by Barbara Unger, GMP Quality Expert, and GMP Regulatory Intelligence Editor-in-Chief
While the drug GMPs haven’t changed much, if at all, in recent years, the FDA is planning for significant changes in how drug GMP inspections are scheduled and conducted. The FDA recently made available a description of their new operating model that will ensure integration of review and inspection activities for human drugs. This model continues the FDA’s efforts to refine inspection operations as described in their recent reorganization of the Office of Regulatory Affairs (ORA). It aligns and supports the New Inspection Protocol Program. The MRA between the EMA and FDA allows health authorities to maximize their abilities to focus inspection efforts on high risk sites and rely on each other’s inspection outcomes. Taken together, these changes will permit:
- A more risk based focus on inspection scheduling and conduct;
- Consistency and transparency in the conduct of these inspections and decision making that results;
- Leveraging the different expertise of reviewers and inspectors to maximize inspection coverage;
- A common understanding of the roles and responsibilities for the four inspection types;
- Support for additional communication with sponsors, particularly for generic drugs, regarding inspection outcomes.
This publication describes the roles and responsibilities for three types of human drug inspections: pre-approval, post-approval routine GMP inspections, routine surveillance inspections, and For-Cause inspections. The publication identifies which area within the FDA leads the inspection, how planning is accomplished, the conduct of the inspection, and the communication of results from the inspection. This was also the topic of a presentation by Alonza Cruse, Director of Office of Pharmaceutical Quality Operations in ORA, at the recent PDA/FDA joint regulatory conference in Washington DC.
We will take a look at each of these in turn.
Those of us who ‘grew up’ with CBER regulated products have often seen pre-approval inspection conducted by teams including reviewers and GMP inspectors from either the Center or the field offices. And, even in the past five years, recombinant DNA therapeutic product PAIs were often conducted by similar shared teams with both reviewers and GMP experts. PAIs are conducted to assure ‘that any manufacturing facility named in the application is capable of manufacturing the drug in conformance to Current Good Manufacturing Practice (CGMP) requirements and that the data submitted in the application are accurate and complete.’
The decision as to whether a PAI is needed to support a product approval decision is made by CDER with ORA participation. SOPs will be developed in the future to clarify responsibilities of each party in this decision-making process. If a PAI is deemed necessary, it is led by ORA with CDER participation. A team of individuals are identified to provide consistency in this process and provide the final recommendation regarding the inspection portion of the marketing application approval process.
Communication of the inspection outcome is described in the EIR and includes any observations made in the 483 issued at the end of the inspection. The outcome of the inspection and whether the facility is ‘approvable’ or not must be made by the PDUFA identified date. The outcome is communicated to the facility owner or drug sponsor (when these are different) through regulatory meetings, an information request letter, a discipline review letter, or a complete response letter.
These inspections are product specific and focus ‘…largely on the process validation lifecycle and any manufacturing changes that may have occurred following approval.’ Further changes in risk, as seen by the agency, may prompt this type of inspection.
The decision regarding a post-approval inspection of this type is made by the ORA pre-approval manager in conjunction with the multi-functional team identified for PAIs. This team includes risks in a ‘life-cycle dashboard,’ and if a PAI is not necessary, then the site becomes subject to the periodic surveillance inspections. The publication does not provide additional information to differentiate this type of inspection from the routine surveillance inspection described below. Perhaps when the FDA publishes SOPs regarding this process, additional clarification will appear. In my opinion, this type of inspection may be used to follow up on products made using novel technologies or first in class type of product approvals where the FDA has limited experience with the processes. We’ll see how this works out in the future.
This appears to be the routine ‘biennial’ inspection though the inspection frequency will be based on the FDA identified risk criteria. The inspection may not be product specific but rather assesses conformance to CGMPs. Personally, I’m not sure how you do that without having some product specific component to the inspection. Otherwise, it essentially becomes an SOP review which fails to address whether firms follow their procedures in day-to-day manufacturing and testing operations. The operating model states this type of inspection applies to drug substances, drug products, in-process materials, as well as over the counter monograph drug products.
The ORA conducts the inspections prioritized by the ‘CDER’s surveillance risk model’ with center participation where requested. Preparation for these inspections includes a consolidated review of: inspection history, recalls, shortages, customer complaints, foreign regulator inspection outcomes, information from Field Alerts or Biological product defect reports, quality metric data if any have been submitted, and a list of all products manufactured at the site.
Within 45 days of the end of these inspections, the ORA completes the EIR and a proposed classification for the inspection: Official Action Indicated (OAI), Voluntary Action Indicated (VAI), or the one we all want, No Action Indicated (NAI). Forty-five days later the Office of Manufacturing Quality makes a final classification. There seems to be a very complicated back-and-forth activity that potentially includes the Office of the Chief Counsel, the ORA, and the OMG if the decision is to be modified or upheld. Bottom line though, if there’s a classification of NAI or VAI, the ORA issues a ‘decisional letter within 90 days following the inspection closing.’ For inspection classified as OAI, both OMQ and ORA communicate with the facility.
Section V.E. of the Generic Drug User Fee Act 2018-2022 addresses the timing of these communications with sponsors and facilities. By May 31, 2018, when issues are identified during an inspection that could prevent approval of an NDA, ANDA, or PAS, the applicant will be notified of these issues within 90 days of the close of inspection. By October 1, 2018, the FDA will notify the applicant of inspection outcomes that do not impact approvability of a pending application within 90 days of the close of the inspection. The FDA will also develop expedited re-inspections after remediation. It seems that this notification timing would be unlikely to prevent a CRL for manufacturing issues, since the remediation of a problem serious enough to hold up approval is generally not one that can be resolved in a month or two. Nonetheless, timely decision making and communication of inspection outcomes is valuable to both the industry and the FDA.
These inspections are generally conducted in response to a specific event or communication that identifies potential risks to patient safety and product quality. For example, complaints for the potential lack of sterility in drug products may frequently prompt for-cause inspection.
The ORA leads these inspections that focus on a specific issue. Like the surveillance inspections, outcomes are communicated within 90 days of the inspection close. Information gained during this inspection is included in the facility specific information that is reviewed prior to future inspections.
CONCLUSIONS and QUESTIONS:
The new operating model provides detail on the various roles and responsibilities of participants in human drug GMP inspections. It also provides detailed flow charts of the activities and RASCI charts for the stakeholders. What it appears to lack is information on the timing of when the model will be implemented. Perhaps some of that will be forthcoming soon. It also seems that the Office of the Chief Counsel may return to playing a role in warning letter issuance, see the reference in section 4.3.
One of the most interesting aspects is the communication of problematic inspection outcomes (those that are classified OAI) to the facility or applicant. OAI inspection outcomes would be communicated to the facility/applicant by 90 days after the close of inspection. In the Operating Model, this appears to apply only to surveillance (routine periodic) GMP inspections and for-cause GMP inspections. Negative outcomes from pre-approval inspections become evident by the PDUFA date with issuance of a non-approval letter. GDUFA II specifies that this applies to NDAs, ANDAs, and PASs.
We await a more fully developed model based on this document along with the necessary policies and procedures to support its implementation. This will also include implementation of the New Inspection Protocol Project. It would be a challenge to see that all of this might happen before the end of 2018. Ideally though, the FDA will begin implementing some of these aspects and then incrementally add others. We have yet to see implementation of the New Inspection Protocol Program, so implementation of the new model may take a few years, at best. These programmatic changes should benefit both the industry and the FDA, but the length of time to implement them leaves the FDA in the uncomfortable position of continuing to make promises without being able to demonstrate actual accomplishments and effectiveness.
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