The US Food and Drug Administration (FDA) held a public meeting in late August to gain feedback on its proposed quality metrics guidance, which outlines the agency’s approaches to collecting and using data to aid in its regulatory review, compliance, and inspection policies. So what was the feedback and where does the industry go from here? DCAT Value Chain Insights (VCI) takes an inside look.
The quality metrics is expected to play an important role in meeting the FDA’s interest in advancing a risk-based inspection schedule and enabling it to better predict and potentially mitigate drug shortages. Several industry groups, including ISPE, PDA, and GPhA among others, provided input at the meeting. The input from this public meeting will help inform potential revision of the draft guidance and the planned implementation of this program by the FDA.
The FDA's draft guidance
Establishments involved in the manufacture, preparation, propagation, or processing of human drugs, including oversight to ensure quality, currently use quality metrics as part of the process validation lifecycle and pharmaceutical quality system (PQS) assessment. The draft guidance outlines the FDA’s authority to require owners and operators of such establishments to provide, upon request, records and information that the FDA may inspect under section 704 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and describes an initial set of requests the agency intends to make.The FDA intends to make its requests at the time the draft guidance is finalized and to provide notice in the Federal Register. The draft guidance describes the data that the agency plans to request, the uses the FDA intends to make of the requested data, and the quality metrics that FDA intends to calculate.
The requests for this information applies to establishments involved in the manufacture, preparation, propagation, compounding, or processing of finished dosage forms (FDFs) or active pharmaceutical ingredients (APIs) used in the manufacture of covered drug products. Covered drug products would include: drug products that are the subject of an approved application under section 505 of the FD&C Act or under section 351 of the Public Health Services (PHS) Act; products that can be marketed pursuant to an over-the-counter (OTC) monograph; and marketed unapproved drug products. The provisions do not apply to compounders operating under section 503A or registered as outsourcing facilities under section 503B of the FD&C Act; medical gas manufacturers; positron emission tomography manufacturers; and manufacturers of blood and blood components for transfusion, vaccines, cell therapy products, gene therapy products, allergenic extracts, human cells, tissues, and cellular and tissue based products and non-recombinant versions of plasma derived products.
The quality metrics program is expected to play an important role in addressing risk-based inspection scheduling and in the prediction, and potential mitigation, of drug shortages. The Food and Drug Safety Innovation Act of 2012 (FDASIA) requires that the FDA inspect establishments that are required to register with the FDA that are engaged in the manufacture, preparation, propagation, compounding, or processing of a drug or drugs in accordance with a risk-based schedule established by the FDA. The provision replaced the requirement that the FDA conduct inspections of certain domestic drug establishments at least once every two years.
This risk-based schedule of inspections for drugs is to be based on known safety risks posed by establishments that are required to register. These risks are based on certain factors (1) the compliance history of the establishment; (2) the record, history, and nature of recalls linked to the establishment; (3) the inherent risk of the drug manufactured, prepared, propagated, compounded, or processed at the establishment; (4) the inspection frequency and history of the establishment, including whether the establishment has been inspected within the last four years; (5) whether the establishment has been inspected by a foreign government or agency of a foreign government recognized and, (6) any other criteria that the FDA deems necessary and appropriate for purposes of allocating inspection resources. The FDA intends to use quality metrics to support its understanding of the inherent risk of manufacturing establishments and products and as the basis for criteria it deems necessary and appropriate for purposes of allocating inspection resources.
In addition to comments on the guidance generally, the FDA used the August public meeting and is using the written comment period to request comments and related supporting information on the following topics, as described in the draft guidance: (1) optional metrics related to quality culture and process capability/performance, (2) frequency of quality metrics data reporting, (3) an alternative approach to reduce the reporting burden based on the data collection timeframe, and (4) an alternative approach that would allow inclusion of a limited text field for data points or metrics.
ISPE. Diane Hagerty, vice president, Genentech, Inc., and one of the members of the International Society of Pharmaceutical Engineering (ISPE) Quality Metrics Team leaders, provided feedback from ISPE, one of several industry stakeholders offering comments at the FDA's public meetings. ISPE’s comments were based from ISPE membership and were largely based on objective experience gained through Wave 1 of the ISPE Quality Metrics Pilot Program. ISPE’s 2014 pilot mirrored many of the proposed metrics within the new FDA draft guidance.
ISPE supported the FDA’s draft guidance for serving three primary objectives in the near and long term: (1) risk-based inspection scheduling (near term); (2) the potential to provide early indicator of drug shortage (longer term); and (3) risk-based principles for reduced post-approval manufacturing change reporting categories (longer term).
Among its suggestions, ISPE proposed a phased introduction to the guidance. For example, ISPE recommended starting with higher-risk facilities or products, starting with facilities for finished dosage forms and deferring API reporting to later phases of the program, or starting with voluntary reporting during the initial learning period. ISPE also requested more transparency from the FDA on how quality metrics data will be used, along with refined FDA definitions.
Additionally, ISPE recommended that the FDA consider revising the structure of the proposed metrics reporting templates in order to better reflect how industry is currently gathering data and to thereby potentially decrease the reporting burden on companies. In the public meeting, ISPE also commented that, based on its experience gathered from the Quality Metrics Pilot Program–Wave 1 (completed in May 2015) and Wave 2 (currently ongoing), the reporting burden projections included in the Federal Register Notice accompanying the draft guidance appear to be “significantly underestimated.” For example, ISPE noted the anticipated costs for firms to adjust internal information technology (IT) systems and for incorporating additional review and retention of data to support verification during inspection. ISPE also noted that collecting and analyzing metric data by site is the current practice for industry, and that site risk-based inspection frequency planning is best accomplished by reporting data by site. It said that there would be significant additional burden for industry to report data by product, differentiated by site, and that additional evidence is required to demonstrate how the proposed quality metric data at a product level, differentiated by site with annual reporting frequency enables prediction of drug shortages.
With respect to the quality metrics themselves, ISPE recommended starting with three metrics: lot acceptance rate (report by site, differentiated by product); product quality complaints (report by product only); and invalidated out-of-specification (OOS)) (report by site, differentiated by product). ISPE recommended to defer as potential future metrics: annual product review on time, optional metrics related to quality culture and process capability/performance.
PDA.The Parenteral Drug Association (PDA) President Richard Johnson offered comments. Among its recommendations, PDA said that a company's quality culture is critical, but cannot be easily assessed through metrics. It also said that trending of metrics within a site/company/products is preferable to direct comparison between sites/companies/products, even within a segment of similar products or manufacturing sites. It also said that the FDA might consider adding a "right first time" metric in the future. PDA said that feedback from its 2014 PDA Quality Metric Conference recommended starting with a rework /reprocessing rate and developing a common definition/understanding of which deviations are valuable to define the “Right First Time” metric.
PDA will include all the recommendations covered by Johnson and other recommendations, in its written comments on the draft guidance, which are due to the FDA in September. PDA has led a number of initiatives with respect to the quality metrics initiative, including working with the FDA to sponsor several information-gathering workshops, conducting an industry survey on quality culture in 2014, and publishing a Points to Consider on Pharmaceutical Quality Metrics last year. The PDA will publish the results of the 2014 quality culture survey in September and is holding a third Pharmaceutical Quality Metrics Conference in November 2015.
GPhA. David R. Gaugh, senior vice president for sciences and regulatory affairs with the Generic Pharmaceutical Association (GPhA) provided feedback as well. A key point raised by GPhA is that while it believes that FDA’s draft quality metrics guidance is based on good intentions, it may exceed the FDA’s statutory authority. It raised several concerns. The first issue was whether the FDA’s authority to require quality metrics would extend outside the United States. A second concern that with the quality metrics approach, the FDA would be requesting metrics in advance of inspections. GPhA pointed out that inspections are records that companies already keep, and are not new records as the FDA is requesting under the draft quality metrics guidance.GPhA said there is no authority to require manufacturers to generate new records for investigators. It also said that metrics are not necessarily kept in the way that the FDA is prescribing, and that information about contractors and suppliers may not be available as specified under the draft guidance. GPhA said that the FDA should request metrics directly from contractors, in keeping with their direct regulatory relationship with them, and that the FDA should not request application holders to gather and compile data from contractors, given that contract holders are not parties to contractor FDA inspections.
GPhA also questioned the view of the FDA that refusing to supply quality metrics is equivalent to refusing an inspection and therefore a product may be rendered products adulterated with that refusal.The association emphasized that refusing metrics is not refusing an inspection.It said that the draft guidance imposes de-facto increased inspection penalties for failure to report voluntary information, but that there should be no penalties for not supplying voluntary information. Overall, GPhA said that the draft guidance imposes rigid, binding rules and is not reasonable. “FDASIA requires requests be provided within a reasonable timeframe, within reasonable limits, and in a reasonable manner, but what the guidance specifies is not reasonable,” said GPhA in its comments offered at the public meeting.
Like ISPE, GPhA also pointed to additional costs and resources that would be required of companies to implement the quality metrics initiative. In its feedback, GPhA said that internal metrics collection processes and systems will need to be bolstered to provide 100% traceability as external reporting to FDA and that infrastructure and systems to support metrics reporting externally will require significant, added ongoing cost that must be factored into the burden. GPhA also said: “Although the FDA has engaged with industry, there are many surprises in this guidance that have not been fully vetted (e.g., product-level reporting and the idea of covered/reporting establishments) and that create significant burden and complexity for industry. The process now seems unduly rushed, considering the significance of this initiative.”
GPhA also said that the guidance may have some unintended consequences. For example, GPhA noted that companies that make low-volume products in one campaign per year may require a different look at metrics than some other manufacturing models. It also said that companies may be incentivized by the FDA metrics to make choices on products and sites to the detriment of drug supply (for example, discontinue difficult-to-make products or US production at certain sites). It also said that production volumes, launches, and narrow therapeutic range products may flag manufacturers as inherent risks, regardless of good quality metrics performance. It also said that the FDA should make metrics definitions clear using industry feedback and provide ability to have the metrics context included to prevent misinterpretation.