A recent report published by the ECA Academy looks back over the last fiscal year (October 2018 to September 2019) to review the FDA warning letter trends among pharmaceutical manufacturers.
Here, we’ve summarized this report’s findings, as well those detailed in another comprehensive research report published to Pharmaceutical Online, which examined drug inspection observational trends by analyzing publicly available data from fda.gov.
Where applicable, we’ve provided links to relevant resources and next steps for those looking for guidance and assistance in mitigating trending risks in the new year and beyond.
1. Fiscal year 2019 saw the most warning letters issued to makers of finished medicinal products in recent history.
The last 12 months saw a total of 81 warning letters issued to finished product manufacturers worldwide, the most since the fiscal year 2015.
As ECA points out, this is in contrast to the number of warning letters sent to API manufacturers, which has fallen since peaking in 2017.
2. The majority of pharmaceutical warning letters were issued to US companies.
Over half (46 to be exact) of the 81 warning letters were issued to companies located in the United States. A detailed list of each region is below:
- United States: 46
- India: 12
- China: 10
- South Korea: 5
- Singapore: 2
- Costa Rica: 1
- France: 1
- Canada: 1
- Spain: 1
- Taiwan: 1
- Turkey: 1
3. The most frequently-cited GMP violations in warning letters concern basic requirements.
The specific issues contained within these recent warning letters reveals a continuation of a trend that’s been running for years: lapses in meeting basic GMP requirements.
The responsibilities of the quality control unit laid out in 21 CFR 211.22 was the top most-cited issue, followed by written procedures; deviations laid out in 21 CFR 211.100.
Here’s a more detailed breakdown of the top six pharmaceutical citations in the fiscal year 2019:
- 21 CFR 211.22 - 41 Warning Letters - Responsibilities of the quality control unit
- 21 CFR 211.100 - 31 Warning Letters - Written procedures; deviations
- 21 CFR 211.165 - 29 Warning Letters - Testing and release for distribution
- 21 CFR 211.192 - 27 Warning Letters - Production record review
- 21 CFR 211.166 - 22 Warning Letters - Stability Testing
- 21 CFR 211.84 - 22 Warning Letters - Testing and approval or rejection of components, drug product containers, and closures
4. The number of inspection observations for drugmakers has increased.
As analyzed and compiled by Barbara Unger in an impressively researched column for Pharmaceutical Online, the frequency of Forms 483 issued to pharmaceutical companies has continued its steady rise over the past few years.
In the fiscal year 2019, there were a total of 779 Forms 483 issued for drug inspections compared to 716 in 2018, 694 in 2017, and 691 in 2016.
Source: FDA FY2019 Drug Inspection Observations And Trends, Barbara Unger, Pharmaceutical Online
Note that for this and the following sections covering inspection observation trends, the data presented adheres to the analysis methodology and limitations described in the introduction of the column referenced.
5. Six §211 citations increased dramatically between fiscal years 2018 and 2019.
Also noted in the column, “six regulations saw a significant increase in the frequency with which they were cited between 2018 and 2019. This includes:
- §211.100(a) Production and process controls shall be supported by written procedures
- §211.188 Master production and control records
- §211.113(b) Control of microbiological contamination
- §211.25(a) Personnel qualifications
- §211.165(a) Appropriate lab tests shall be used to determine conformance to specifications
- §211.67(b) Equipment cleaning and maintenance”
6. §211.22(d) was the most frequently cited compliance deficiency throughout fiscal year 2019.
Again, given the caveat of the limited public data available (the FDA’s data includes only Forms 483 issued through its electronic system and omits API manufacturers), some notable findings emerge regarding specific §211 citations.
The most frequent deficiency pertained to §211.22(d) Procedures applicable to the quality unit shall be in writing and shall be followed, which moved from the second most frequent citation to the first from the previous year.
The following list offers the top four most frequent citations throughout the last fiscal year.
- §211.22(d) Procedures applicable to the quality unit shall be in writing and shall be followed
- §211.192 Investigations of discrepancies
- §211.42(c) Facilities shall include defined areas of sufficient size
- §211.160(b) Laboratory controls shall include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedure
The chart labeled “Table 1” in the column referenced offers a visualized breakdown of trending citations over the years. Access the full article here or open the chart (.png image file) in a separate window here.
7. OTC drugmakers were subject to greater scrutiny from regulators. Many issues point to basic GMP deficiencies.
As we explored in an article this past April, 2019 saw the FDA put a greater compliance focus on over-the-counter (OTC) drugs and other health product manufacturers. In a July 2019 column for Pharmaceutical Online, we analyzed these OTC-specific compliance trends, pulling out the following common issues appearing in warning letters.
We’ve summarized the common themes of noncompliance below, but full details can be found in our article here.
- Documented Adherence to Relevant Regulations and Standards
Many recent warning letters to OTC manufacturers highlight fundamental issues related to the understanding and practical implementation of the 21 CFR 200 series, as well as relevant USP standards that address specific types of products and the systems used to produce them.
- Establishment and Suitability of Analytical and Microbial Testing and Validation Methods
Inadequate method development (method suitability and validation in particular) is another common theme in recent warning letters issued to OTC drug manufacturers. These critical processes are complex, often involving wide specifications, broad parameters, and the inherent variation that comes from working with living organisms.
- Nonconformance Management
Another recent trend afflicting OTC drugmakers mirrors a broader and well-documented trend throughout the drug and device space: inadequate nonconformance management. As demonstrated by a large number of citations issued specifically for “inadequate, incomplete, and undocumented investigations,” these warning letters offer evidence of a long-standing perception that an outsized focus is placed on immediate nonconformance correction rather than on thoroughly investigating and executing corrective and preventive actions following a comprehensive root cause analysis.
- Roles, Responsibilities, and Authority of the Quality Unit
The internal quality unit (QU) has been the target of many recent warning letters to OTC drug and health product manufacturers as an underlying cause of product quality and GMP compliance problems. Numerous firms have been cited for having an inadequate QU. In the most egregious examples, firms lacked this designated team entirely. More often, however, regulators have cited firms for a lack of written procedures that govern the responsibilities and functions of this group. 21 CFR Part 211 is clear about the need to establish a “quality control unit” with the documented responsibility and authority to make critical decisions.
Based on a growing number of relevant warning letters, as well as analyses of enforcement trend data and public statements made by the FDA, it’s clear that a renewed focus has been placed on evaluating manufacturers of OTC drug and health products in key areas of GMP.
These areas of enforcement focus include ineffective quality units, poor testing of incoming materials and components (i.e., relying on a supplier’s certificate of analysis), poor product testing, poor analytical and microbial testing and validation methodology (including method suitability), and inadequate nonconformance management.
Takeaways, Resources, and Next Steps
Publicly available warning letter and inspection observation data provide powerful resources for understanding areas of regulatory focus and a benchmark for evaluating potential vulnerabilities within the quality system and beyond.
In general, this year's trending issues demonstrate a continued focus on investigating and citing firms for deficiencies in basic GMP requirements and an overall uptick in total citations across the pharmaceutical space. Manufacturers of OTC and other health products have come under increased scrutiny for a lack of basic GMP competencies and adherence to requirements. In some cases, the language used by regulators and the details of the issues they observe suggest a deliberate decision to forgo compliance as a cost-saving measure.
The observed lack of adequate written procedures and responsibilities for the quality unit has remained a trending issue throughout recent history and its recent uptick has resulted in numerous warning letters.
Download our relevant resources below for practical insight into mitigating many of the trending issues throughout the life sciences.
The OTC Drug Manufacturer's Guide to CGMP Compliance & Quality Management
Gap Analysis Remediation: A Guide to Resourcing & Implementation
The Complete Guide to Compliance Remediation Projects
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In many of its warning letters, the FDA has “strongly recommended” engaging a third-party consultant qualified in the relevant regulations to assist in meeting CGMP requirements.
While we help many companies resolve Forms 483 and warning letters, we also help prevent them from being issued in the first place. At The FDA Group, we plan and conduct effective internal quality audits to ensure your quality system is completely aligned with all documentation and operations — the critical part of any internal audit. More broadly, we assess your current systems and make the necessary improvements for ensuring regulatory expectations are met across all functions of your organization. Read our case studies to learn how we've helped firms meet a variety challenging life science goals.
In addition to assisting in project-based consulting capacity, we help life science organizations fill key roles on their team through contracted and direct hire engagements. Explore our service areas to learn how we can locate, secure, and manage top industry talent, and/or work in a project-based capacity to evaluate, correct, and maintain your quality system.
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