Demystifying FDA’s KASA Initiative… and how it aims to improve drug product, facility, and corporate quality monitoring

What is KASA and why does FDA need it?

Due to issues stemming from the large volume of generic drug applications submitted to the agency and the fact that some of the submissions are have gaps evident in product, facility or corporate quality culture, FDA recognized the need for improved regulatory tools to address these challenges.  This sparked the concept for FDA’s Knowledge-Aided and Structured Application (KASA) initiative to counter these observed trends. 

The development of KASA received unanimous support at the September 2018 Pharmaceutical Science and Clinical Pharmacology Advisory Committee meeting (1), and ever since the CDER initiative has been receiving a great deal of attention.  However, further clarity on how this tool is intended to be developed and utilized; the benefits gained from it; and, most importantly for the pharmaceutical industry, how it will impact the regulators’ assessment of drug products, facilities, and corporate quality is needed. The following article attempts to demystify KASA, provide critical understanding of this tool’s intended function, and describe potential impacts of KASA on the pharmaceutical industry.

The KASA initiative is set to receive significant appropriations, approximately $27.0 million requested, in the President’s 2020 budget.  FDA has stated that KASA provides a platform that “…would support the capture and management of all required information about a drug product, facilitate risk identification, mitigation and communication, and provide a structured template that would completely replace an unstructured text based narrative review…..This would result in more consistent drug product evaluations and seamless knowledge management across generic and brand-name drugs that would enhance product surveillance based on quality risk .”(2)

CDER’s Office of Pharmaceutical Quality (OPQ) is leading the development of KASA.  Although KASA was originally conceived out of necessity due to the volume and diversity of generic drug applications, its future use is likely to be extended to the new and biologic products CDER regulate.  This is anticipated since OPQ performs quality assessment for all of these types of applications and is striving for the same quality and assessment standards across all the drug products they are responsible for regulating. 

The intention of KASA is to arm regulators with an additional, powerful tool to efficiently and effectively assess factors impacting product risk.  This will also lend a more in depth understanding of the maturity of corporate quality culture.  KASA is being designed to address various challenges encountered by FDA while regulating drug products throughout their lifecycle, such as allowing FDA to:(3)

• Efficiently and appropriately assess the pharmaceutical quality data and CMC information contained in the large volume of applications FDA receives, initially focusing on ANDAs (Abbreviated New Drug Applications) submitted for generic drug products 
   
• Enhance risk management and risk-based regulatory decisions to be organized and summarized in a structured assessment
   
• Optimize computer-assisted knowledge management throughout the lifecycle of the product
   
• Reach consistent, logical, efficient, and risk-based regulatory decisions and improved communication of these decisions to industry

How is KASA designed to work?
 

1. Initial Risk-Assessment

KASA will be used by OPQ staff as a tool during their Integrated Quality Assessment (IQA) process to reach quality-related regulatory decisions, including drug approvals, developing reactions to non-conformance situations, and potentially surveillance inspection forecasting.  This tool is being designed to rely on sponsors submitting applications with pharmaceutical quality (PQ) and Chemistry, Manufacturing & Controls (CMC) data and information in appropriate sections of the eCTD. 

The eCTD modules contributing to KASA will be the entirety of Module 3 and the Quality Overall Summary (QOS) portion of Module 2.  The FDA intends to have established standards for submitting PQ/CMC information within these application modules.

Once the application is received by the agency, KASA will be auto-populated with data and information provided in the designated modules of the submission.  The IQA process will be initiated with the initial risk-ranking calculation.  This inherent drug product quality risk will be initially assessed considering product specific criteria and an initial inherent risk of the product’s Critical Quality Attributes (CQAs) (Figure 1).  KASA is being designed to use a computer-based algorithm to calculate the inherent risk-ranking score, which is intended to consider the following factors:

• Drug substance and drug product information
   
• Unit operations (connected to CQAs)
   
• Risk to all quality areas (e.g., chemistry, microbiology, process, facilities)
   
• Scale-up
   
• Facility’s/firm’s known capabilities (such information is anticipated to be summarized in the OPQ/Office of Quality Surveillance’s [OQS’s] facility dossier):
   
  • Historical experience with unit operation or similar products
     
  • Previous inspection outcome(s) and how recently the facility has been inspected
     
  • Robustness of quality oversight and adherence to current good manufacturing practices (CGMPs) (e.g., field alert reports, recalls, regulatory actions, etc.).

Initial risk will be ranked as low, medium, or high based on predefined ranges.  Risk-ranking is proposed to be calculated using failure modes, effects and criticality analysis for quantitative risk assessment.  The severity of the ranking is proposed to be based on the probability of occurrence, severity of potential harm, and the likelihood of the ability to detect failure related.

The risk-ranking component of KASA is being designed to provide the regulatory assessor with a structured, partially-populated (e.g., information auto-populated from the submission and/or used to calculate the risk-ranking score) IQA template to initiate the performance of their quality assessment.

Figure 1. Summary of four (4) critical elements pertaining to FDA's proposed KASA initiative

2. Risk Mitigation Assessment

Using the KASA-generated, risk-ranked, appropriate IQA template, the agency will perform the quality assessment of the drug product and its proposed manufacturing process to ensure that all inherent risks are mitigated to the extent possible.

This regulatory assessment will be designed to focus on risk mitigation throughout the manufacturing process and from the facility(ies) perspective linked to the product’s CQAs. Assessment is directed to all identified risk areas to prevent poor drug product quality or patient harm.  There is intended to be knowledge management of information gathered during the assessment process captured in KASA. 

Due to the knowledge management capabilities during the assessment process, the more KASA is utilized and populated with information, the more knowledge the agency will have at their disposal regarding factors impacting their regulatory decisions and the better the tool will become at identifying risk associated with applications, products, or facilities.  Thus, the agency will be able to make regulatory decisions based on product, facility, supply chain, or corporate risks to optimally utilize resources to ensure safe and effective quality drug products are available to patients.

3. Lifecycle Knowledge Management
 

As noted, a primary intention of KASA is to assist FDA assessors with the performance of their reviews more efficiently and effectively arming the FDA with real-time information about the drug components, drug product, manufacturing processes and facility information impacting their assessment and regulatory decision making.  

Additionally, the tool is intended to improve knowledge transparency throughout the product’s lifecycle management, including improved visibility into product’s, facility’s and overall corporate quality.  All steps in the regulatory oversight of a product will be available to assessment staff, from initial approval of a product in an NDA/BLA, throughout post-approval changes in supplements, and during its transition to  generic versions, as ANDAs or biosimilars.   

In addition to KASA, assessors will also likely be armed with facility dossiers to provide additional quality information. Both tools utilized together should provide vastly improved knowledge management between desk assessors of applications and what investigators encounter at facility inspections.  Currently product quality assessment, performed in CDER, and facility inspection, led by Office of Regulatory Affairs for small molecule products, information is maintained in various repositories.

In some instances, information is not readily accessible to all relevant staff.  KASA should improve inspection information accessibility to desk assessors since it will feed directly into the tool.   Also relevant to KASA and IQA, real-time facility dossiers are being established by OQS from all available drug product, facility, and corporate quality information.  Processing of this available information through a powerful informatic system will allow for detection of control strategy outliers.

Other regulatory activities, such as performing pre-approval inspections, product-specific post-approval, or surveillance inspection planning, will likely be impacted by KASA and related facility dossiers.  KASA will inform assessors about inherent product risks or recent concerns with a facility or company (e.g., such as in extreme cases with data integrity concern).  This will allow for inspection recommendations to be made and any risk(s) identified to be communicated to the investigator to ensure the inspection focuses on high-risk areas. 

Conversely, inspection information will be readily available to desk assessors to ensure risk mitigation has been demonstrated at the facility or alert assessors to areas of concern that were not initially apparent in the initial risk-assessment or in the application.  Information available in KASA and/or the facility dossiers can be also leveraged to ensure agency resources are being optimized for pre-approval and surveillance inspection planning.  This will ensure inspection resources are focused on the highest-risk products, manufacturing processes, and facilities.

Potential Impacts of KASA

There are many desired benefits from KASA for the agency.  Anticipated benefits gained for OPQ from KASA include:

• Improved retention of agency historical knowledge as corporate and regulatory information in KASA will be accessible to assessment staff and no longer potentially lost with staff turnover
• Significantly decreased or removal of bias, preference, and/or opinion in the regulatory decision-making process, as computer-assisted risk ranking will be performed, and risk mitigation will be assessed in a standardized format using the KASA tool and review template
• Access of  assessors to real-time information impacting their assessment and decision making
• Transparency of knowledge throughout the lifecycle management of the application, drug product, facility(ies), and/or company 
• Improved and more consistent regulatory communications
• Improved forecasting and prevention of developing issues associated to quality, such as drug shortages, supply chain challenges, lacking or diminishing product quality, and facility or corporate quality culture decline. 

For example, during calendar years 2013-2017, 62% drug shortages resulted from quality issues (1).   It is entirely possible that if KASA had existed during this time period, many of these drug shortages could have been mitigated or prevented all together due to early detection of the quality issues.

Moving Forward

Industry should be prepared for regulators to have better organized knowledge regarding drug products, facilities and corporate cultures.   It is imperative for industry to invest resources into quality by design to ensure quality is thoughtfully engineered into the development of products and throughout their lifecycle.

This approach will also ensure that any transition to a complete and strong corporate quality culture is realized.  Tools, such as KASA and facility dossiers, are being developed by the agency to target and monitor areas of quality concern. Regulatory incentives are also being developed and implemented for those demonstrating a quality culture.

Companies are encouraged to identify and mitigate risks associated with their drug product, manufacturing process, and facility(ies) before the regulators do, as developing tools will assist regulators in identifying unmitigated risks efficiently and declining trends related to this will be obvious to regulators to address.

Recently FDA partnered with St. Gallen University to develop a Quality Metrics Research Final Report which includes a model for pharmaceutical quality system excellence (1).  This model identified critical indicators of pharmaceutical quality culture maturity in manufacturing facilities.  Regulatory tools, such as KASA, can be designed to automatically assess these indicators in applications, facilities, or companies. 

This can provide assessors with a real-time, unbiased, computer-assisted assessment of all pertinent information to assess the maturity of the quality culture.  This information can be considered when a specific drug application is being considered for FDA approval.  Also, this will provide target indicators for those  areas where pharmaceutical quality culture is lacking to be readily identified.

This will allow FDA to proactively dedicate the appropriate resources to mitigate these quality concerns.  Additionally, these tools could potentially also be used to identify and reward companies demonstrating mature quality culture, such as a decreased inspection frequency.

FDA’s development of the KASA is likely to have a global impact.  Not only will it allow for improved regulation of products available to U.S. citizens, but if developed and utilized successfully, this may have global regulatory implications.  Other regulatory authorities have expressed interest in FDA’s KASA initiative.  If FDA’s initiative is successful, other global regulator authorities may consider the development of a similar system to allow for optimal utilization of resources and consistent, risk-based regulatory decisions based on real-time information.

There is still at least one large mystery remaining regarding KASA.  How long it will take to develop and implement this tool?  The development of this tool may take a considerable amount of time and resources to design and implement, as it has rather lofty expectations.  This makes it unpredictable as to when KASA’s impact on the quality assessment and regulatory processes will be realized by industry.

References:

1.   www.fda.gov.

2.   Department of Health and Human Services Fiscal Year 2020: Food and Drug Administration

      – Justification of Estimates for Appropriations Committees. www.fda.gov.

3.  Woodcock, J.  “Efficient Generic Drug and Biosimilar Review and Surveillance Processes”,

Association for Accessible Medicines. February 20, 2018. https://accessiblemeds.org/sites/default/files/2018-02/Janet%20Woodcock.pdf.

4. Yu, L.  “Pharmaceutical Product Development: Evolving Regulatory Landscape”. 4^th 

     PQRI/FDA Conference on Advancing Product Quality, Bethesda, MD, USA. April 9, 2019.

     https://pqri.org/wp-content/uploads/2019/04/PQRI_KASA-Presentation_V4.pdf

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