CLINICAL RESEARCH


An evaluation and assessment of the risks associated with a change require internal cross- functional discussions which would lead to a concrete deliverable—namely the comparability protocol.


the financial resources of the sponsor. So what can/should be done before implementing a CMC change and before conducting added safety or clinical studies?


An evaluation and assessment of the risks associated with a change require internal cross-functional discussions which would lead to a concrete deliverable—namely the comparability protocol. As a result of such efforts, the protocol will have taken into account the acquired knowledge, additional information required regarding the new product, supply requirements for supporting ongoing clinical studies, and the potential for introducing additional innovative improvements. In drafting this comparability protocol, the following points with associated deliverables should be considered:


1. What are/will be the changes? Tabulate the “before” and “after” states and provide a rationale for each change. In doing so, consider the impact not just at the step in which it is implemented, but throughout the entire process which ends with the finished drug product. This allows for discussions which take each step into account and allows for planning a thorough control strategy on the process and quality of the product.


2. What additional characterization (beyond release) is required that will demonstrate comparability or lack thereof? A biological product may require more extensive characterization efforts than those required for a pharmaceutical product. The same change does not affect a biological product the same way it affects a pharmaceutical product due to the complexity of structure and its impact on the activity of the active substance.


3. What is the depth of historical knowledge and who has the information? These can include published data as well as those generated during research/discovery and any other development efforts. Often, due to the complexity of the manufacturing process, there are limited batch data for biologics; therefore a consideration of CMC changes has to include discussions and an exchange of information with functions within and outside of general CMC operations.


4. What are the sources of variability? In the early phases of development, methods may not be validated. Therefore, variation in the product profile may not be due to the process, but rather due to methods with a high level of uncertainty. Knowledge of uncertainty (variability) due to the analytical methods is an important factor in assessing the risks associated with a change and potential impact on critical quality attributes.


5. What are the patient population and the disease status? The benefit/risk ratio has to be positive to the patient. It is often the case that CMC changes cannot be evaluated in isolation from the targeted product profile which has to take into account factors such as the patient population (adults vs children), availability of other products, indication, and expected morbidity vs mortality of the disease. This is also the question that may be viewed as an opportunity to improve the product quality through the introduction of innovative concepts such as continuous manufacturing, real- time release, and Quality by Design.


Case Study


The following section provides a theoretical scenario where the sponsor of a biological product (recombinant protein) is planning to investigate the effectiveness of a Phase II product for the treatment of a rare disease affecting children and adults. There is currently no approved product for the indication being studied. However, other investigational products are being studied for the same indication by competitors. The Phase II studies initially did not take into account a larger than expected number of patients to be included in the clinical trials. Therefore, the manufacturing process needs to be scaled up to allow for a larger clinical supply. The Process Development department proposed increasing the cell expansion volume. A cross-functional team is asked to develop a proposal which takes into account not only all the scientific data for establishing comparability, but also the financial resources required for implementing the scale-up efforts.


If the proposal is deemed


feasible and acceptable (scientifically, financially, and logistically), then a comparability protocol would be written for internal approval and discussions with FDA.


The first deliverable requires the CMC team members to tabulate all changes, such as noted in Table 1, to address the first question, “What changed?” The table lists side-by-side changes to upstream and downstream steps.


It is obvious that the impact of the scale-up efforts is not limited to the upstream production steps. This increase in scale has an impact on the subsequent steps in the formulation and final production of the finished drug substance.


Addressing the characterization question, the CMC team members consider the structure of the molecule, the duration of the manufacturing process, the added purification step, and the impact on the activity of the products. During these discussions, the team reviews existing stability data, forced degradation studies, the complexity of the molecular structure (eg, glycosylation pattern), etc.


Historical data collection for the inclusion in statistical analysis often leads the CMC team to discussions with other departments such as Research and Development. A comprehensive review of all available historical (eg, Discovery and Research, Clinical, Non-clinical) and current data will allow the team to determine the number of batches/data points required for establishing statistical comparability of the new product to the old product. The CMC team in this case study determines there is limited knowledge of the secondary structure of the active substance. Therefore, additional orthogonal methods are identified and recommended to be performed in order to better establish the relationship between the structure and activity of the active substance.


Assigning a source to the variability is a positive outcome of the statistical discussions and review of all available data. The CMC team identifies the variability of critical methods, such as potency, and, as a result, proposes the development of new methods and the validation of existing methods. This, in turn, requires resources for method comparability in addition to those needed for testing samples of the


Pharmaceutical Outsourcing | 44 | March/April 2015


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