Almost every clinical stage drug substance development project that is outsourced to a CDMO by a pharma/biotech sponsor starts with what would seem like a straightforward scope. However, the scope defined at the beginning of the project often undergoes changes during its execution due to various reasons. This could be due to new information from the ongoing development activities, requests from the sponsor’s regulatory affairs team (following a new regulatory guidance), new information from drug product group (e.g. solubility of drug substance), suggestions from other stakeholders within the sponsor’s clinical development group (e.g. new information on efficacy) or sometimes simply due to lack of planning and clear assessment of what is needed eventually from the project at the initiation. The following are some of the main areas with regard to where scope changes often occur during the course of a development project.
Although in most cases, specifications are signed off at the beginning of the development project, the agreed test parameters and limits often change once the learning from the development work starts coming in. Unanticipated process changes (e.g. use of a new synthetic route/starting material) could result in the re-assessment of impurity limits. Similarly, the use of new or additional solvents in the process may lead to revision (or sometimes addition of) organic volatile impurity (OVI) limits. Depending on the need for use of metal catalysts, the metal impurity limits have to be aligned to the regulatory guidance. Test parameters such as powder X-Ray diffraction (pXRD) pattern could become more critical than anticipated if the process impact on the solid form and the dependency of the solid form on the intended dosage form are not properly assessed at the beginning.
One of the natural consequences of specifications change is the requirement for relevant analytical methods development and validations. New test parameters & limits would mean additional analytical activities related to methods development and may be validations. In certain cases, replacing current analytical methods with new methods may be required depending on the sensitivity of the relevant analytical instruments and/or as a consequence of decision to have a more reliable analytical method than what was originally indicated in the scope (e.g. replacing NMR methods with HPLC; or replacing HPLC methods with UPLC methods; for better separation of impurities). Also, any gaps in understanding the analytical test procedures involved may sometimes result in additional activities to achieve the set specifications.
Introduction of additional parameters in the process such as particle size/polymorphism/salt formation could also lead to scope changes. Revised process requirements such as the need to conduct the reactions at higher/lower temperatures or changes in the type of reactors (e.g. Stainless Steel to Glass-lined) will lead to renewed evaluation of relevant manufacturing equipment suitability and availability.
In addition to the above, there are other areas where scope changes may creep in. These include delayed designation of regulatory starting materials and intermediates, unclear requirements of audits at CDMO, more stringent handling requirements (based on potency of the molecules), genotoxic & nitrosamine impurity evaluations etc.
Majority of the scope changes would usually result in extended project timelines and additional costs. When scope changes involve additional process and analytical activities, CDMOs also have to figure out ways to quickly allocate resources on priority to carry out the activities inserted into the scope mid-way through project execution. Availability of relevant plant equipment becomes critical when major process changes occur as part of scope creep and this obviously would lead to production scheduling conflicts. Delays in GMP documentation are another off-shoot of scope changes which may impact timelines.
It is not realistic to always expect that scope changes in drug development programs can be completely avoided
However, it is also possible to minimize snags in project execution timelines and budgets originated from scope changes. A thorough understanding of how the project deliverables tie into the input requirements of other groups such as drug product team, quality assurance and regulatory affairs group etc. at the beginning of the project would help significantly in avoiding surprises later on. In addition to discussions with other in-house stakeholders, sponsors could also get insights from CDMOs with experience in handling diverse development projects to finalize the scope. Since it is also important to prudently manage budgets for development programs, segregation of mandatory and optional activities within the scope will help not only to prioritize resources and spending, but also will help the CDMO to be aware of the optional activities and be prepared to undertake them if necessary on short notice.
It is not realistic to always expect that drug development programs to be perfectly planned that scope changes can be completely avoided. While a well thought-out scope planning can certainly help define the activities and deliverables better at the project initiation, working with CDMOs who have a reasonably large pool of resources (process and analytical) and decent experience in managing the execution of additional activities on short notice comes to rescue when scope changes are inevitable after project initiation. Willingness by the CDMO to understand and accept the request for scope changes, consultation approach to properly define the additional activities required, ability to allocate resources quickly to execute the activities and transparent communication throughout this process are key to manage project timelines in drug substance development. A productive combination of sponsor’s planning and CDMO’s flexibility is a proven path to successfully ensure deliverables of drug development programs
The flexibility and capability of the CDMO to accommodate scope changes mid-way through the project is a critical dependency for meeting program objectives and timelines
About the author: Mani Bushan Kotala, PhD is an Assistant Vice President at Laurus Synthesis and manages multiple process chemistry groups working on projects that involve diverse chemistry (heterocyclics, nucleosides, carbohydrates etc.) and complex scale up challenges. His group has successfully developed and commercialized several NCE molecules for global pharma/biotech sponsors. Dr. Mani has >15 years of industry experience and authored multiple patents and publications. He obtained his Ph.D. in Organic Chemistry from Indian Institute of Chemical Technology, Hyderabad and has worked at Johns Hopkins University and University of Kansas in the US for his post-doctoral research.