FDA Releases Discussion Paper on Distributed and Point-of-Care Manufacturing
FDA’s discussion paper, written for stakeholders and for public comment, focuses on thematic 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 (BLA) where emerging and advanced manufacturing technologies can be adopted.
“This working paper presents areas for further consideration and potential policy development that CDER has identified based on the assessment of the application of the existing regulatory framework to MD and POC activities. A regulatory framework for the assessment of advanced manufacturing will address these areas while considering how potential changes could affect existing technologies and facilities,” the agency wrote.
Considerations for DM
In the discussion paper, the FDA outlined a number of areas for DM consideration. The agency noted that existing requirements for registering and listing traditional manufacturing facilities may not be compatible with mobile manufacturing platforms without a permanent physical address, phone number or owner, as mobile units may be moved from one place to another. It may also impact how the FDA conducts inspections of manufacturing facilities. “The FDA may need to consider the need to assess and/or inspect units after they move to new locations. Unit mobility and increased manufacturing sites could present logistical and resource challenges for FDA’s facility assessment and inspection functions,” they said.
Additionally, the structure of the application could impact the regulatory submission and review of more than one drug made with the same MD platform, the agency noted.
If the location of an MD facility changes, applicants may be required to demonstrate bioequivalence at that new location, and the change in location may require the applicant to generate analytical comparability, transfer and method validation as well only stability data. “The need for this additional data (especially stability data) would overwhelm applicants who make multiple and/or frequent location changes and increase FDA’s evaluation responsibility,” the FDA said.
The agency noted that while a pharmaceutical quality system (PQS) may connect or network multiple mobile units, internationally harmonized guidelines on pharmaceutical quality systems recommend facility-level inspections. “CDER does not have experience in evaluating the central PQS of a manufacturing platform of distributed units that move frequently. In such cases, a DM unit’s complete quality management system may not reside in the physical manufacturing space and may oversee multiple sites,” the FDA said.
The FDA offered questions about DM for discussion, including asking stakeholders and the public if there are other components of the current regulatory framework that apply to DM, new regulations or guidance that could help DM transparency, DM scenarios not explored in the discussion document that should be considered, and how a mobile DM installation might compare or differ from a fixed installation. The FDA also requested information on reporting of DM unit movement, how often DM unit movement is expected to occur, details on product quality comparability once the DM unit is moved, and how the facilities would comply with current good manufacturing practices (CGMP) requirements once the move is complete.
Considerations for the POC
For POC manufacturing, the FDA again raised the issues of compliance with CGMP regulations and registration once an end-user operated POC unit 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 the FDA’s ability to perform inspections.
“For example, a pre-approval inspection of the PQS facility may include review of POC unit controls and data generated at host sites; However, reviewing the product and observing interactions between the end user and the POC unit at the host site can be difficult depending on the number of POC units and how they are deployed,” wrote the agency.
“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 single drug doses could have difficulty meeting approved drug specifications. “Applicants may have difficulty developing safeguards to ensure that only approved pharmaceuticals meeting specifications can be manufactured on the POC unit. Based on previous interactions, applicants might have questions about the distinction between POC drug manufacturing and drug compounding. Applicants may also struggle to develop adequate cleaning procedures or other design controls to prevent cross-contamination between different products manufactured on the same unit,” the agency explained.
Questions the FDA posed to stakeholders and the public regarding the POC include scenarios not described in the discussion paper and the potential for new regulations and guidance for transparency on the POC. The 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 in a healthcare facility, a manufacturer remotely operating a POC platform in a healthcare facility with staff as end users, and a healthcare facility purchasing a POC manufacturing platform to operate independently. Additionally, the FDA noted that it is 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 input from stakeholders on what is required for POC units at a host site to be maintained and validated, how end users should be qualified and trained, and how to ensure that Qualified and trained end users are the only operators of a POC. Platform.
Other questions posed by the FDA included how materials distributed or sold for POC platforms would consist of only qualified components, safeguards to identify and prevent deviations in non-compliant drugs, record keeping details for drugs dispensed by the end user in the POC platform, and how all of the above affects biologics in healthcare settings “where end users would be expected to perform extensive preparation or substantial handling (e.g., cell isolation, cell processing, combination with scaffolds, etc.) of the product”.
Following the publication of the working document, the FDA announcement he 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 such as technical challenges at the adoption, challenges and considerations in complex biologics, terminology, expectations for good manufacturing practices and operation of pharmaceutical quality systems.