Quality by design (QbD) submissions should be incorporated into the Pharmaceutical Development Report of Module 3 of the Common Technical Document. This template was included in the draft example of a QbD submission distributed to participants attending the FDA/GPhA QbD workshop held in Bethesda, Md. May 4-5.

A repeated concern mentioned by industry at the conference was where - and how - QbD information should be presented or incorporated into abbreviated new drug applications. While question-based review (QbR) information should be in Module 2, sponsors were advised to place QbD information in Module 3.

The information, which should go in Section 3.2.P.2, should contain the following:

Analysis of the reference product. This section should summarize the reference listed drug (RLD) product label and compendial information, as well as provide a review of the literature regarding the analytical profiles of the active pharmaceutical ingredient, preliminary experiments conducted on the RLD, and a review of the inactive ingredients with the Inactive Ingredients Guide.

QTPP. This section should address the type of dosage form, the route of administration, strength, tablet weight, dosage design, pharmacokinetics and appearance - and the justification for each of these parameters.

Drug substance. In this section, manufacturers should demonstrate a "thorough knowledge of the physicochemical and biological properties" of the drug substance, including solubility, water content, particle size and crystal properties. "It is important that the sponsor understands how these properties can influence the performance of the drug product and manufacturing process." In addition, the compatability of the drug substance with excipients used in the drug product should be evaluated. Those drug substance characteristics deemed critical material attributes need to be discussed and a rationale given for why the proposed limits and specifications were established.

Excipients. This section should include the "why, what and how" of excipients, including why they were chosen, what do they do and how do they influence the drug product performance and manufacturability. Prior knowledge regarding excipient compatibility, stability and performance should be provided and discussed in detail.

Drug product. This section should describe the development of the formulation, which includes the critical quality attributes, and this is where information on prior knowledge or formal experience should be discussed. This section should highlight the evolution of the formulation design from initial concept to the final design. This should include what properties of the drug substance, excipients, container closure system, and dosing device if applicable, were considered when making a final decision on the development of the proposed drug product. Data from excipient range studies, pilot or pivotal bioequivalence studies, in-vitro dissolution studies that were used to either confirm or modify the drug product formulation should also be described.

Process development. This section should summarize the manufacturing process. Manufacturers can use prior knowledge and experience with similar dosage forms or use formal design of experiments and studies. "It is important that sponsors understand the impact process parameters have on the in-process material attributes and drug product CQAs. This can be done by conducting risk analysis and developing mitigation strategies."

Identification of the critical process parameters. This section should highlight the type of process testing and/or process studies that were done to obtain knowledge and understanding of the manufacturing process. Some examples of these parameters include: identification and rationale for equipment and process; order of ingredient addition; blend time studies; hold time studies; milling conditions; temperature studies; and granulation studies.

Scale up. In this section of the pharmaceutical development report the results of batches manufactured at various scales and the impact of process parameter changes should be described. Any significant differences observed between the manufacturing processes used to produce registration and exhibit batches versus the commercial scale production should be outlined. If scale up has not occurred then it is important that an analysis be done on what the potential scale up parameters should be based on prior knowledge.

Control strategy. The control strategy should demonstrate that a combination of input material controls, process controls and monitoring, design spaces around individual or multiple unit operations, and final product specifications were used to ensure consistent quality.

QbD Information Should be in Module 3 of CTD

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