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28 Aug 2020

Oral Solid Dose Regulatory Hurdles and How to Approach Them

In your quest to meet the regulatory requirements for your oral solids project, you may encounter significant hurdles. Anticipating these early on and thoroughly planning your approach can help. Experts in the Pfizer CentreOne global network, Gillian Miller, Process Analytical Technology and Data Analytics Lead and Beth Kendsersky, Global Regulatory Chemistry, Manufacturing and Controls (CMC) Lead, discuss common regulatory challenges and how to approach them.

My oral solid product has added complexity
Regulatory expectations are dependent on the complexity of the solid oral dosage form. Are there any novel or compendial excipients in your dosage form that require additional controls to ensure the quality and stability of the product? Is your process understood well enough to know which parameters have an impact on your product’s ability to meet its critical quality attributes, i.e. do you have an adequate control strategy? Does your dosage form have modified release characteristics? Are validated methods in place? These are just a few of the questions that should be considered to understand the potential regulatory risks for your oral dosage forms.

Good analytical method development is also central to enabling the monitoring of a product’s quality. Specifically, dissolution is a critical quality attribute for oral dosage forms and the development of a discriminating dissolution method is important. Appropriate specifications must also be in place to monitor the identity, strength, quality, purity and potency of your product throughout its life-cycle and these specifications are frequently a point to negotiate with global regulatory agencies. Specifications that are too loose risk passing batches that are not of an adequate standard while specifications that are too strict could cause the rejection of batches with acceptable quality. To address this challenge, companies and regulators are increasingly focused on what is termed clinically relevant specifications (CRS). These are specifications that take into consideration the clinical impact of variations in the critical quality attributes (CQA) and process parameters assuring a consistent product performance.

My batch has been rejected

Common reasons for batch rejections (1) include gaps in product quality, gaps in the investigation process and wider quality management issues within an organization.

To minimize the risk of any kind of rejection, it’s important to improve fundamental product quality by taking an end-to-end life-cycle approach and establishing a harmonized best practice process within your organization. Within the process itself, it’s also possible to mitigate batch rejection by thorough in-process testing, implementing process analytical technology (PAT) and designing the appropriate controls.

It’s also key to utilize a cross functional approach internally and engage with the regulatory authorities themselves to ensure a greater chance of project success. At Pfizer CentreOne we form a multi-functional team during development consisting of analytical R&D, chemical R&D, product development, commercial operations & supply and regulatory CMC members. Working together, this team can identify the risks to the program, develop a strategy to mitigate these risks and decide when to seek regulatory feedback on your strategy.

Regulatory meetings are one of the best tools to seek clarity and discuss solutions with the regulator directly. It’s important to collaborate closely with regulators from the outset of a project and reach out to discuss potential risks and issues before the marketing authorization is filed. There are also organizations within the regulatory agencies that can provide additional help if you have a complex or innovative process or complex dosage form such as FDA’s emerging technology team (ETT) .

My oral solids product is destined for multiple markets

The lack of international regulatory harmonization for drug products means that there are still different requirements globally to gain approval of your solid oral dosage form products. The key is to ensure that you know the requirements in those markets well or work with an experienced partner who does.

The regulatory requirements in major ICH countries (i.e. US, EU and Japan) are well documented but often subject to interpretation. In addition, a common hurdle for other markets globally is not being sufficiently aware of regional regulatory requirements, particularly in Africa, Middle East, Latin America or Asia Pacific markets. For example, detailed method information, final process validation data, unique formats for summary information and other ancillary GMP type documents are required in several of these markets' submissions to gain regulatory approvals.

From a logistical standpoint, you must be aware of where your product will be marketed to ensure that the dosage form can withstand the shipping requirements. Characteristics such as tablet hardness may be critical if a product is being shipped globally and shipping studies are required to assess how it is affected in transit. There may also differences in commercial trade dress (tablet size, shape, marking) in markets that will require increased quality system scrutiny.

There’s a gap in my New Drug Application (NDA filing)

Tablets and capsules account for around half of all NDAs making them the most common dosage form today (2). While there is an extensive precedent and less complexity compared to non-traditional dosage forms, the development work behind an oral solid dose product can still become a regulatory hurdle if it is insufficient.

A lack of detailed development work early on, covering issues of excipient function and molecule characteristics for example, can lead to gaps when filing your NDA. You may be working with a formulation that is fit for purpose but not perfect, which will result in an increase in the number of CMC changes after approval. This often happens for a breakthrough product when product development has been accelerated. Regardless of this, risk assessments of your product and process and the establishment of an appropriate control strategy is necessary to mitigate regulatory risks. This can be done using a quality by design (QbD) approach to develop an oral solid dose that is both robust and meets all regulatory requirements.

1. MHRA GMP inspection deficiency data trend 2016; Analysis of FDA WLs from 2015-2017

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