Question Based Review (QbR) - can it result into approval of ANDAs’ within 10 months?

ICH’s initiative of new quality paradigm of a robust quality system and QbD based development lead to an adoption of these concepts in US, EU, Japan and other nations. Many stringent authorities started developing a regulatory framework to encourage submissions based on these concepts. One such initiative by FDA was termed as Pharmaceutical Quality for the 21^st Century.

Question-Based Review (QbR) was introduced by FDA to encourage QbD based submissions by firms manufacturing generics. Office of Generic Drugs (OGD) within the FDA developed the template and highly recommended it for Abbreviated New Drug Applications (ANDAs).

FDA took this step as most of the ANDA submissions at that time were voluminous but without a comprehensive scientific rationale or explanations. A holistic approach of development was either not present or not shared with regulators transparently. The data presented focussed primarily on the chemistry and the specification, but critical aspects of formulation and process development were missing. FDA felt a dire need of a question-based review system as they experienced that firms are yet not conducting quality by design-based development. The increasing number of post-approval changes, due to new data being generated during scale-up and commercial manufacturing only suggested that the product was not designed with a holistic approach. Managing the increasing number of supplements was becoming cumbersome for the FDA. Hence, they highly recommended firms to focus on building a robust product through a robust process. QbR encouraged firms to provide the data upfront in the original submissions rather than working on course corrections later due to deviations or aberrations during commercial batches manufacturing. 

FDA’s concept of the ‘desired state of quality’ was aligned with the concepts of quality by design and emphasized on efficient and flexible manufacturing to ensure high-quality products. Another important objective of the FDA to have a question-based review was to have a more open and transparent sharing of information between the regulators and the industry. FDA wanted firms to focus on critical aspects concerning to material attributes, or process parameters by doing a thorough risk assessment. An obvious advantage of better understanding of the product and process was that it would help the industry to set a reasonable specification rather than a conservative one.  The focus of the submission changed to development strategy, product development report and understanding scale-up manufacturing. Change from a reactive to a proactive system of designing study lead to a scientist working with the attitude of ‘right first time’.

So, what is this QbR? It’s a framework for the assessment of a product developed based on good science. This framework suggested a format for providing the Quality Overall Summary (QOS), which as per the ICH-CTD format, is module 2 of a submission. The purpose of module 2 is to summarise critical and key aspects of the quality data provided in module 3 of the submission. By introducing QbR based QOS, Office of Generics Drugs’ (OGD) intended to ask the right questions and let the industry know upfront what they expect them to do. FDA has gone the extra mile to share model quality overall summary for extended and immediate-release formulations. For injections, they have shared models for providing information with respect to chemistry as well as microbiology including sterility assurance. You can visit the FDA’s website and easily find all these templates.

A detailed study of the examples provided by the FDA, will make it evident that the entire intention is to ensure that a firm understands aspects of the drug substance and the formulation variables (Input) and the extent to which it affects the performance of the product (Output). It intends to know whether a firm has identified critical steps during manufacturing through optimization trials, and whether appropriate in-process controls have been established for scaling up during commercialization.

Let me explain with an example. While developing an Immediate Release (IR) tablet formulation, one of the critical quality target product profile is ensuring a bioequivalent product. For achieving this we need to prove pharmaceutical equivalence and one of the critical quality attributes to achieve this would be the dissolution of the tablet and a matching dissolution profile.

Now based on prior knowledge we can predict the following:

1)     Dissolution is highly impacted by the hardness of the tablet. 

2)     Both formulation as well as the process impact hardness, hence impact dissolution and drug release. 

3)     Considering input material (API, Excipients), both - their quality attributes and the amount used has an impact on dissolution. The most important material parameters which have high impact and hence categorized as high-risk are drug substance (active pharmaceutical ingredient) attributes such as particle size, polymorphism, and solubility. If your formulation is designed to include disintegrant as one of the excipients then the quantity of that would also impact the dissolution. Similarly, the amount of any lubricant may impact the dissolution. Specific grades of the material may be required to meet the dissolution characteristics. The ratio between the disintegrant and lubricant also impacts hardness.

4)     Coming to process parameters, one of the high impact and high-risk parameters affecting hardness and dissolution would be compression. Another unit operation impacting these would be milling.

So, formulation and process optimizing trials would consider all such risks and design a control strategy with the combination of material controls, process controls around unit operations, before setting the final specification which will be the release and stability specification for commercial batches. Many firms would opt for a Design of Experimentation (DOE) to propose a design space for high risk attributes such as hardness of tablet or particle size of drug substance to have flexibility during commercial manufacturing.

By way of QbR, the questions by OGD/FDA will ensure all the above understanding is shared upfront by firms while answering them. All these efforts by FDA were to reduce the reviewer’s time as it promotes a mechanistic understanding of the product. Obvious benefit would be reduction in review cycle and lesser deficiencies or queries. Another perceived benefit based on the risk assessment and level of understanding of the product and process, is that the reviewer will be in a position to classify the product as a lower risk and reduced supplement category in the future.

As evident, this approach has clear benefits for both the regulators and the industry. This compels me to highly recommend 1) A QbD based development and 2) A QbR based submission. 

So now the big question is will it result into approval of ANDAs within 10 months? My experience has been very positive and encouraging, wherein few of the generic products got approved within 10 months of submission. In the current scenario wherein the FDA’s goal under Generic Drug User Fee Act reauthorization (GDUFA II) is to meet the review and approvals of 90% ANDAs within 10 months of submissions, a high-quality submission based on the above concept will be a win-win situation for both. 

In the end, I would urge all my regulatory folks to start understanding and implementing QbD and QbR concepts, if not done yet. It transforms our job into an enriching and fulfilling experience. Happy learning!!