FDA releases discussion paper on distributed and point-of-care manufacturing

Regulatory NewsRegulatory News | 14 October 2022 |  By 

The US Food and Drug Administration (FDA) has released a discussion paper on emerging and advanced manufacturing technologies concerning the distributed manufacturing (DM) and point-of-care (POC) manufacturing of drugs and biological products that fall under the purview of the Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER).
 
FDA’s discussion paper, written for stakeholders and for public comment, focuses on topic areas and policy development for CDER and CBER drugs and biologics intended to be marketed under a new drug application (NDA), abbreviated new drug application (ANDA), or biologics license application (BLA) where emerging and advanced manufacturing technologies can be adopted.
 
“This discussion paper presents areas for additional consideration and potential policy development that CDER identified based on evaluating the application of the existing regulatory framework to DM and POC activities. A regulatory framework for advanced manufacturing evaluation will address these areas while also considering how potential changes could affect existing technologies and facilities,” the agency wrote.
 
Considerations for DM
 
In the discussion paper, FDA outlined a number of areas of consideration for DM. The agency noted existing requirements for traditional manufacturing facility registration and listing may not be compatible with mobile manufacturing platforms without a permanent physical address, phone number, or owner as mobile units can be moved from one place to another. This may also impact how FDA conducts inspections of manufacturing facilities. “FDA may have to consider the need to evaluate and/or inspect units after they move to new locations. The units’ mobility and the increase in manufacturing locations could present logistical and resource challenges to FDA’s facility evaluation and inspection functions,” they said.
 
Additionally, the application structure could impact the regulatory submission and assessment for more than one drug manufactured with the same DM platform, the agency noted.
 
If the location of a DM facility changes, the applicants may be required to show bioequivalence at that new location, and the location change could require the applicant to generate analytical comparability, method transfer and validation as well as stability data. “The need for these additional data (especially stability data) would burden applicants making multiple and/or frequent location changes and increase FDA’s assessment responsibility,” FDA said.
 
The agency noted that while a pharmaceutical quality system (PQS) may connect or network several mobile units, internationally harmonized guidance on pharmaceutical quality systems recommends inspections at the facility level. “CDER does not have experience evaluating the central PQS of a manufacturing platform of distributed units that move frequently. In such cases, the full quality management system for a DM unit may not be in the physical manufacturing space and may be overseeing multiple locations,” FDA said.
 
FDA proposed questions about DM for discussion, which included asking stakeholders and the public if there were other components of the current regulatory framework that applies to DM, new regulations or guidances that could aid in transparency for DM, unexplored DM scenarios in the discussion paper that should be considered, and how a mobile DM facility could compare or differ from a fixed facility. FDA also asked for information on reporting the movement of a DM unit, how often a DM unit movement should be expected to occur, details of product quality comparability once the DM unit has moved, and how facilities would comply with current Good Manufacturing Practice (CGMP) requirements once the move is completed.
 
Considerations for POC
 
For POC manufacturing, FDA again raised the issues of complying with CGMP and registration regulations once a POC unit operated by an end user is in a new host site environment. The agency noted that a new POC unit environment could impact an applicant meeting drug quality standards with traditional tools and affect FDA’s ability to conduct inspections.
 
“For example, a pre-approval inspection of the PQS facility may include the review of POC unit controls and data generated at host sites; however, the examination of product and the observation of interactions between the end user and the POC unit at the host site may be challenging depending on the number of POC units and how they are deployed,” the agency wrote.
 
“FDA may be challenged by the need to assess quality at all or multiple POC unit host sites during an inspection at the location where the PQS resides,” they said.
 
The agency described another potential challenge in that applicants with POC platforms that produce unique drug doses might have difficulty meeting approved drug specifications. “Applicants may face challenges developing safeguards to ensure that only the approved drug product(s) meeting specification can be made on the POC unit. Based on previous interactions, applicants might have questions on the distinction between POC drug manufacturing and drug compounding. Applicants may also have trouble developing adequate cleaning procedures or other design controls to prevent cross-contamination between different products produced on the same unit,” the agency explained.
 
Questions FDA asked of stakeholders and the public concerning POC include undescribed scenarios in the discussion paper, and the potential for new regulations and guidance for transparency on POC. FDA also asked how stakeholders imagine relationships between POC platforms and healthcare facilities, such as a manufacturer of a POC platform located locally and also at a healthcare facility, a manufacturer remotely operating a POC platform at a healthcare facility with staff as end users, and a healthcare facility purchasing a POC manufacturing platform to operate on their own. Additionally, FDA noted it was seeking more information and examples of how a POC unit would move inside a designated location within a host site, such as a hospital pharmacy.
 
The agency also wanted stakeholders to weigh in on what is needed for POC units at a host site to be maintained and validated, how end users should be qualified and trained, and how to ensure qualified and trained end users are the sole operators of a POC platform.
 
Other questions asked by FDA included how distributed or sold materials for POC platforms would consist only of qualified components, safeguards to identify and prevent deviations in nonconforming drugs, details of recordkeeping for drugs dispensed by the end user in the POC platform, and how all of the above affects biological products at healthcare facilities “where end users would be expected to perform extensive preparation or substantial manipulation (e.g., cell isolation, cell processing, combining with scaffolds, etc.) of the product.”
 
Following the publication of the discussion paper, FDA announced it is co-hosting a virtual workshop in November with the Product Quality Research Institute (PQRI) to discuss DM and POC manufacturing topics with stakeholders and engage with them on areas like technical challenges to adoption, challenges and considerations in complex biologics, terminology, expectations for good manufacturing practices, and Pharmaceutical Quality Systems operation.
 
Discussion paper
Federal Register notice
Workshop announcement

 

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