Constructing the CTD Module 3: A Primer…

Constructing the CTD Module 3: A Primer…

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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 a variety of sources.

Although sometimes all chemistry development is undertaken in-house, it is more common that the module 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 prevent being boxed into a single-sourced strategy, if possible. All of these changes require documentation and evidence of control, if possible, beginning at the initiation of the project and planned proactively as far out in time as possible. For purposes of putting together Module 3, it is particularly important to get it right from the start. It is extraordinarily difficult to have to go back in time to some primary source and try to reconstruct after the fact, particularly if the people responsible are no longer available or if other links are missing.

The challenge inherent in describing manufacturing development data and changes is to convince FDA reviewers that it is appropriate to consider and to integrate nonclinical and clinical data obtained at various points during development, having studied drugs that might have been considerably different at these points.

Agency reviewers need to understand clearly how the drug has evolved and, ultimately, be able to agree that all nonclinical and clinical data derived during development are somehow informative and relevant to the drug product that ultimately would 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.

The Quality and Availability of CMC Content Present in Dossier is Critical!

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 the CTD 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 (S.2.2 and P.3.2), specifications (S.4.1 and P.5.1), analytical procedures (S.4.2 and P.5.2) and stability (S.7 and P.8) sections served as an introduction to and summary of all the compliance data available on the drug, and continue to be closely reviewed.

However, now more than in the past, the conformance sections, Controls of Critical Steps and Intermediates, and the Manufacturing Process Development (S.2.3, S.2.6, 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 perspective of the reviewers 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, and should 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.

Under these principles, 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 include qualification of impurities by toxicologic studies. Another case in point could be explaining the need for inclusion of a special reprocessing step because of such issues as minimizing toxic contaminants or maximizing a process that requires expensive ingredients or has poor yields.

The quality overall summary (QOS) 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 a preferred way to compare and contrast data over batches, over time, and across improvements in the manufacturing process.

Adequate Resources Required for Compiling the Full CMC Dossier (Not just for marketing but for making a good submission)

It is especially important that companies approve adequate resources to accomplish the task of assembling all of the required CMC content for the dossier, and that the work is initiated in a timely manner. Personnel resources need to be viewed not as person-hours but person-months to prepare the CMC dossier. Some CMC sections, such as product stability or process validation, can take longer than 6 months to generate the CMC data that then needs to be compiled and described in the dossier. Remember, if you do not have the CMC data, it is most difficult to write up that specific section in the dossier. When the FDA states that they want full CMC information provided in the dossier, they mean exactly that.

How important is it to meet the CMC regulatory compliance for the BLA or NDA dossier? Take note, if the FDA considers your CMC submission to be incomplete, they can refuse to accept your submission. According to their own manual of policies and procedures, a refusal to file can occur due to any of the following CMC deficiencies:

  • Incomplete description of the source material (including characterization of relevant cell banking systems or establishment of regulatory starting materials) and the product
  • Incomplete description of production of API, including description of fermentation, harvest and purification processes, synthetic processes for small molecule and process validation and testing
  • Incomplete description of manufacturing steps for production through finishing, including formulation, filling, labeling, and packaging (including all steps performed at outside (e.g., contract facilities) 
  • Omission of data demonstrating consistency of manufacture
  • Absence of formulation development studies, where appropriate, or rationale for selection of formulation
  • Incomplete description of lots and manufacturing process utilized for clinical studies
  • Omission of data demonstrating absence or removal of adventitious agents where such agents are potentially present
  • Incomplete data demonstrating equivalency to clinical trial product when significant changes in manufacturing processes or facilities have occurred
  • Failure to describe changes in the manufacturing process, from material used in clinical trial to commercial production lots
  • Absence of data establishing stability of the product through the dating period, and a stability protocol describing the test methods used and time intervals for product stability assessment

For many products, it can take over 2000 hours alone just to summarize all the completed CMC reports and place them into the proper FDA format for the dossier starting from zero. This task cannot be rushed.