Introduction
The development of a drug product is a long and costly journey which starts from basic research and moves down a path that requires much development, and takes turns at points where decisions have to be made. At the end of this path, one hopes to arrive at a safe and effective product for the treatment or prevention of a disease or condition. While commercialization of the product is one possible happy ending to this long journey, one also has to be prepared to reach a potential dead end where the “no go” decision has to be made. Moving along this path requires careful planning and the flexibility to convert potential hurdles into new opportunities. One area where such flexibility is important involves changes that have to be made. These changes may be to the clinical plans, financial arrangements, or they may be chemistry and manufacturing changes. Changes affect investigational drugs differently compared with those affecting approved products. The number of unknowns while in the investigational phase is higher than that when in the commercial phase. The manufacturing process is not yet fully developed, the knowledge of the potency, toxicity, and impurities is not complete yet, and the safety profile of the drug may have to be further improved. While considering changes to an approved drug, the sponsors have the option to consider the “no change” state, and this is not often feasible for drugs in clinical trials. The changes are either planned—in order to improve product safety and efficacy—or imposed as a result of factors beyond the sponsor’s control.
This article provides an overview of a strategy which has been applied to investigational drugs when dealing with inevitable Chemistry Manufacturing and Control (CMC) changes. The goal is to present 5 questions to be asked when assessing the risks associated with the implementation of a change. A brief discussion of the regulatory requirements is provided, followed by a case study to which the recommendations are applied.
A Discussion of Regulatory Requirements
Both European Medical Association1 and the U.S. Food and Drug Administration (FDA)2,3 have extensive requirements for addressing changes to approved products. There are additional guidance documents which describe categorization of changes to approved products. This is understandable, as approved drugs can reach a much larger patient population, hence the need to clarify regulatory expectations for reporting CMC changes to an approved application. While the regulatory documents provide clarity for assessing changes to an approved product, they do not address CMC changes to investigational drugs.
The FDA guidance document4 provides a thorough list of references to help sponsors with the evaluation of changes and the assignment of a reporting category. The Committee for Medicinal Products for Human Use5 provides some guidance on changes which require notification of the competent authorities, but it also notes that “…the Sponsor should decide on a case by case basis if an amendment is to be classified as substantial or not.” Another FDA guidance document6 provides a short reference to clinical materials impacted by a change: “If a Sponsor can demonstrate comparability, additional clinical safety, and/or efficacy, trials with the new product will not be needed… FDA will determine if comparability data are sufficient to demonstrate that additional clinical study (ies) is (are) unnecessary.” In the same guidance document, FDA notes that “the most important factor to FDA while assessing product comparability is whether the manufacturing changes can have a significant impact on the safety and efficacy of the investigational drug.” The sponsors of unapproved products are encouraged to consult with FDA when considering CMC changes before they are implemented.
The bottom line is that not all changes affect drug products in the same manner. Investigational products (pharmaceutical or biologics) have different characteristics. Some may be new chemical entities, with much uncertainty regarding the structure or mechanism of action. Some investigational products may have a simpler manufacturing process than others. There may be more historical data associated with some products that are not readily available/attainable for novel products.
Prior to implementing a change to investigational products, one has to assess the risk and impact on critical quality attributes, target product profile in addition to the financial state of the company. As mentioned above, the state of “no change” is often not an option. It is also a reality that performing additional nonclinical or clinical studies to demonstrate comparability of the “new” and “old” products presents a constraint on 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:
- 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.
- 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.
- 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.
- 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.
- 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, realtime 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.
Table 1. Changes to the Manufacturing Process*
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 old and new product. Variability of the process may be identified by analyzing a larger than usual number of samples included for release, in-process, and stability testing.
Lastly, the sponsor wishes to rely on the existing safety data from Phase I to proceed with Phase II studies. In order to avoid performing additional clinical studies with the new product and relying on the existing safety data, cross-functional discussions will focus on the review of the product's toxicity, safety data, and release data from Phase I batches. The outcome of this discussion for this case study is the calculation of the overall benefit/risk and ability to demonstrate comparability through analytical data only, without having to perform additional toxicity studies.
The CMC, Clinical, and Non-clinical team representatives are now in a position to present to the Management an estimate of resources required to implement the scale-up efforts, and additional studies which have to be performed (characterization, method validation, and stability) in addition to the justification for not performing added toxicity or safety studies. In this case study, the Management team determines a positive ratio for only a small portion of the patient population (eg, adults and not the children), and concludes that investment in building the scientific knowledge of the product is needed irrespective of the need for scale-up. Therefore, a comparability protocol will be written for submission and discussions with FDA.
Conclusion
While confronting changes, we often turn to the CMC team for answers, but we have to be aware that there is not a CMC answer to every question raised as a result of a change. Consideration of CMC data is a necessary part of addressing changes, but it may not be sufficient to address all concerns. Developing a product is a well-planned journey that takes into account the influence of scientific, economic, and human factors. The CMC team has a role to play in consideration of these factors. When unexpected turns present themselves, the team is well positioned to provide scientifically sound data to evaluate the quality of a product; and establish analytical comparability between the old and new products, which is often the most economical approach. Product quality has a direct impact on risk to the patients, which is only one aspect of the human factor. The other dimension of the human factor involves the level of risk the Management is willing to take as a part of change implementation which is beyond the reach of CMC and varies among sponsor and drug candidates.
References
- Commission Regulation (EU) No 712/2012 of 3 August 2012 amending Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products. Official Journal of the European Union. 2012;(L209):4-14. Available at: http://ec.europa.eu/health/files/eudralex/vol-1/ reg_2012_712/reg_2012_712_en.pdf. Accessed February 25, 2015.
- U.S. Food and Drug Administration. CFR-Code of Federal Regulations Title 21. Biologics Licensing, Changes to An Approved Application. 21 CFR § 601.12. 2014. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=601.12. Accessed February 26, 2015.
- U.S. Food and Drug Administration. CFR-Code of Federal Regulations Title 21. Applications For FDA Approval To Market a New Drug, Supplements and other changes to an approved application. 21 C.F.R § 314.70. 2014. Available at: http://www.accessdata.fda.gov/scripts/ cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=314.70. Accessed February 26, 2015.
- U.S. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Guidance for Industry: CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports. 2014. Available at: http://www.fda.gov/downloads/Drugs/.../Guidances/UCM217043.pdf. Accessed February 26, 2015.
- European Medicines Agency Inspections. Committee for Medicinal Products for Human Use (CHMP). Guideline on The Requirements to The Chemical And Pharmaceutical Quality Documentation Concerning Investigational Medicinal Products in Clinical Trials. 2006. Available at: http://ec.europa.eu/health/files/eudralex/vol-10/18540104en_en.pdf. Accessed February 26, 2015.
- U.S. Food and Drug Administration. Center for Biologics Evaluation and Research. Center for Drug Evaluation and Research. Demonstration of Comparability of Human Biologics Products Including Therapeutic Biotechnology-derived Products. 1996. Available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122879.htm. Accessed February 26, 2015.
Jilla K. Boulas is a Senior Regulatory Consultant with Complya Consulting Group, LLC, in Woburn, Massachusetts, USA, involved in assisting/consulting clients in the design and implementation of CMC strategies throughout the lifecycle of pharmaceutical and biopharmaceutical medicinal products. Her recent activities include the design of comparability protocols/reports, postapproval change management protocols, change control process management, and regulatory strategies for CMC technical issues.