Revolutionizing FDA’s Quality Assessment of Regulatory Drug Applications with Knowledge-Aided Assessment and Structured Application (Kasa): An Innovative Approach

Introduction

The FDA’s Centre for Drug Evaluation and Research (CDER) is in charge of evaluating the effectiveness of medications that are sold to humans. All pharmaceuticals that are commercialized must be produced in accordance with defined quality criteria. Each dose must be free from contaminants and flaws and be both safe and effective. Patients and consumers can feel confident in their upcoming dose of medication because of its quality [1].

The Office of Pharmaceutical Quality (OPQ) was established by CDER in 2015 to: Establish a standardized procedure for ensuring quality across the whole drug product lifecycle (development → commercial manufacturing), Over the course of the drug’s life, evaluate all quality-related improvements that were suggested following application approval & Keep track of the quality of all regulated manufacturing facilities and pharmaceutical products [1].

An OPQ quality evaluation establishes if a drug’s formulation, production procedures, and manufacturing facilities provide a medication that is safe and effective for the target population. An OPQ quality assessment covers: Drug substance, Drug product and manufacturing: Process, Facilities, and Microbiology, Bio pharmaceutics [1].

From the summary-based review in the 1990s through the question-based review and risk-based approach in the 2000s to the integrated quality assessment in 2015 and beyond, the FDA has continued to develop its regulatory evaluation system. The challenge for the agency to effectively and reliably monitor pharmaceutical quality has grown as a result of the complexity of novel medication regimens and drug delivery systems. Practically speaking, due to initiatives from the 21 Century Cures Act, the FDA has seen a significant increase in the volume of regulatory drug applications with the reauthorization of the Prescription Drug User Fee Act (PDUFA VI), Bio similar User Fee Amendments (BsUFA II), and Generic Drug User Fee Amendments (GDUFA II). The FDA is looking to design a new system called Knowledge-Aided Assessment and Structured Application (KASA) in order to deal with these issues and manage the information influx [2].

The KASA system is a data-based platform for applications that assist knowledge management and structured quality evaluations. KASA is designed to: 1) Capture and manage knowledge during the lifecycle of a drug product; 2) Identify and communicate risks for the facilities and processes used to manufacture drug products using established rules and algorithms; 3) carry out computer-aided analyses of applications to compare regulatory requirements and quality concerns among the facilities and drug products in the repository of permitted items; 4) Offer a structured evaluation that completely obliterates narratives written in text and information summaries from applications [2].

The KASA system enables the FDA to record crucial assessment data as highly detailed structured data in a prescribed manner, enhancing the effectiveness, consistency, and objectivity of regulatory activities. KASA marks a substantial conceptual shift and revolutionizes the FDA’s capacity to implement sensible, thorough regulatory actions. In order to expand KASA to encompass drug substances, all generic dosage forms, new drug and biologic applications, and post-approval adjustments throughout the course of the next five years, the FDA will be seeking feedback at this advisory committee meeting. Additionally, the FDA will solicit feedback on the necessity of developing digitalization in KASA, including data standards and mobilization via cloud-based servers [3].

The Why of KASA

The agency is aware of the need for internal transformation to keep up with public demands, rising public expectations, and technical improvements in the twenty-first century. In the past, CDER assessments relied on freestyle narrative writing (word documents) that contained data that was copied and pasted, unstructured information, and a summary of the application. Such a framework hinders capacity to share knowledge and effectively manage the FDA’s array of approved drug items and facilities, and it may lead to inconsistency and inefficiency. Additionally, it limits ability to make decisions because assessors only consider a small portion of the vast amount of data available to the FDA when evaluating each application [2].

To address the aforementioned issues, OPQ created the KASA system to update the quality evaluation of drug applications and incorporate structured data. This encourages uniformity and makes it possible to use a crucial knowledge management tool, both of which enhance efficiency and the process of overall quality assessment [2].

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Structured Application

In the future, applications submitted with streamlined layouts and organized data that link with the assessment system would considerably improve knowledge-aided evaluation. The FDA presently accepts regulatory drug applications in the electronic common technical document (eCTD) format. Because the submitted content does not adhere to the development flow, contains unstructured data, and varies in the amount of granularity offered, the eCTD causes difficulties for FDA assessors despite its great advantages. Additionally, because the documents are in PDF format, it is difficult to search for and mine the information, which makes lifecycle management difficult [2].

The modification of ICH M4Q (R1) and pharmaceutical quality electronic data standards are two ongoing projects that will help with the “structured application” portion of KASA. It is possible that recommendations for submission structure will be provided in the future to better integrate with KASA’s structured evaluation process. Applicants would then be able to concisely and consistently list the efforts taken to reduce inherent hazards through development studies and control methods. According to this paradigm, the KASA template would be filled out automatically using tools to extract information from the structured submission, such as specifications and essential process parameter ranges. By freeing the assessor from administrative duties, this would increase assessment effectiveness by enabling assessors to concentrate on high-risk areas [2].

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Benefits Offered by KASA

The KASA system replaces the present unstructured text document used for regulatory application assessment with an issue-based regulatory and technical assessment that uses structured data and information with standardized formatting, common terminology, and a uniform output.

Both regulatory submission and assessment move to structured data format enabling efficient regulatory submission and assessment, information sharing, knowledge management, and data analytics This enhances knowledge management inside the agency as well as the consistency, transparency, communication, and objectivity of regulatory activities [2].

With access to structured knowledge, KASA provides technologies that allow assessors to automatically extract historical data and facility information to better inform the regulatory review and decision-making process. By utilizing rules and algorithms, KASA makes it easier to assess risk while lowering the amount of effort and subjectivity required for documentation. The built-in rules and algorithms, along with the outlier detection, enable assessors to concentrate on high-risk issues and areas, which enhances the effectiveness and quality of the regulatory evaluation. Finally, KASA conveys the remaining product, manufacturing, and facility risk for each regulatory submission by assessing hazards and mitigation measures. The agency’s evaluation of post- approval adjustments and the lifecycle management of drug products are made easier with the agency’s assistance in clearly defining the key mitigating factors and residual risk. This can assist in concentrating resources for post-approval and follow-up inspections on the riskiest products [2].

Where KASA is today

By utilizing 1) structured data (as opposed to narrative information), 2) sophisticated analytics, and 3) knowledge management, OPQ’s KASA system was envisioned as a way to modernize FDA evaluation in 2016. Multiple OPQ and CDER co-workers worked diligently and in partnership to develop this KASA concept throughout multiple revisions. Through the development, testing, and application of KASA prototypes over time, the KASA vision has been improved [2].

The FDA moved KASA to the cloud in 2020, storing KASA quality evaluations on FDA servers in a FISMA-high environment with the highest level of security to guarantee the preservation of sensitive data. The FDA is utilizing the adaptability and speed of cloud computing by shifting the quality evaluations there, allowing for effective knowledge management and data analytics using structured data. This big KASA launch, known as KASA 3.0, represents an important milestone in the modernization of quality assessment as a whole. KASA 3.0, which is used to evaluate the quality of generic solid oral dosage forms, marks an important development and implementation milestone. In order to operationalize KASA, which is now used by three assessment disciplines (drug product, manufacturing, and bio pharmaceutics) for the quality evaluation of generics, OPQ has made great strides [2].

On continuing KASA’s development, OPQ is concentrated. Following the launch of KASA 3.0 for generics, long-term goals include extending KASA to drug substances, all generic dosage forms, novel medications, biologics, and post- approval adjustments throughout the course of the following five years [6].

Conclusion

KASA is a system created to update the way regulatory drug submissions are evaluated for quality. KASA symbolizes a paradigm shift away from the antiquated assessment procedures of the past and toward a new, more effective method of managing data and resources. Through knowledge management, KASA helps to:

1. Ensure patient-focused quality standards and the objectivity of regulatory actions.
2. Improve science- and risk-based regulatory approaches and
3. Improve regulatory oversight through lifecycle management of products and facilities.

The KASA method ultimately enhances OPQ’s emphasis on pharmaceutical quality, the cornerstone for guaranteeing the safety and efficacy of medications. Through modernization, it elevates the agency’s quality control to the next level [7].