Dissolution Method at Full Development

Starting from where last edition ended, this episode focuses on that final dissolution method adopted for release and registration stability studies of your Phase 3 clinical trial materials (CTM), also to be proposed as the commercial QC method in a regulatory filing in CTD Module 3 as part of an application for product marketing approval.

Suitability of a dissolution method is a major risk impacting the in vitro performance evaluation of a solid oral dosage form. As such, it will be scrutinized during a biopharmaceutical regulatory review for its development history and challenged for any perceived deficiencies or deviations from the published regulatory guidance, such as the 1997 FDA Guidance on Dissolution Testing of Immediate Release Oral Solid Dosage Form.

Method development history of a dissolution method must show rationales for every defined method parameters. It usually starts from screening the aqueous solubility of the active pharmaceutical ingredient as a function of pH, ionic strength, and if necessary, concentration of various solubility enhancers. Solubility profile of the drug substance subsequently informs the selection of dissolution media for testing. Per the regulatory guidance, sink condition of a dissolution medium is desirable but not required, and the use of solubility enhancers in a dissolution medium is to be avoided unless justified. Even if a drug substance has no pH-solubility dependence, unbuffered neat water is not a desirable QC dissolution medium due to the lack of ambient pH control. Among different types of compendial dissolution apparatus, USP Apparatus I (Basket) or II (Paddle) is preferred unless otherwise justified. For best sensitivity of a method, agitation speed is to be mild, starting at 75 rpm for a basket-based method or 50 rpm for a paddle-based method. Higher agitation speed must be justified, for example, based on the need to meet method precision requirements or the desired method robustness. For immediate release solid oral dosage forms, the goal of a dissolution method is to acquire a complete release profile, defined by having two time points below 85% release and three time points above 85% release. However, this is not always possible for a drug product containing highly soluble, BCS class I or III drug substances, to which a separate FDA guidance applies for standard dissolution methods.

During dissolution method development, one must keep in mind that a dissolution method is always specific to a defined drug product. As a drug product changes in dose range, formulation, or manufacturing process in response to the outcomes of clinical studies or manufacturing scale-ups, the method must be re-assessed, and re-developed if necessary, to adapt to the changes in the drug products. For example, selection of a dissolution medium based on the highest dose of a drug product must be re-evaluated along with other dissolution parameters if the highest clinical dose changes. The flow diagram below provides a high-level summary of the process in dissolution method development.

After a dissolution method is defined from a systematic method development, the work is not done without a documented understanding of its performance expected by a regulatory biopharmaceutical reviewer. Is the dissolution method bio-relevant? If not or uncertain, then how adequate the method is in ensuring the consistency of the drug product quality in a manufacturing setting? Can the method discriminate drug product in-vitro performance on account of variations in quality attributes of drug substance or excipients? How the manufacturing scale, selection of the equipment train, and the settings of process parameters impact the product dissolution performance? Is the method sensitive to small but deliberate formulation variations? These questions stemming from the Quality-by-Design paradigm for pharmaceutical manufacturing can only be addressed with information of which testing multiple batches of appropriate drug products with the right dissolution method is essential. Ideally, by the time DOE studies are initiated for the formulation and the process, a well-developed dissolution method is already in place to generate dissolution data as a DOE output. In the case that the final proposed dissolution method in a regulatory filing was not the version initially used in the DOE studies, testing with the final method can be repeated with the DOE samples to bridge the gap. If necessary, aberrant drug products can also be specifically made with the sole purpose of demonstrating the discriminatory power of a proposed dissolution method against changes in critical material attributes, such as drug substance or key excipient particle size/specific surface area, critical formulation components, such as the content of disintegrant, lubricant, surfactant, binder, glidant, etc., and critical process parameters, such as the sequence of blending, time of mixing, sieve size in a milling step, important granulation parameters, compression force, etc. At times, there will be tension between the need of an analytical scientist to demonstrate the discriminatory property of a dissolution method and the objective of a formulation scientist to have a robust formulation and process, as the same data can be interpreted in favor of one or the other. To align efforts toward an approved drug product with adequate control in place, the CMC management must lead and guide technical SME's to rise above their silo mentality. On the one hand, without an acceptable method, all associated data from the DOE studies become meaningless, defeating the QbD rationales justifying the formulation and the process. On the other hand, without demonstrating a robust formulation and process, no drug products can be reliably manufactured or approved. Therefore, developing a regulatory acceptable dissolution method and the corresponding drug products are intrinsically intertwined. A coherent team with aligned efforts is the key to supporting the overall CMC mission in delivering quality drug products consistently and reliably to patients.

A justifiable and validated dissolution method sets the stage of defining the dissolution acceptance criteria as part of the pharmaceutical specification development to be discussed in the next news letter edition.