based on the customer’s regulatory strategy, so both parties collaborated to create a comprehensive control strategy for PGIs, which encompassed a combination of mutagenicity testing, impurity fate and purge demonstration, and development of multiple analytical methods and purification procedures to control the various impurities at appropriate points in the process.

This strategy reduced the number of PGIs that had to be tested for in the end product, and a robust process was developed and successfully executed at multi-kilogram scale, meeting all specifications.

Regulatory changes cannot necessarily be foreseen, but companies must be aware of evolving regulatory requirements, particularly when transferring legacy products. The increased scrutiny and analytical burden required to meet today’s standards can significantly change the required time and scope of a seemingly straightforward project.

The process is totally safe, unless you deviate

A customer’s project used a reagent that is commonly accepted to be stable, but was known to potentially become unstable if dehydrated. Hazard evaluation of the process under normal operating conditions did not indicate a problem, however during the hazard studies prior to manufacture modelling and simulations showed that there was a potential for thermal runaway with the explosive equivalent of 12 kilograms of TNT if a distillation step within the process was not monitored correctly.

Conclusion: Minimize Risk And Maximize Results

The outcome whenever challenges arise in tech transfer and scaling up API manufacturing is a project requires more time and resource spent on it, which leads to higher costs. To mitigate risk, anticipation of potential pitfalls is key, and alongside experience and expertise, tools exist to help predict chemical problems, but nothing can factor in every variable. How a CDMO responds to challenges is the measure of a company, and strong collaborative approach between CDMO and customer with open communication is essential to reach the ultimate goal, which is the manufacture and delivery of API to ensure patients have access to drugs.

References
1. ICH M7 Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk https://www.ema.europa.eu/en/ich-m7-assessment-control-dna-reactive-mutagenic-impurities-pharmaceuticals-limit-potential.

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Mike Gibson began his career as a synthetic chemist at AstraZeneca, and joined Sterling (then ChiRex) in 1998 as a process chemist. Over the last 25 years at Sterling, Mike has taken on a number of roles including as a Product Manager, Research and Development Director, and now as Chief Technical Officer.