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While stakeholders generally welcome improvements to quality initiatives, they are concerned with how the new requirements will be implemented for more complicated supply-chain models.
The drug industry flooded the regulations.gov website with comments on FDA’s Request for Quality Metrics, with many of the comments coming in the form of concern over how manufacturers will report their data to the agency and how the data will be used by the agency to guide further regulatory action. Further, many commenting companies questioned who in the supply chain would ultimately be responsible for reporting to FDA-as well as what specific data would be necessary, how these data would be interpreted to assess overall product quality, and how to determine whether a quality program was successful or not. Questions were also raised about the methods of reporting that would be required and the overall burden to the industry as far as adding resources to perform quality testing, which Sanofi said in a comment could “increase the potential for drug shortages because some companies may make choices based on FDA metrics to the detriment of the drug supply, by discontinuing products, increasing drug prices, or diverting resources from other quality activities.” Sanofi even questioned FDA’s legal authority to collect metrics and the agency’s ability to take enforcement action if a site does not submit a quality metrics report.
Approximately 15 pharmaceutical manufacturers submitted formal comments to FDA, and numerous trade groups-including the Pharmaceutical Research and Manufacturers of America (PhRMA), the Generic Pharmaceutical Association (GPhA), the Biotechnology Industry Organization (BIO), the Parenteral Drug Association (PDA), the Pharma & Biopharma Outsourcing Association (PBOA), and the International Society for Pharmaceutical Engineering (ISPE)-voiced their concerns as well. ISPE itself submitted a nearly 60-page response to FDA’s request for comments.
Many stakeholders called for a phased approach to the submission of quality metrics to allow companies to alter processes to meet requirements, if necessary. Celgene specifically requested that the initial phase of implementation be optional. Additionally, as Grifols pointed out in a comment, although the draft document says that manufacturers of blood and blood components for transfusion are exempt from submitting quality reporting metrics, Grifols says it is unclear if the guidance will include biologic manufacturers in general.
PhRMA: The draft requires “significant revisions”
Industry trade group PhRMA is concerned that FDA is grossly underestimating the burden that manufacturers will encounter in the collection and reporting of data, the group said in a comment.
Both PhRMA and GPhA agree that guidance should not govern such quality issues. Instead, the quality efforts FDA presents in its guidance should be a product of formal rulemaking activity, especially if the rules therein are expected to be mandatory, rather than voluntary, the trade groups noted.
BIO supports a phased approach
Many industry players voiced concerns about how quality reports will shape further action by FDA. BIO wrote, “We understand that regulatory relief (e.g., less frequent inspections, post-approval manufacturing change categories) may be granted based on positive high-quality metrics; however, it is unclear whether FDA would use low-quality metrics as an indicator to increase inspections at a particular entity.” BIO also wrote that phasing FDA’s changes over a two-year period (or even a period of two-three years, as suggested by other commenters)-in which FDA would have open dialogue with industry on quality data metrics-may be necessary to properly define and identify the data that are of most value in the decision-making process. The agency adds, “An assessment period will also allow FDA and industry to identify any unintended consequences that may arise from the collection of these metrics.”
Data disclosure from the outsourcing community
Cook Pharmica, a contract and development manufacturing organization (CDMO), said it had "considerable concerns about providing information outside of the scope of what is currently provided within the Annual Product Review," mostly because in its role as a CDMO, Cook does not own the license or production rights to the medications produced at its locations. Because of this technicality, Cook suggests sending its data on each product to the license holder for the license holder to submit to FDA; it says that this approach “ensures each license holder has appropriate visibility and accountability for their products' data.” Cook said it would be a major burden to its business to have to submit data to FDA directly.
BIO noted that the application holder should be responsible for submitting quality information to FDA. In contrast with this view, Sanofi wrote in a comment that it favors site-by-site metrics reporting, and said that contract companies, such as contract manufacturing organizations (CMOs) and CDMOs, should be required to submit their own data to FDA. PBOA, however, said that site-based metrics for “variable product types, lifecycle, or frequency/volume of manufacture” would create inaccurate, unbalanced ratings across sites.
Cook added that although FDA says it will not make quality information public, it asked that FDA take extra measures to guarantee that the information not be made public-even under the Freedom of Information Act (FOIA) -to protect “trade secrets and commercial or financial information which could harm the competitive posture or business interests of a company.”
Cook also pointed out that differences between foreign and domestic production sites would create inconsistencies, saying that reporting requirements would have to be the same regardless of plant location, else it may put an undue burden on US-based manufacturers and would “create a skewed or incomplete risk-ranking model.”
Who in the supply chain should be required to report quality metrics?
Concerns also swirled about assigning out-of-specification (OOS) rates, how they will be calculated (i.e., with what mathematical equations), and the scope of tests that would be required to determine if something is OOS. Another CDMO, Hovione, said in a comment that while it generally supports FDA’s quality initiative, quality for finished dosage forms (FDFs) and APIs must be assessed in the same way. Sanofi specifically requested that FDA exclude API manufacturers from reporting requirements, and Baxter disagreed with FDA that the FDF manufacturer be responsible for providing quality data on both the FDF and API. Teva said that if CMOs were to be required to report quality metrics, manufacturers should not be in charge of managing those entries or serving as a conduit to the data reporting. Teva added, “It is unlikely that CMOs and other suppliers would agree to this level of involvement in their operations.” Perrigo, as a company that manufactures APIs, argued that API manufacturers should be required to submit their own quality data on quality, as the API manufacturer won’t always know if the finished product sponsor used its API in drugs headed to the US or to international markets and in which drug their APIs were ultimately used. Gilead asked specifically how FDA plans to assess quality when there is an API used by a manufacturer for different products (i.e., should there be one report for the supplier of the API or multiple reports for each different combination product that uses that API?).
Baxter also requested removal of the requirement to report the number of lot release and stability tests conducted per product and asked FDA to consider final product testing only, as some products are more complex by nature (such as gene therapies) and may require more tests than other products.
A call for less frequent, more tailored reporting
Reporting requirements may be more difficult to fulfill for complicated supply chains, Novartis claimed in a comment, and FDA is underestimating the effect quality reporting requirements will have for those working with various interconnected partners. Teva estimated in its comment that for a product that uses contract services, up to 120 data points per product may be required per year. For Teva’s more than 500 active product applications, the number of data points that would be required for the year for these products alone could exceed 18,000.
Baxter called for less frequent reporting when "there is evidence that the establishment is operating in an ongoing state of control," and suggested that manufacturers be able to design their own reporting programs based on their products in question, provided these metrics are within FDA parameters.
Other issues that stakeholders tackled included the definition of lot and what to do about partial lot rejections (Allergan); how to handle/register alternate sites of manufacture that are on file but not used and the logistics of reporting on a facility when there are multiple facilities in the supply chain (Amneal); the fact that product complaint rate does not consider lot volume (Takeda); the fact that product complaints do not account for patient error or unsubstantiated claims (Celgene); and the concern that submitted data may not be evaluated in context (Novartis).
Celgene notes that although metrics have the potential to provide benchmarking opportunities for the industry, it says that reporting measurements should come “with the understanding that the metrics may not be direct indicators of quality itself.” The industry generally supports the introduction of a free text field in reports, although a few commenters mentioned that the 100-character text field may not be long enough to include additional information that could be relevant to a quality assessment.