Back to the drawing board for FDA’s revised quality metrics plan?

The U.S. Food and Drug Administration’s (FDA) revised plan to collect quality measurement data from manufacturers has drawn criticism from a major pharmaceutical industry group over the measures proposed by the agency, as well as its methods of program development. Others complained about the lack of focus of the proposed program, while two industry groups also expressed serious reservations about the aim of the program as a whole.

Still, on a positive note, an industry group and a major manufacturer praised the plan’s flexibility in allowing manufacturers to decide which metrics to report.

The FDA issued calls for comment when it released its revised quality metrics proposal in March. (RELATED: Quality Indicators: FDA Seeks Feedback on Streamlined ProgramRegulatory guidance March 8, 2022)

The proposal is the FDA’s attempt to revive its previously stalled efforts to obtain manufacturing quality data to reduce potential drug shortages. Feedback was a bit more supportive of this blueprint’s flexibility compared to previous iterations. (RELATED: Industry wants FDA to rein in quality metrics program, Regulatory guidance March 30, 2017).

The agency stressed in an announcement that this program would be different from the original draft guidance on quality measures unveiled in 2015, as well as the revised draft guidance released in 2016.

The FDA has identified four areas, with individual metrics within each of the areas, as appropriate for reporting: manufacturing process performance, pharmaceutical quality system (PQS) effectiveness, laboratory performance, and supply chain robustness. The reporting facility would select the most appropriate metrics in each practice area and notify FDA how they were calculated. The FDA has also sought comment on whether facility-level reporting is appropriate.

Leased flexibility

Pfizer and the Parenteral Drug Association (PDA) supported the flexibility of the proposed quality metrics program.

Pfizer said: “In principle, we agree with the proposed direction of the FDA QM reporting program and the flexibility on what metrics are reported, as well as the ability for each estimate to be able to define how the metrics are calculated. .”

Still, Pfizer noted that “the program introduces potential ‘incentives’ but does not address specific regulatory and supervisory incentives, such as possible reduced inspection frequency.”

PDA also supported the flexibility of the proposal. The group writes that “enabling a site to select those metrics within a specified practice area that are most appropriate to their operations and best characterizes their site’s maturity or opportunity for improvement is a positive development for the industry”.

PSI calls for increased engagement

In its comments, the International Society for Pharmaceutical Engineering (ISPE) said the FDA needs to seek more outside engagement from industry to develop the program.

“The current approach of issuing guidelines, piloting programs, commenting on case requests, and responding to surveys at FDA conferences provides limited opportunities for dialogue. The expertise that all parties could provide to develop this important initiative could be better harnessed,” PSI wrote.

In addition, the group said its members do not support any of the four practice areas suggested by the FDA.

For example, members told PSI that supply chain robustness “may be relevant to the business performance of some companies, however, there was not a high level of support for these measures in our survey with many strong comments that they were beyond the scope of a quality metrics reporting program.

Bristol-Meyers Squibb also expressed concern about including supply chain strength as an indicator. “BMS is concerned about the inclusion of the Supply Chain General Practice Area because it may be redundant or duplicate other initiatives such as the CARES Act volume reporting requirement.”

The ISPE also said its members were “biased” on the FDA’s recommendation to report process capability values, and therefore, “cannot recommend inclusion of this metric.”

The group said the number of batches manufactured during a reporting period “may be insufficient to support the calculation of process performance as well as the variable and inconsistent definition of specification acceptance criteria”.

In addition, the ISPE stated that the PQS measure of effectiveness was not supported by its members. ISPE also recommends moving the performance metric from the lab to the manufacturing process performance domain and removing the invalidated/reversed out of specification (IOOSR) metric from the list of potential metrics.

AAM and PBOA have serious doubts

Two groups, the Association for Accessible Medicines (AAM) and the Pharma & Biopharma Outsourcing Association (PBOA), a trade association representing contract manufacturers, have expressed reservations about the program.

The AAM said the FDA proposals are not aligned with the group’s proposal outlining five principles for reporting key quality measures in a 2021 while the paper. These principles include the following: quality measures must be within the boundaries of clear statutory authority, quality measures data must be collectable and participation must be feasible, quality measures must be formalized by product types and product risk and quality measures should not create “perverse” incentives. .

The AAM wrote that the FDA’s proposed quality metrics program is not aligned with any of these principles and “in many respects it departs even further from them than some of the previous Quality Metrics Reporting Program proposals.” FDA quality measures”.

The group adds, “We are concerned that potential new guidance proposed by the FDA for a quality metrics reporting program still lacks appropriate legal authority, may incorporate metrics that have not been validated, and may not be relevant to quality, and would encourage the submission of metrics that do not make sense and would not advance public health.

Along the same lines, the PBOA complained about the lack of focus in the FDA’s proposal and recommends that the agency “better define its purpose and the intent behind this initiative.”

“Without collecting data in a targeted manner and with a clear purpose, our members are concerned about how these metrics will be interpreted and how they may incorrectly reflect quality maturity status or direction. The PBOA is also concerned that the metrics collected will vary significantly depending on the metrics of the site relative to the products, the development status of the drugs being measured, the annual manufacturing demand, and the age of the product/ manufacturing process.

The group also wrote that “there is no clear and positive incentive for CDMOs to participate in the program, only negative incentives. Incentives that the FDA has cited in the past have been discussed and focus on sponsor/MAH goals. »

Supported establishment site metrics

In other areas, BMS said it supports the inclusion of settlement site metrics. The use of these metrics “will allow the reporting of meaningful metrics for the operations of the institution. Measures should be selected to enable an institution to monitor its own operations and drive continuous improvement.

BMS also recommended that the agency take a phased approach to rolling out the program.

Organic products are not sufficiently taken into account

In terms of specific products covered by the plan, the Biosimilars Council said the quality measurement program is not suitable for manufacturers of biologics.

The proposal does not “sufficiently take into account the inherent differences between specific product categories (ie, biologics versus chemically synthesized small molecule pharmaceuticals). Particularly due to the complexity of biological products, it would be inappropriate to compare the metric data of one biological site to other incomparable sites, such as that of a simple oral solid. For example, bioassays can have high invalid rates compared to a typical analytical method of high performance liquid chromatography (HPLC).

The board said, “Because the FDA intends to use quality measurement data to develop compliance and inspection policies and practices, biologics could be subject to treatment. unfair if these differences between product categories are not taken into account. Therefore, manufacturers of biosimilars can choose not to participate in the program.

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