For the purposes of my practical explanation, it is necessary to produce an admittedly unbalanced discussion that shortchanges some sections of the Quality modules, but that includes considerable discussion of other sections that can largely influence the ultimate success or failure of an application.
The Quality Modules 2 and 3 are well-defined components of the Common Technical Document (CTD) containing both drug substance (active ingredient) and drug product sections, each containing required presentations of Chemistry, Manufacturing and Controls (CMC) information, covering processes and key control parameters, and various justifications supported by qualification and validation studies.
The information required, and the organization of the information, are carefully specified in guidance documents; however, today, sponsors have some latitude in how data are presented, and important messages are formatted in the compilation of an application. This information provides detailed evidence that a drug’s characteristics are well defined and well-controlled, such that one can assure that the next lot manufactured is essentially the same as the preceding lot.
In preparing Module 3, provide a detailed interpretation and analysis of the regulations and requirements in defending strategy. For authors to accomplish their goals, they must clearly understand and agree on what the goals are. In essence: how is the product designed? What are the weakest aspects of the data package, and what are the scientifically driven strategies for addressing those weaknesses? What are the immediate and long-term outcomes that the sponsor wishes to achieve for the program? If the author maintains focus on the answers to these questions, the final submission documents will serve to demonstrate the “quality” of the starting materials, intermediates, drug substance, and/or drug product to the satisfaction of regulators.
For many drugs, the manufacturing development program has truly evolved, often such that substantial differences can exist between a drug substance or product early in development versus that which is proposed for marketing. Part of the difficulty in constructing a cohesive and coherent Module 3 is the common situation where the generation of CMC data comes from various sources. Although sometimes all chemistry development is undertaken in-house, it is more common that the modules must rely on the data contributions of both in-house and outside parties.
As drug development accelerates, the pressure to generate batches of drug substance and drug product for nonclinical and clinical trials increases greatly. GMP standards are high, including documentation requirements for the analytical and stability programs supporting manufacturing.
At the same time, technical experts in manufacturing are investigating more efficient process schemes and frequently look to alternate contractors to shave costs and potentially prevent being boxed into a single-source strategy. All of these changes require documentation and evidence of control, beginning at the project's initiation – if possible – and planned proactively as far out in time as possible. For putting together Module 3, it is particularly important to get it right from the start. It is extraordinarily difficult to go back in time to some primary source and try to reconstruct after the fact, especially if the people responsible are no longer available or if other links are missing.
The challenge inherent in describing manufacturing development changes is to convince FDA reviewers that it is appropriate to consider and integrate data obtained at various points during development. Agency reviewers need to understand clearly how the drug has evolved and, ultimately, agree that all CMC data derived during development are somehow informative and relevant to the drug product that would ultimately reach the market.
Because it is rarely the case that a drug remains the same during the years of development, it is important that all ongoing chemistry and manufacturing changes are documented, and the ramifications of product differences understood. When the history of changes has led to improved purity and tightening of release specifications, the story is easy to tell; if this is not the case, considerable creativity may be necessary. Pharmaceutical development reports include drug substance (active ingredient), drug product, and analytical reports and need to tell the story of the evolution of these three development aspects throughout a product’s development. If development reports are poorly prepared or unconvincing, the result can easily be an almost endless cycle of agency queries and sponsor responses, prolonging the review cycle and delaying approval times.
Module 3, and the development work that provides the data for the module, is unique in that it should tell a story rather than simply being a collection of data. Although every section of Module 3 plays a vital role in supporting the ultimate approval of a new drug, several sections now stand apart from each other in a few respects.
Traditionally, the manufacturing process description, specifications, analytical procedures, and stability sections served as an introduction to and summary of all the compliance data available on the drug, and continue to be closely reviewed.
Now more than in the past, conformance sections – Controls of Critical Steps and Intermediates, Manufacturing Process Development – afford the opportunity to craft discussions, approaches, explanations, and justifications so that supportive data can be highlighted and less-than-stellar findings put in perspective. These sections can, therefore, influence the reviewers' perspective more so than in the past, so it is preferable to tackle difficult potential issues head-on within these sections rather than wait for regulatory reviewers to notice problematic data.
The general format of the conformance sections should follow the outline of the detailed compliance data in Module 3, emphasizing critical key parameters of the product, the data on potential and actual impurities arising from the synthesis, manufacture, or degradation of the active ingredient. It should also convey the basis for setting the acceptance criteria for individual and total impurities, and state how the proposed impurity limits are qualified based on the impurity levels in batches of the drug substance used in the nonclinical studies, in the clinical trials, and in typical batches manufactured by the proposed commercial process.
The Quality Overall Summary (Mod 2) separately covers drug substance (active ingredient) and completed drug product. For both entities, the quality summary attempts to convey the critical concepts of characterization, consistency (batch to batch), process control, and establish the connection between clinical drug supplies and the proposed to-be-marketed product. Whenever possible, tabular presentations are preferred to compare and contrast data over batches, over time, and across improvements in the manufacturing process.
Under the principles of QbD as laid out in ICH Q8 and 11, explanations and justifications may be included, for example, providing justification in cases where guidance was not followed or discussing key issues for which it is appropriate to integrate information from manufacturing, clinical, and even nonclinical programs. An example of such a key integrated issue would be the qualification of impurities by toxicologic studies. Another case in point could be explaining the need to include a special reprocessing step because of such issues as minimizing toxic contaminants or maximizing a process that requires very expensive ingredients or has poor yields.
The technical information submitted in the Quality Modules of the CTD, and the organization of the information, is modular and carefully specified in guidance documents. However, sponsors have latitude in how data are presented, and important messages are formatted in the compilation of a CTD application. Ultimately, the timeliness of the FDA’s review and approval status of a drug’s Quality section is best served by the preparation of well-designed modules. Insights and recommendations are provided to help maximize the potential for a successful outcome.
The CTD is merely an agreed-upon format for the presentation of summaries, reports, and data. Indeed, the actual content of the CTD modules must still conform to requirements and recommendations found in the regulations and in Food and Drug Administration (FDA) guidance documents. Likewise, there may be particular components that are required by other ICH regions. The preparation of CTD submissions for various national regulatory authorities should be geared toward meeting those unique regulatory standards.
Getting this content right will save valuable time and subsequent effort since Module 3 is accepted by the regulatory bodies of the major global health authorities. Sponsors should, however, maintain awareness of additional country-specific requirements for their products and continue to participate in an active dialogue with these authorities.