Summary of FDA’s “Report on the State of Pharmaceutical Quality: Fiscal year 2021”

By Mark Land, M.S., RAC, AAHP President


In August of 2022, the United States Food and Drug Administration (FDA) published its fourth annual Report on the State of Phar­maceutical Quality. The report presents key data used to characterize drug and site quality for consumers and patients in the U.S.  The report is published by the Office of Pharmaceutical Quality (OPQ) and covers FDA-registered drug manufacturers and drugs, including biological products, regulated by CDER to inform stakeholders about the quality of the U.S. drug supply.

Manufacturing Site Demographics

The FY2021 CDER Site Catalog (current as of November 2021) includes 4,451 drug manufacturing sites, a 3% increase over FY2018. Of the total drug manufacturing sites in FY2021, 39% are in the “No Application” sector, which indicates that all products manufactured at the site are marketed without an approved FDA application. This sector includes over-the-counter (OTC) monograph products, marketed unapproved prescription drug products, and homeopathic products. The remaining 61% of sites manufacture at least one application product. The top five countries based on the number of sites in FDA’s inventory are U.S., India, China, Germany, and Canada. Understanding the locations of drug manufacturing sites and their trends helps FDA better plan for future surveillance and outreach.

Quality Surveillance with Foreign Regulatory Authority Inspection Reports and Record Requests

While COVID-related travel restrictions continued to limit FDA’s ability to inspect sites in FY2021, alternative tools were used to provide quality surveillance. These tools enabled FDA to assess sites that would otherwise have been out of reach. In particular, the Mutual Recognition Agreement (MRA) program enabled FDA to receive and rely on inspection reports from MRA partner agencies. This includes inspections conducted both within and outside their countries. During FY2021, using inspection reports from MRA partners, FDA reviewed and classified 139 site inspections in 18 MRA partner countries and six other countries. FDA also used its authority under section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) to request records and other information in lieu of or in advance of inspections to assess compliance with Current Good Manufacturing Practice (CGMP) requirements for sites that FDA would otherwise have been unable to assess. During FY2021, FDA conducted 288 surveillance systems-based assessments, using information from 704(a)(4) requests, that resulted in 21 Import Alerts.

Drug Product Demographics

The CDER Product Catalog includes all registered prod­ucts, which consist of application products (NDAs, ANDAs, and BLAs) and non-application products (including OTC monograph, marketed unapproved prescription drugs, and homeopathic products). For FY2021, FDA’s Product Catalog contained 16,280 application drug products. Each application may include multiple products of differ­ent strength, concentration, or sizes. The Product Catalog contains more than 140,000 non-application products with a unique National Drug Code (NDC), including 75,300 OTC and 15,640 homeopathic products.

Note from AAHP: Homeopathic drug products represent 10% of all drug listings with FDA.

Essential Medicines

In October 2020, in response to Executive Order 1394410, FDA published a List of Essential Medicines, Medical Countermeasures, and Critical Inputs known as EM. This executive order seeks to ensure sufficient, reliable, and long-term domestic production of these products and minimize potential shortages. The published EM list contains 227 drug and biological product essential medicines and countermeasures, including analgesics, antivirals, antico­agulants, antihypertensives, and antimicrobials. There are no homeopathic medicines on the EM list.

Product Quality Defects (PQDs)

The Agency receives and evaluates mandatory, as well as voluntary, post-market quality reports. FDA’s post-market regulations require that application owners notify FDA about significant product quality defects in marketed products. Voluntary reports include MedWatch (MW) and consumer complaints (CC) that can be submitted by consumers, patients, and healthcare professionals when product quality fails to meet expectations. During FY2021, CDER received 11,512 quality-related MW, 4,115 FARs, 273 CC, and 205 BPDRs, which are similar quantities to FY2020.

Note from AAHP: While non-application products are not specifically required to file post-market quality reports, homeopathic product owners should be aware of this process and consider reports to FDA in the event of a significant product quality defect.

Import Alerts and Recalls

During FY2021, FDA placed import alerts on 49 sites for refus­ing inspections, refusing 704(a)(4) records requests, non-com­pliant laboratory testing, and non-compliant findings from inspections and record requests. The largest number of import alerts were for sites in China and Latin America. Manufacturers of hand sanitizer products accounted for all import alerts issued for non-compliant laboratory testing.

Although most recalls are voluntary, they may be driven by a com­pany’s own initiative or by an FDA recommendation. For the second year, the number of total recalls and Class I recalls increased. In recent years, Class II recalls have not shown any trends. Class III recalls, those with the least public health impact, have been steady.

Note from AAHP: Refusing inspections or records requests cause FDA to consider that products manufactured at that site are adulterated, giving rise to import alerts against products originating from that site. Recalls are a tool to limit risks to public health. The process begins by completing a Health Hazard Assessment (HHA). Completing the HHA characterizes the potential risks to consumers and aids in determining whether a recall is necessary. It is important to consider associations with all batches.

Research on the State of Quality

FDA conducts research to understand where pharmaceutical manufacturing is adhering to compliance standards and where opportunities exist for improvement.

The Relationship Between Inspections and Recalls

To better understand recalls, OPQ analyzed the temporal relationship between FDA site inspections and subsequent recalls. Several statistically significant associations were found:

  • Regardless of the inspection outcome, there were more Class II recalls in the 12 months following surveillance inspections than occurred outside of that 12-month window.
  • For Voluntary Action Indicated (VAI) outcomes, there were more Class III recalls in the six months following surveillance inspections than occurred outside of that six-month window.
  • Class I recalls are more likely to be associated with two inspection outcomes: final Official Action Indicated (OAI) classification and an initial OAI classification that was reclassified to VAI after resolution of violations.

Note from AAHP: It is mandatory that an investigation be conducted to determine any extension to other batches that may have been associated with the specific failure or discrepancy of the recalled batch. Keeping FDA informed of your progress in any extension investigation and/or mitigation of risks is important.

Complex Products and Quality

Complex product sites tended to have higher Site Inspection Scores (SIS) than non-complex sites; 7.65 vs. 7.00, respectively.

Note from AAHP: While most homeopathic products are not classified as complex products, the principles of controlling complex manufacturing operations can be a helpful tool if you are considering changes in formulation, equipment, or process methods.

FAR Submissions and Site Quality

FDA explored data about FAR submission rates to better understand the factors that correlate with FAR submissions and how those factors reflect site quality. Sites that filed FARs tended to be domestic sterile facilities with multiple approved applications. Inversely foreign, non-sterile sites with fewer applications tended to file fewer FARs. While sites are required to submit an initial FAR after receiving information concerning significant quality problems with distributed drug products, there is no similar requirement to submit a follow-up or final FAR. Nevertheless, doing so is recommended.

The Quality of Hand Sanitizer Products

FDA’s continued close monitoring of hand sanitizers in FY2021 identified products containing methanol and other toxic substances. These products were identified in FDA’s list of hand sanitizers consumers should not use. Thirty FDA’s hand sanitizer web pages have received more than 20 million page views and have been among FDA’s most visited web pages.

Control of Organic Impurities in OTC Monograph Products

OPQ recently used the FD&C Act 704(a)(4) authority to obtain data on the state of organic impurity control for non-application OTC products. Requests were sent to 13 manufacturers of 15 commonly used nonprescription oral drug products. The results found a wide range of organic impurity control, ranging from adequate (i.e., impurities have been specified for finished product release and on stability) to inadequate or no organic impurity criteria.

Note from AAHP:  The impurity profile of a drug or any of its ingredients can vary over time or from supplier to supplier. Impurity specifications at product release and during stability are a GMP requirement. Consider impurities for all ingredients in your drug product, active ingredients, or otherwise.

Sampling and Testing

To help assure the high quality of drugs available in the U.S., CDER samples and tests drug products each year as part of surveillance and focused sampling assignments (e.g., hand sanitizer, nitrosamines, opioids, and heparin). Sampling and testing gained additional importance during the COVID-19 public health emergency. With many inspections postponed, FDA sampled and tested products to surveil the industry and aid in identifying non-compliant products.

Note from AAHP: In recent years, warning letters have been issued to homeopathic manufacturers after sampling and testing by FDA. You may not know your products have been sampled or tested and then are surprised during an inspection or upon receipt of a warning letter. The best way to avoid a negative outcome after FDA sampling and testing is to improve the robustness of your specifications, sampling, and testing plans. Poor outcomes from your own testing should encourage improvements in ingredient specifications and process controls.

Commitment to Quality

FDA has made programmatic advances for two initiatives, NIPP and QMM, that are building better tools for characterizing the quality of drug manufacturing sites.

NIPP is modernizing FDA’s inspections program by improving how data from surveillance and pre-approval inspections are recorded, assessed, and reported. Collecting structured data on inspections enables more efficient and robust analytics that drive objective and data-driven decisions.

QMM (Quality Management Maturity) is, as described in OPQ’s recent QMM White Paper, the state attained by having consistent, reliable, and robust business processes to achieve quality objectives and promote continual improvement.

During FY2021–FY2022, FDA executed two pilot programs to develop the criteria used to objectively measure a manufacturing site’s QMM. The pilot programs assessed site maturity levels as evidenced by proactive management of product availability risks, effective application of quality risk management across business units, investments into digitalization, and advanced analytics. The pilot programs also provided evidence for operationalizing an assessment framework that can accurately and objectively discern between maturity levels within and across practice areas.

Note from AAHP: If you haven’t done so yet, take the time to read FDA’s QMM White Paper and benchmark your own quality system against standards established by FDA.