This program includes inspectional guidance for determining compliance with the Quality System (QS) regulation, Medical Device Reporting (MDR) regulation, Medical Device Tracking regulation, Corrections and Removals regulation, and the Registration and Listing regulation for PMA inspections.
The QS inspectional goal is to perform a comprehensive assessment of the firm's quality management system for compliance with the appropriate regulations. Preapproval and postmarket PMA QS inspections should generally be conducted using the Quality System Inspection Technique (QSIT). Guidance for performing an inspection is provided in the Guide to Inspections of Quality Systems, August 1999, also called the QSIT Guide.
Note: FDA has the authority to inspect component manufacturers, when necessary, but rarely performs inspections of component manufacturers outside of the PMA program. When inspecting a component manufacturer (except foreign component manufacturers), the investigator should issue an FDA 482, however; the investigator should not issue an FDA 483 to the component manufacturer. If issues are identified during the inspection of the component manufacturer, they should be further investigated at the finished device manufacturer during the PMA inspection. These issues should be handled through the device manufacturer's purchasing control activities under the requirements of 21 CFR 820.50 and acceptance activities under the requirements of 21 CFR 820.80 and any issues identified should be cited on the FDA 483 for the device manufacturer during the PMA inspection. If it is decided to conduct an inspection of a component manufacturer as part of the preapproval of a PMA, it is not necessary to add the component manufacturer to the routine follow-up or postmarket PMA inspection workload planning.
PMA Preapproval Inspection
The PMA preapproval inspection will assess the firm's systems, methods, and procedures for the specific PMA devices to ensure that the firm's quality management system is effectively established (defined, documented, and implemented). All PMA preapproval inspections should be conducted as Level 2 Comprehensive Inspections, covering all four major subsystems (Management Controls, Design Controls, Corrective and Preventive Action (CAPA), and Production and Process Controls (P&PC)), as explained in the QSIT Guide. Refer to Part III of CP 7382.845, "Inspection of Medical Device Manufacturers," for further guidance on Level 2 inspections.
Before initiating the premarket approval inspection, the investigator should review the manufacturing section of the PMA application and any other documents provided by Office of Compliance (OC)/Field Operations Branch (FOB) in preparation for the inspection. It is important to ensure that a manufacturer has completed all process validation activities at the time of the inspection. Refer to Section B for further instructions regarding process validation activities.
Inspectional time for the PMA preapproval inspection should be reported under PAC 83001; however, if the inspection also includes coverage of other areas, divide the inspectional hours between the relevant PAC codes, as appropriate.
PMA Postmarket Inspection
The PMA postmarket inspection will assess the firm's systems, methods, and procedures for the specific devices to ensure that the firm's quality management system is effectively established (defined, documented, and implemented) and effectively maintained. The PMA postmarket inspection should also confirm that commitments made by the firm at the time the applications were approved have been completed or are underway in accordance with those commitments.
Inadequately-controlled changes to a newly-marketed device often lead to complaints and/or service repairs as indicators of performance problems, as well as additional changes in the design, manufacturing process, and/or quality assurance systems relative to the PMA device. Therefore, there should be a focus on these areas to ensure that there are no indications of potential performance problems. The PMA postmarket inspection includes the assessment of postmarket information on the specific PMA devices covered during the inspection and should include:
- Review of any relevant recalls,
- Review of any relevant MDRs,
- Review of any corrections and removals,
- Review of complaints,
- Review of any significant changes in device specifications or in the manufacturing specifications, focusing on the firm's process validation activities, and
- Follow-up on any previous FDA 483 observations, to include the corrections, corrective actions, and systemic corrective actions for the observations and the related systems
Available postmarket information for the PMA device should be reviewed as much as possible as a part of the preparation for the inspection, in order to facilitate efficient time spent at the facility. This review of postmarket information should be documented in the EIR. Any potential problems identified as a result of the review of postmarket information should be investigated and developed during the inspection.
The PMA postmarket inspection can be conducted as a Level 1 (Abbreviated), or Level 2 (Comprehensive) inspection. Regardless of the type of inspection that is conducted, all applicable satellite systems must be covered during the PMA postmarket inspection, as these areas are not covered during a PMA preapproval inspection. For Level 1 inspections, the selection to cover either the P&PC subsystem or the Design Controls subsystem should be determined based upon the review of postmarket information (conducted prior to the inspection), subsystems that were covered during any previous inspection, and any other indicators such as design or manufacturing changes. Refer to Part III of CP 7382.845, "Inspection of Medical Device Manufacturers," for further guidance on Level 1 and Level 2 inspections.
Inspectional time for the PMA postmarket inspection should be reported under PAC 83001A; however if the inspection also includes coverage of other areas, divide the inspectional hours between the relevant PAC codes, as appropriate.
The following statement should be included on each FDA 483:
This document lists observations made by the FDA representatives during the inspection of your facility. They are inspectional observations and do not represent a final Agency determination regarding your compliance. If you have an objection regarding an observation, or have implemented, or plan to implement, corrective actions in response to an observation, you may discuss the objection or action with FDA representatives during the inspection or submit this information to FDA at the address above. If you have any questions, please contact FDA at the phone number and address above.
For all medical device inspections, the FDA 483 should contain the following additional statement:
The observations noted in this form FDA 483 are not an exhaustive listing of objectionable conditions. Under the law, your firm is responsible for conducting internal self audits to identify and correct any and all violations of the quality system requirements.
Satellite Program Areas
Refer to Part III of CP 7382.845, "Inspection of Medical Device Manufacturers," for a discussion of coverage of satellite program areas including MDRs, Corrections & Removals, Tracking, and Sterilization.
Refer to Part III of CP 7382.845, "Inspection of Medical Device Manufacturers," for a discussion of sampling records for reviews.
Special Instructions Concerning Process Validation
At the time of the PMA application, a manufacturer may not have completed all of the required process validations and, therefore, CDRH may not have conducted a review of this data. It is expected that at the time of the inspection, the manufacturer will have completed validations of all processes requiring validation. Therefore, implementation of the process validation activities should be focused on during the inspection, as a thorough review of completed process validations may not have been conducted by CDRH during the review of the PMA application.
If it is identified during the inspection that process validation activities have not been successfully completed by the manufacturer, the investigator should conclude the inspection. Refer to Part V, Section A for further guidance on regulatory/administrative follow up.
Special Instructions Concerning Design Controls
Investigators should ensure that the design and development activities for the PMA devices are sufficiently covered during an inspection. In some cases, one facility may not cover all activities related to the PMA devices. There are a number of multi-establishment firms that conduct all design activities at a single facility (sometimes referred to as a research and development (R&D) center or a corporate design facility). If the establishment scheduled for inspection is serviced by an R&D center or a corporate facility, review the establishment jacket, before beginning the inspection, consult the agency's on-line OEI databases and/or directly contact the district involved. For PMA preapproval inspections, the R&D center or the corporate design facility should be inspected regardless of the facility's inspectional history. For PMA postmarket inspections, determine if the home district of the R&D center or the corporate design facility has conducted a design control inspection of that facility within the previous two years. If such an inspection was conducted, it will not be necessary to conduct a design control assessment at the establishment scheduled for inspection. If an inspection was not conducted within the previous two years, issue an assignment to the home district of the R&D center or the corporate design facility requesting a design control inspection for the devices listed in the PMA postmarket inspection assignment.
Some manufacturers may have their PMA devices designed under contract. These manufacturers must comply with the requirements for using contractors or service suppliers under 21 CFR 820.50 as well as ensure compliance with 21 CFR 820.30. The manufacturer must maintain or have readily accessibility copies of a Design History File for any PMA devices that are in production.
Observations relating to design controls placed on the Form FDA 483 should be limited to the adequacy of the procedures and/or controls established by the manufacturer. Any issues related to the adequacy, safety, or efficacy of a particular design should not be placed on the Form FDA 483. Investigators should discuss any such issues in the EIR, collect complete documentation, and submit the documentation to CDRH for further review.
If the firm has made significant design or manufacturing changes to the PMA device that require the submission of a PMA supplement, the investigator should attempt to get CDRH/OC and/or OIVD concurrence during the inspection before placing the observation on the Form FDA 483. When CDRH concurrence cannot be obtained before the completion of the inspection, the observation should not be placed on the Form FDA 483. Investigators should discuss the issue in the EIR, collect complete documentation, and submit the documentation to CDRH for further review.
Special Instructions for Sterilization Processes
Sterilization processes for PMA devices may be conducted at the device manufacturer or a contract sterilizer. Inspectional coverage of the sterilization process should follow the Sterilization Process Controls section found in the QSIT Guide. Sterilization processes are covered as a sub-part of the Production and Process Controls subsystem under QSIT. The instructions for inspecting sterilization processes are applicable at the following types of facilities:
- device manufacturers that sterilize their own product,
- device manufacturers that use contract sterilizers, and
- contract sterilizers
Note: The portion of the inspection spent covering sterilization processes should be reported under PAC 82845S.
Refer to Part III, A.6, of CP 7382.845 "Inspection of Medical Device Manufacturers," for guidance on collection of samples relating to sterilization issues.
Many contract sterilizers have a significant number of customers who manufacture PMA devices. Therefore, inspectional assignments for PMA postmarket contract sterilizers may not be issued for each PMA product if the facility meets the following criteria:
- The facility was inspected during the previous two years,
- The facility was found to be in compliance with the Quality System regulation; and,
- The same sterilization method was covered as the one identified in the PMA.
For domestic contract sterilizers, an e-mail will be sent from OC/FOB to the district office requesting confirmation that the criteria outlined above has been met and an inspection is not necessary.
PMA postmarket inspection assignments for contract sterilizers will still occur in situations where the above criteria were not met or in the following situations where:
- Changes in the sterilization process cannot be clarified or checked by reviewing sterilization records at the finished device manufacturer;
- Information obtained from the manufacturer discloses a possible problem at the contract sterilizer; and/or,
- Information needs to be verified.
Note: The inspectional policy/strategy described above is only applicable to PMA postmarket inspections of contract sterilizers. CDRH/OC will continue to issue PMA preapproval inspection assignments for contract sterilizers.
General reporting requirements for PMA preapproval and PMA postmarket inspections are listed in the Field Reporting Requirements section of this document. Refer to the IOM, Subchapter 5.10 — Reporting, for general EIR formats. Always include the device, device class, PMA number, and subsystems covered in the EIR.
QS Observations — If there are observed violations of the QS regulation requirements, place them on the Form FDA 483, even if the medical device has not been placed into interstate commerce yet. The submission of a PMA expresses the applicant's intention to place such device into interstate commerce once approval is granted and, therefore, observations need to be placed on the Form FDA 483. The QSIT Guide provides guidance concerning major QS requirements and the identification of major deficiencies. The most serious system deficiencies should be noted on the Form FDA 483 first, then by subsystems if possible.
Note: Refer to the IOM, Subchapter 220.127.116.11 — Annotation of the FDA 483, for information concerning annotation of the Form FDA 483.
FDA Field Accomplishments and Compliance Tracking System (FACTS)
When selecting specific manufacturing processes for the PMA devices to represent profile classes, investigators should give preference to:
- CAPA indicators of process problems,
- processes used to manufacture high-risk components and, subassemblies, as called out in the definition of the term "product" in 21 CFR 820.3(r),
- processes that have a high risk of causing medical device failure,
- processes that require process validation,
- processes that are new to the manufacturer,
- processes that cover a variety of process technologies and profile classes,
- common processes used in multiple products, and
- processes not covered during previous inspections.
Note: If all profile classes are not directly covered during an inspection, but are covered indirectly under CAPA, then all profile classes that the firm is involved with can be listed on the appropriate FACTS screen.
Since the QSIT approach covers systems, the findings from the inspection can apply to all profile classes at the firm.