A new report from the FDA’s Office of Pharmaceutical Quality OPQ runs the numbers on the state of U.S. pharmaceutical quality in FY 2021, highlighting growth areas and topics that received heightened scrutiny. This year’s report also gives updates on two quality maturity pilots; AgencyIQ dives into these programs and hits the data highlights in the OPQ report.
Background on OPQ
- The FDA’s Office of Pharmaceutical Quality (OPQ) resides within the Center for Drug Evaluation and Research (CDER); it is the office that is “responsible for ensuring that drugs legally marketed in the U.S. are safe, effective, and meet quality standards,” according to OPQ’s report on drug quality for FY 2021.
- The OPQ “state of pharmaceutical quality” report, released this week, is the fourth such annual report and the second one to include Covid-19 pandemic-era data. In contrast to last year’s report, the 2021 “Report on the State of Pharmaceutical Quality” had a less intensive focus on CDER’s adjustments prompted by the pandemic. This year’s report discusses in some detail “two initiatives that will enable new approaches to inspect, characterize, and advance quality.” The first is the New Inspection Protocol Project (NIPP). The second initiative addresses quality management maturity (QMM).
- Somewhat confusingly, OPQ produces two major reports annually: an “annual report” issued after the end of the calendar year, and this pharmaceutical quality report, typically issued near the end of a fiscal year, covering the preceding fiscal year (the FDA’s fiscal year runs from October 1 – September 30). The 2021 annual report, like those that preceded it, provides a high-level overview of OPQ activities in the prior year. The pharmaceutical quality report goes into detail on facts and figures regarding OPQ’s activities for the prior fiscal year, and also highlights important initiatives and new projects the office is pursuing. AgencyIQ is diving into OPQ’s progress on two key quality projects, and also (see further down) hitting the high spots of the report’s data. [ Read AgencyIQ’s analysis of the 2020 OPQ pharmaceutical quality report here.]
OPQ’s update offers some new information about the agency’s evolving approach to drug quality oversight, especially related to NIPP.
- Bolstering FDA’s inspection efficiency under NIPP: As announced by then-Commissioner Scott Gottlieb in 2018, NIPP is intended to leverage a standardized set of protocols to collect structured electronic data from facility inspections. Under the rubric of the agency’s “commitment to quality,” the NIPP’s main goal is to update the FDA’s use of data from surveillance and pre-approval inspections. Some sterile surveillance and pre-approval inspections have used the NIPP approach since 2018, according to the report. The FDA has been working on these approaches for non-sterile inspections as well, developing protocols that collect structured data for each system in a surveillance inspection and for each objective in pre-approval inspections. Technology updates have been ongoing in the background to support use of structured inspection data, noted OPQ.
- The technology and administrative infrastructure to move inspection data out of silos and away from narrative-based forms is being built – slowly. Recently, Principal Deputy Commissioner Janet Woodcock spoke of cross-cutting modernization efforts that OPQ’s NIPP work will support. Woodcock, who recently transitioned to her current FDA position following a stint as Acting Commissioner, has taken the reins for these modernization efforts, providing support and council to seven units within the FDA: the Office of Digital Transformation (ODT), the Office of the Chief Scientist (OCS), the Office of Operations (OO), Office of Regulatory Affairs (ORA), Office of Food Policy and Response (OFPR), Center for Food Safety and Response (CFSAN) and the Center for Veterinary Medicine (CVM).
- Speaking at an early August media event hosted by the Alliance for a Stronger FDA, Woodcock called out inspections, a cross-agency function, as showing how inefficient and siloed information and administrative processes can hamstring important agency activities. Centers request inspections, but the workflow isn’t well integrated with ORA, said Woodcock. This is an example of the FDA’s “very poor knowledge management,” said Woodcock; an undesirable downstream effect is “inconsistency in regulatory decisions…if we can’t keep things where they are accessible, staff may not be aware of the decision” that would set an important precedent, she pointed out.
- Currently, said Woodcock, data elements related to inspections are not standardized. Since the reports themselves do not use standardized data elements, conducting any kind of data aggregation for research and reports involves a laborious manual process that must sweep prose narratives for data.
- Data about the establishment being inspected is similarly poorly integrated into the inspection process, further complicating the work of inspectors, others at ORA, and FDA Centers. All of this means that “trend analysis is very difficult,” said Woodcock. Overall, the effect is “very poor knowledge management, she noted, with resulting “inconsistency in regulatory decisions.” Though Woodcock didn’t specifically refer to OPQ’s NIPP efforts, the efforts to quantify inspection data will certainly contribute to Woodcock’s envisioned cross-cutting reforms.
- OPQ reports that data from about 75 surveillance inspections using NIPP protocols are be used to “identify potential associations between site characteristics and the distribution of observations” that an inspector might report on a Form 483. The agency plans to use natural language processing techniques to mine text-based data from inspection reports to “detect emerging trends and extract useful information,” according to the report. In sum, the NIPP work should eventually serve to give FDA a broad picture of its own inspection programs and the results of that work – a picture that is currently hazy at best.
Additional details about OPQ’s QMM proposal
- The report also cites OPQ’s ongoing work to develop the concept of QMM. In April of this year, OPQ unveiled a whitepaper, Quality Management Maturity, which it said was intended to support the development of a framework “to objectively rate the QMM of pharmaceutical manufacturing sites.”
- As described by OPQ, QMM represents an elevated state of drug quality. The foundation of quality is adherence to CGMPs, which sets the ground-level state of basic compliance. The next step is adherence to the International Council for Harmonization’s (ICH) Q10 guideline – which has been adopted by the FDA – which recommends an approach for the adoption of Pharmaceutical Quality Systems (PQS) to guide continual improvements to the product over its lifecycle. The Q10 guideline also indicates specific management responsibilities regarding planning, communication and reviews. QMM represents a third step, reliant on the prior two, in which a company “thoroughly” implements the Q10 approach “to promote continual improvement,” according to the FDA.
- As the FDA notes in the paper, while it currently assesses many aspects of pharmaceutical quality for the purposes of risk-based inspections, it does not currently assess QMM. Instead, QMM “falls solely on the manufacturer” to implement as part of adherence to the Q10 guideline, which is a voluntary recommendation, though the agency acknowledges that industry is also gathering drug quality metrics to better understand “the behaviors that assure quality and reliability in the pharmaceutical supply chain.”
- What would a QMM rating program entail? While the white paper was light on details, it did describe some of the key elements. FDA emphasizes the important of “quality culture” – an environment in which all persons responsible for manufacturing take ownership for the quality of products. As the paper notes, “a quality culture is necessary to achieve high levels of QMM.”
- FDA has also stressed the importance of the QMM being “objective and consistent across manufacturing sites and agnostic to the product or size of operations.” Notably, this approach is the opposite of FDA’s approach to the broader quality metrics program, which has proposed a flexible approach tailored to product type and facility preference. [ Read AgencyIQ’s analysis of FDA’s new quality metrics approach here.]
- The OPQ report highlights the FDA’s QMM progress to date on two new pilots. In October 2020, FDA began two new pilot programs to assess companies’ QMM, with measures of maturity bearing striking resemblance to the agency’s original quality metrics proposal. The pilots, each completed in FY 2022, focused on foreign API manufacturers and on domestic finished drug form (FDF) manufacturers. A variety of methods, including “self-surveys, facilitated interviews based on the assessment rubric, and focused presentations delivered by the site” sought to gather data to help the agency “further develop the criteria and methods used to objectively measure a manufacturing site’s QMM.” These are the methods the FDA presented in its April white paper.
- OPQ reports that the programs were able to measure maturity levels of a given site, which was evidenced by behaviors such as proactively managing availability risks, applying quality risk management effectively, investing in digitalization, and making use of “advanced analytics.” The assessment framework used by the FDA was able to discern between varying levels of quality management maturity, OPQ said.
- In the report, OPQ makes the case that the QMM efforts will eventually provide manufacturers “a competitive advantage through transparency in the workplace,” while giving consumers and payers “more insights into maturity and performance” — though ensuring availability of medicines is the FDA’s primary goal.
- FDA also makes clear that it intends to pair the QMM score with a package of potential incentives, including one major one: “reduced inspection frequency.” Other incentives might include “increased regulatory flexibility in making post-approval changes,” according to the whitepaper. [ Read AgencyIQ’s full analysis of the QMM white paper here.]
- An upcoming meeting of FDA’s Pharmaceutical Science and Clinical Pharmacology Advisory Committee will consider “the impact that a QMM program would have on the pharmaceutical industry, drug shortages, and supply chain resiliency.” [ Read AgencyIQ’s preview of the upcoming adcomm here.]
The report also presents an interesting array of figures regarding the state of manufacturing quality in the US and abroad, for both APIs and finished products
- What’s new and interesting in manufacturing quality data, from OPQ’s point of view? First, U.S.-based drug manufacturing continues to expand. Overall, the number of manufacturing facilities in the U.S. grew by a net 5% in the three years ending in FY 2021. This figure has the U.S. tied with Ireland, which also saw a net 5% expansion, for the countries topping the list for growth; one caveat is that OPQ’s table of inventory shift by nation (showing gains, losses, and net growth/contraction) only includes countries that have more than 50 sites in its product catalog. The biggest net loser? South Korea, which saw a net 9% decrease over the 3 years captured in the table. Net growth for the 14 countries identified on the table, plus an “all others” category, was 3%.
- The CDER product catalog is not small, with “application product” numbers dwarfed by “non-application” ones. In all, the 2021 product catalog has just over 15,000 products with associated applications; these could be new drug applications, abbreviated new drug applications, or biologic license applications. Over 140,000 non-application products, each with a unique National Drug Code, feature in the catalog; of these, most (over 75,000) are over-the-counter products, while over 15,000 are homeopathic products.
- Manufacturers making essential medicines attain higher site inspection scores than those making non-essential medicines. Some context: site inspection scores (SIS), which can range from 1-10, serve as a proxy for CGMP compliance, with higher scores indicating better compliance. The Essential Medicine List was mandated by a pandemic-prompted 2020 executive order and is made up of 227 “drug and biological product essential medicines and countermeasures, including analgesics, antivirals, anticoagulants, antihypertensives, and antimicrobials,” according to OPQ. About 1,000 sites make at least one product that features on the essential medicines list, and these sites score an average 7.45 points on the SIS list, compared with 7 points for non-essential medicine makers. This difference was highly statistically significant (P less than .0001).
- The U.S. drug market continues to rely heavily on India and China for pharmaceutical building blocks for essential medicines. According to the report, 38% of all active pharmaceutical ingredients (API) for essential medicines came from one of these two countries in FY 2021 (as measured by the number of manufacturers), while just 19% of API for these products were made in the U.S.
- By contrast, two thirds of complex medical product production sites are located in the U.S. (37%) or the E.U. or U.K., which collectively made about 31% of complex medical product sites. China and India contributed just 4% and 13%, respectively, to this product type in FY 2021.
- Product recalls were more likely to occur in the 12-month window following an inspection, regardless of the outcome of that inspection, reported OPQ. Class I recalls, the most serious, were more likely to be associated with two particular inspection outcomes: “final Official Action Indicated (OAI) classification and an initial OAI classification that was reclassified” to a Voluntary Action Indicated after the violations were resolved. OPQ uses these data to support its contention that inspections “can reveal that potentially defective products were marketed and can prompt firms to identify potentially defective products.”
- In an ongoing pandemic-spurred pivot, the FDA conducted 288 remote facilities inspections. These resulted in a total of 21 import alerts. The agency also made use of site inspection records obtained under mutual recognition agreements with 18 partner countries and reviewed site inspections from another six non-partner countries to assess a total of 139 sites.
- The FDA continued a sampling program that, in 2021, heavily scrutinized hand sanitizers and continued the agency’s sweeping examination of the U.S. drug supply for nitrosamines. Of 3,861 samples taken by the agency, 35% were non-compliant with FDA regulations, though sampling was weighted toward sanitizers and screening for organic impurities such as nitrosamines, which can cause cancer. This was the fifth straight year in which FDA sampling had found an increased percentage of issues, and was a substantial increase over the prior year (16% rate of non-compliance).
- “Most hand sanitizer manufacturers are located in the U.S. and China,” noted OPQ, but sanitizers coming from Latin America, and Mexico in particular, accounted for well over half of the warning letters issued by FDA over the course of FY 2021. Over 600 product quality defect reports detailing problems such as burning, nausea, and other adverse events, were reviewed by FDA in FY 2021. Of more than 350 hand sanitizer samples, 38% either had impurities such as methanol, or were not potent enough to be effective.
- OPQ reported new data that OTC product manufacturers were particularly likely to have inadequate control processes for organic impurities. Fewer than half (47%) of OTC drug products had what the agency deemed “adequate” organic impurity control, while 20% had control processes that were “inadequate” and 33% had none at all.
- The QMM story will continue in early November, when the meeting of the Pharmaceutical Science and Clinical Pharmacology Advisory Committee will take place on November 2 and 3. AgencyIQ will be in attendance at the virtual meeting and will have an analysis of the committee’s assessment of QMM efforts and the (somewhat) related Knowledge-Aided Assessment and Structured Application (KASA) initiative. [ Read AgencyIQ’s preview of that meeting here.]
- As the FDA’s Woodcock made clear earlier this month, OPQ efforts to quantify inspection data are meant to improve consistency in inspection-related activities, but also to give the agency insight into characteristics of manufacturers that point to higher or lower levels of quality management maturity. To accomplish these goals, the agency must play a long game, and one that’s dependent in large part on funding for administrative and technology upgrades for long-outmoded systems. With the entirety of the agency’s FY 2023 funding currently hung up in a Congress out on recess until Labor Day, the agency’s finding long-term planning a challenge.
- AgencyIQ has provided the highlights, but the OPQ report is just 26 pages of well-illustrated data and is worth perusing in its own right. The link is below.
Featuring previous research by Alexander Gaffney and Laura DiAngelo.
To contact the author of this item, please email Kari Oakes ( [email protected])
To contact the editor of this item, please email Alexander Gaffney ( [email protected])