The US Food and Drug Administration (FDA) issued in December 2018 the final guidance Manufacturing Site Change Supplements: Content and Submission, intended to clarify the responsibilities of medical device manufacturers looking to change manufacturing site for previously approved medical devices. The guidance replaces and clarifies the draft guidance introduced in 2015.
The final guidance document does not present substantially new concepts or thought processes in terms of the content of the site change supplement. The major difference is more clarity on certain aspects that may have been considered ambiguous in the 2015 draft guidance, thus improving its usefulness.
Changes In The Final Guidance
The final guidance provides information to assist manufacturers in understanding the specific circumstances under which a site change requires filing a premarket approval application (PMA) supplement with the FDA. Specifically, the guidance looks at what constitutes a manufacturing site change, when a manufacturer should submit a PMA supplement, what documentation should be submitted to the FDA with a site change supplement, and factors the FDA will consider when determining whether to conduct an establishment inspection prior to approval of a site change supplement.
The guidance provides examples of various situations that could be considered a site change, along with confirmation of whether a supplement needs to be filed, helping manufacturers to align closely with the FDA on whether a submission is required — lowering regulatory risk for the manufacturer.
PMA supplements apply to all Class III device manufacturers (in the US) that already have an approved PMA or a product development protocol, as well as companies manufacturing devices covered under the humanitarian device exemption (HDE) — though HDE devices account for a very small proportion of medical devices within the US system.
All these devices are initially approved through a PMA in the US. After approval, should the manufacturer want to make a change to the device that might affect its safety or effectiveness, the manufacturer must file a ‘180-day supplement.’ The FDA must evaluate this request and approve or deny it within a strict 180-day time frame. The manufacturing site change supplement is a subset to the above; any manufacturer wishing to use a different facility or establishment to manufacture, process, or package its Class III medical devices — previously approved through a PMA — must submit a PMA supplement for the change. HDE holders are required to submit a 75-day supplement.
This final guidance elucidates more clearly to manufacturers what constitutes a site change and when a site change supplement must be submitted to and approved by the FDA. If a manufacturer does not need to submit a site change supplement, then it is important they know to conform to a 30-day notice period prior to the change; this is the process of notifying the FDA that a modification in manufacturing procedure or method is about to be made, at which point the FDA has 30 days to evaluate and approve or reject the application.
What Manufacturers Need To Do
Manufacturers must be prepared to submit a plethora of information to the FDA. Specifically, the guidance provides 13 categories of information that should be included in the site change supplement. Among these, the manufacturer must include an updated description of the device, details stating the nature and purpose of the site change, and a list of manufacturing functions that will be performed at the proposed new site. It is also the manufacturer’s responsibility to submit a flow diagram identifying the individual steps involved in the manufacture, processing, packaging, or distribution of the device at the new site.
It is the manufacturer’s responsibility to provide details on equipment and processes that will be affected by the site change, as well as a list of standards (if any) that will be used in the manufacturing process (this applies to both national and international standards). Manufacturers also will have to submit the process validation and revalidation master plan for the site, including validation procedures and protocols, and a list of processes at the new site that are not in the plans to validate, but will be verified by inspection and test.
It also is important to note that all procedures for environmental control and contamination control — as well as a detailed explanation of how inspection, measuring, and test equipment are routinely calibrated, inspected, checked, and maintained — are required.
If a manufacturer’s site change supplement indicates an intended change in suppliers or contract manufacturers, it is the manufacturer’s responsibility to identify who these are and how their remit will change. Evidence will need to be submitted that demonstrates the supplier’s controls, communication methods that will be used to ensure the supplier fully understands the implemented controls, and the change control mechanism existing between the supplier and the manufacturer.
Procedures for incoming and final acceptance activities at the new site also should be included, if they are different from those contained and approved in the original PMA. It is advisable to review the complete FDA final guidance document without delay if there are any perceived grey areas.
Possibility Of Inspections
The key for manufacturers is to ensure they live by the adage “the devil is in the details.” The more useful supporting detail is provided in the supplement, the higher the chance that the FDA will decide an inspection is not necessary.
The supplement should provide a high level of confidence that device safety and effectiveness are not compromised due to the change in manufacturing site. However, depending on the device’s risk profile, the date of the last site inspection, and the classifications of the current and new sites’ most recent inspections, the FDA may elect to perform a site inspection prior to granting approval for manufacturing at the new site.
If, during a previous inspection, the FDA discovered a major deficiency with the quality system regulation, then a pre-inspection is inevitable. If a manufacturer has had any devices recalled or recorded any adverse events, this too will impact the way the FDA looks at manufacturing the device at a new site, and a site inspection will be likely.
While it is the manufacturers’ responsibility to implement the new guidance, the reality is that regulatory compliance teams already are under considerable time and resource pressures. As such, manufacturers may consider partnering with a third party to ensure that projects and products remain on-track, and that the company’s decisions and actions are efficient, compliant, and consistent with patient safety remaining the business’ highest priority.
About The Author
Mike Wolf is Director of Solutions Delivery at Maetrics LLC, with more than 25 years of in line management and consultation roles. Mike has helped organizations design, implement, and improve quality management systems and processes, as well as achieve and maintain regulatory compliance, including market clearance for new devices and related international licenses or product registrations. Mike recently served as regulatory subject matter expert within a large-scale improvement project at a global orthopedic device company, leading the legacy review and remediation of labeling, regulatory assessment, and premarket product launch processes and records.