Fiscal Year (FY) 2019 was a fascinating year for drug GMP warning letters in the diversity of topics addressed, depth of focus, and trends in enforcement actions. This article is Part 2 of a comprehensive summary of the drug GMP warning letters issued in FY2019, including an evaluation of trends since FY2013. The data presented for FY2019, ending September 31, 2019, is based on drug GMP warning letters posted by the FDA no later than January 20, 2020.

In Part 1, we discussed discussing warning letter trends between FY2013 and FY2019, including an in-depth look at manufacturers by country and data integrity citation trends.

In Part 2, we take a deeper dive into drug product manufacturers that were the recipients of warning letters in FY2019. Drug product manufacturers are a diverse group including firms that manufacture OTC/homeopathic drugs, manufacturers of human cell and tissue products, and prescription dosage form manufacturers of biotech or chemically synthesized sterile products and non-sterile products. 

The narrative and figures address two broad areas, including trends between FY2013 and FY2019 in:  

  1. Particular targets of warning letters, including over-the-counter (OTC) and homeopathic drug products, API manufacturers, and Human Cell Therapy Product (HCT/P) manufacturers.
  2. Notable topics, including but not limited to nitrosamine contamination of Angiotensin II Receptor Blockers (ARBs), API re-packagers, and the first warning letter citing failure to comply with requirements in the Drug Supply Chain Security Act amendments to the FD&C Act.

And finally, we provide conclusions to the data included in Parts 1 and 2.

[NOTE: No need to keep referencing the Govzilla blog—download the full 11-page report for yourself now!]

Analysis of FDA FY2019 Drug GMP Warning Letters

OTC/Homeopathic Drug Products

Figure 1 shows that OTC/homeopathic drug product manufacturers received more than half of the drug product warning letters in FY2019.  This continues a trend that started a few years ago

Figure 2 shows that over half of these firms that received warning letters in FY2019 were in the US, with China and India a distant second and third.  Twenty of the warning letters issued to OTC/homeopathic firms also included a data integrity component. 

Figure 3 shows trends for the issuance of warning letters to these firms over calendar years. Between CY2010 and CY2013, the number of warning letters issued to these firms ranged between 1 and 6. The dramatic increase began in CY2017 and continues through this year. Many of the violations noted in these warning letters identify fundamental failures to understand and comply with GMPs including, but certainly not limited to:

  • Failure to test incoming raw materials and components, including APIs, for identity. Rather, materials and components are accepted on the basis of the supplier’s CoA although the supplier has not been qualified, and the results on the CoA have not been validated and periodically confirmed.
  • Drug products released for distribution without adequate testing including identity and strength of the active ingredient and adequate microbiological evaluation.
  • Manufacturing processes are not validated, and the firm does not have a process for ongoing monitoring to ensure the process remains in a state of control.
  • Absence of basic SOPs for GMP activities including, but not limited to the responsibilities of the Quality Unit, change control, OOS investigations, deviation management, and complaint management, just to name a few.
  • Batch records did not have adequate detail of all the critical manufacturing operations.
  • Inadequacy in water (likely purified water USP) generation and distribution systems, maintenance, sampling, and control.
  • And frequently, all of these shortcomings are combined into a statement that the Quality Unit does not have the appropriate power and authority they should have to ensure that drugs have the quality, purity, potency, and safety that they are purported to have.

The type of deficiencies at these firms clearly skews any metrics that may be done on inspection observations and warning letter deficiencies. This is an important class of manufacturers if only because of the number of individuals their products touch. We likely all have medicine cabinets with at least a few of these products that we use frequently.  We probably have not seen the end of the FDA’s laser-like focus on this product category and I look for more in FY2020.

Human Cell Therapy Drug Products

We previously covered the FY2018 and 2019 inspection observations for the human tissue and cell therapy products.  This is a diverse product category and includes sites such as fertility clinics, stem cell clinics, and gene and cell therapy manufacturers.  This group received 10 warning letters in FY2019.  Four of them were sent to fertility clinics and six were issued to firms selling:

Genetech who received their warning letter on November 19, 2018, distributed their products to Liveyon LLC. 

Liveyon Labs Inc in Yorba Linda, CA received a warning letter early in FY2020, on December 5, 2019. Liveyon Labs initiated a Class II recall of 91 lots of HPVC Cord Blood products on September 28, 2018, and terminated the recall on November 5, 2019. The FDA gives the reason for the recalls as “Human tissue allografts, where in-process controls were not followed allowing tissue to be processed in a manner that could cause contamination or cross-contamination during processing, as well as the introduction, transmission or spread of communicable disease through the use of the tissue, were distributed.”  

Stem cell therapies have been problematic with many firms operating outside the FDA’s framework for regenerative medicines. On June 4, 2019, the courts held that US Stem Cell Inc (FL) and their Chief Scientific Officer “…adulterated and misbranded a stem cell drug product made from a patient’s adipose tissue.” The firm received a warning letter in 2017 for marketing a stem cell product without FDA approval and for significant non-compliance with GMPs. 

This is clearly a problematic area for FDA. I expect letters to human cell and tissue firms to increase in FY2020 and beyond as both gene and cell therapy firms expand in number and enforcement discretion is slated to end for the hundreds of rogue stem cell clinics. 

On the gene therapy side, the Pink Sheet (26 January 2020) recently identified six product candidates currently under review at FDA with five designated as breakthrough therapies. A recent court case in California, however, calls into question the FDA’s approach to the regulation of autologous cell therapy. More to come here, for sure.

Prescription Drug Products other than HCTPs, Parenteral and Non-Sterile Dosage Forms

The remaining warning letters issued to drug product manufacturers include parenteral products and non-sterile drug products including solid oral dosage forms and creams/ointments. FDA continues their focus on parenteral products, particularly those made using aseptic processing, as being in the category of highest risk products.  

Interval Between Inspection and Warning Letters

Figure 4 and Figure 5 present the time interval between the FDA inspection and the issuance of warning letters. These data are rounded to the nearest half month. It has been a stated goal of the FDA to substantially decrease this interval to a target of 6 months. 

The interval for issuance of warning letters for compounding pharmacies continues to be problematic and increased this year to 15.5 months. The interval for warning letters issued to sites in the US has continued to decrease from a high of 10.9 months in FY2016 to 7.2 months in FY2019. For firms outside the US, the interval also decreased from a high of 10.4 months in FY2015 to 6.6 months in FY2019. Taking all warning letters together, the time interval has decreased from a high of 11.9 months in FY2016 to 8.2 months in FY2019, the same interval as in FY2018.

Among the warning letters issued to sites OUS, 26 import alerts were issued in the category of:

  • Failure to follow drug GMPs
  • Distribution of unapproved new drugs
  • Refusal of inspection  

Thus, sixty percent of the firms who received a warning letter were placed under one of these import alerts.

Other Notable Topics in Warning Letters in FY2019

Request for Independent Assessment
FDA generally identifies the information firms must provide in response to warning letters. This year it struck me the frequency with which FDA requests an “independent assessment” of the topics in question. FDA has clearly decided that many firms are not capable of performing an effective assessment and identifying appropriate, effective remediation activities.

Hire Qualified Consultants
In 76 warning letters, FDA either suggests the firm
hire qualified consultants or acknowledges they have done so, sometimes both. Seventy-nine percent of warning letters issued OUS and 62 percent of the warning letters issued for firms located in the US included this recommendation.

Nitrosamine Contaminants
The identification of the various
nitrosamine contaminants in Angiotensin II Receptor Blocker (ARB) API and drug products resulted in a collection of warning letters issued to the following firms, for example: 

These sites manufacture either a “sartan” API and/or drug product. All sites to which these warning letters were issued are in China or India. Although the warning letter issued to Mylan Laboratories Limited was sent to the CEO in the US, the site in question is in India. Among this collection, the one issued to Lantech Pharmaceuticals Limited identified the problematic issue of recovered solvents and the lack of control of these solutions which is now considered to be one source of nitrosamine contaminants. 

In addition to warning letters, dozens of products have been the subject of Class II recalls. The FDA has published methods for identification and quantitation of specific nitrosamine contaminants, along with interim acceptable daily limits. The EMA also addressed this topic and published Information on nitrosamines for marketing authorization holders on September 19, 2019. On October 9, 2019, the EMA published a “Questions and answers on “Information on nitrosamines for marketing authorization holders.” WHO also published information on nitrosamine impurities.  

Failure to Comply with DSCSA
In FY2019, FDA issued the first
warning letter that cites failure to comply with requirements of the November 2013 PLAW-113publ54 (DSCSA) amendments to the FD&C Act. This warning letter was issued to McKesson Corporation in San Francisco, CA, on February 7, 2019, based on observations from a form 483 issued at the close of the inspection on July 3, 2018. First of a kind enforcement actions are always of interest in terms of what they tell us about the FDA’s potential future enforcement in this area.  Also, the text in the enforcement action provides insight into what the FDA found to be the specific objectionable activity or process so others who operate in this area may evaluate their procedures and processes.

The warning letter, dated February 7, 2019, identifies an inspection of the corporate headquarters in San Francisco, CA. The warning letter identifies three deficiencies where McKesson Corp failed to comply with the requirements of section 582(c)(4), identification of suspect product and notification. The warning letter describes three examples supporting their conclusions and three examples of inadequate corrective actions. Effective January 1, 2015, trading partners are required to quarantine and investigate suspect products to determine whether it is illegitimate and to notify FDA and trading partners if the illegitimate product is found. FDA published guidance on the topic, Identification of Suspect Product and Notification, in December 2016. This was clearly a situation where the firm had plenty of time to come into compliance.

Certificate of Analysis
Another interesting group of warning letters addresses the topic of
information that re-packagers include on the certificate of analysis (CoA) provided to customers. FDA places a high priority on ensuring a secure and accurate supply chain based in part on documentation accompanying purchased products, particularly certificates of analysis. Four warning letters were issued in FY2019 where repackagers did not identify the original manufacturer of the API, but rather transferred the information to their own letterhead and did not include any information regarding the original manufacturer. Three of the firms are located in the US, the fourth is located in India. The three firms that received the four warning letters including this deficiency include:  

Failures at Multiple Sites
Spectrum Laboratories received two warning letters based on their practices at two sites. They attempted to convince FDA that their practices were satisfactory, though that seems to have been woefully unsuccessful
.  The June 4, 2019 warning letter to Spectrum notes that because six of the repackaged APIs list only Spectrum’s name on the label, this falsely represents that Spectrum is the manufacturer. Thus, the FDA deems these APIs to be misbranded because the labels are false and misleading. FDA also notes that both of the sites had similar deficiencies and thus “…failures at multiple sites demonstrate that management oversight and control over the manufacture of drugs are inadequate.” Although the second Spectrum site received a warning letter for this same shortcoming, FDA did not note the issue of misbranding.

Conclusions

FY2019 was a fascinating year for drug GMP warning letters both in the diversity of topics addressed, depth of focus, and trends in enforcement actions. The most significant news is that the number of warning letters issued to sites in the US increased significantly. For the first year since I started monitoring this in FY2013, warning letters issued to firms in the US constituted a majority of the drug GMP warning letters, far outpacing India and China combined. 

Warning letters issued in FY2019 were issued to a diverse group of firms both inside and outside the US. The number issued to OTC firms and HCT/P firms both increased. We saw a decrease, however, in the number of warning letters issued to compounding pharmacies/outsourcing facilities that began in FY2017. Similarly, we saw a decrease in the number of warning letters that identify data integrity shortcomings, again for the third year.  

FDA issued a cluster of warning letters to firms associated with Angiotensin II Receptor Blocker (ARB) APIs and drug products, including mention of the use of recovered solvents in at least two of them. Another group that received warning letters were re-packagers who neglected to identify the original manufacturer of the product on CoAs. Along with these two groups, this year saw a focus on the API and drug product manufacturers for Angiotensin II Receptor Blockers (ARB). Enforcement for this group of products also included recalls of hundreds of lots of products. This year we also saw many warning letters where FDA requested “independent assessments” from firms who received warning letters and recommended that many firms hire qualified GMP consultant(s) to assist them in coming into GMP compliance. 

Now, for FY2020 predictions. I see a continuing focus on OTC manufacturers; there are many of them and they seem to fail to understand the fundamentals of GMPs. The enforcement discretion with stem cell clinics is supposed to cease at the end of the year, but a court case in California could have a significant impact for the FDA’s jurisdiction in the area of autologous stem cell clinics. At least six gene therapy products are currently under review at FDA so we will see those PAIs along with the start of routine inspections of the gene therapy firms that now have approved products. Sterile drug products, particularly those produced using aseptic processing, will remain a priority. FY2020 could well be as interesting as FY2019!

[NOTE: No need to keep referencing the Govzilla blog—download the full 11-page report for yourself now!]

Analysis of FDA FY2019 Drug GMP Warning Letters

ACKNOWLEDGMENTS: 
I want to acknowledge the kind assistance provided by Eileen Counihan and Zachary Unger in helping me learn and negotiate the pivot tables that made this article possible.  

A version of this article first appeared on BioProcess Online. 

Download the Special Report

Quality Week report sidebar

What You Will Learn from This Report:

How a major pharmaceutical company designed a program to train future leaders in quality

An industry-led initiative to advance the state of quality in the pharma industry

A pharma GMP leader’s tips for supporting quality culture within an organization

An update on FDA’s Quality Maturity Model

Redica Systems Enforcement Analytics

Compare two companies of your choice.

Enter your email address and someone will contact you shortly to customize your report.

Redica Systems Enforcement Analytics

Evaluate Your CDMOs

Enter your email address and someone will contact you shortly to customize your report.

Redica Systems Enforcement Analytics

Compare the inspection history of your CDMO sites.

Enter your email address and someone will contact you shortly to customize your report.

Redica Systems Enforcement Analytics

Compare the enforcement history of your CDMOs.

Enter your email address and someone will contact you shortly to customize your report.

Redica Systems Enforcement Analytics

Monitor compliance at your Clinical Investigator sites.

Enter your email address and someone will contact you shortly to get you started.

Redica Systems Enforcement Analytics

Prepare for inspections of Clinical Investigator sites.

Enter your email address and someone will contact you shortly to provide more Clinical Investigator data about your sites.

Redica Systems Enforcement Analytics

Prepare for your next inspection.

Enter your email address and someone will contact you shortly to explore enforcement trends. 

Redica Systems Enforcement Analytics

Prepare for your next inspection.

Enter your email address and someone will contact you shortly to explore observations and trends. 

Redica Systems Enforcement Analytics

Prepare for your next inspection.

Enter your email address and someone will contact you shortly to run your custom report.

Redica Systems Enforcement Analytics

Get help choosing the right CRO.

Enter your email address and someone will contact you shortly to customize your insights.

Download the Special Report

Download your copy of THE FDA INSPECTION LANDSCAPE IN MID-2020 AND A LOOK AT VIRTUAL INSPECTION

In this summary we identify:

  • Trend analysis of FDA inspections through mid-2020
  • Strategies for preparing and hosting virtual inspections
  • New technologies to support remote inspections
Redica Systems Enforcement Analytics

Upgrade your inspection strategy.

Enter your email address and someone will contact you shortly to get the reports and analysis you need to prepare for your next inspection.

Download the Special Report

CDMO Comparison opt-in

In this summary we identify:

FY2018-FY2020 GMP data for Lonza & Catalent

Top GMP primary citations

Top FDA 483 observations

Panel Discussion – Remote Audits

Panel Discussion opt in image

Featuring Panelists:
—Barbara W. Unger, Unger Consulting, Inc.
—Jerry Chapman, Redica Systems
—Stephanie Gaulding, Pharmatech Associates

Who Will Benefit?
This session will be valuable to GMP quality, regulatory, compliance, and management personnel in FDA-regulated industries who want to have a conversation on remote audits and get to know what is going on in the industry.

Turning Failure into Success

Presented on Tuesday, April 27, 2021 by Steve Greer, Executive Coach, Genesis Assist, and former Quality Leader, Procter and Gamble

What you will learn:

  • How to use the Leadership SOS Model to transform quality culture
  • How to strengthen quality systems to eliminate human error
  • How to generate ideas on how to set your organization up for success for shareholders, FDA, and staff
Redica Systems Enforcement Analytics

Get Full Access to Redica Enforcement Analytics

Enter your email address and someone will contact you shortly to answer all of your questions and get you started.

Quality Management Systems for Small Pharma and Biotech Firms

Webinar: QMS for Small Pharma and Biotech Firms

Presented by Fenton Fong, Founder, Managing Director, & Principal at xCellarate

Get instant access to the webinar video and slides.

What you will learn:

  • Common challenges small pharma firms face when developing a QMS
    Recent enforcement trends involving the Quality Unit
    Impact of the COVID-19 pandemic

Download the Special Report

APAC ad

In this summary we identify:

GMP data from FY2017 to FY2020 for the Asia-Pacific region

Top 3 GMP primary and secondary citations

Top 3 483 observations

Download the Special Report

An Analysis Of MHRA’s Latest Annual GMP Inspection Deficiencies Report

In this summary we identify:

  • Data from 2019 UK MHRA Inspections
  • Trends from 2015, 2016, 2018, and 2019 inspections
  • Conclusions drawn from an analysis of drug inspection data

Experience the Power of Redica Systems

Redica_Vert_Periwinkle_RGB_Large

SEARCH Find the inspection records you want by inspector’s name, company name, site, city, country, etc.

WARNING LETTERS Easily search the largest database of FDA Warning Letters by date, company, FDA office, or subject

SITES Quickly assess inspection records including dates and inspectors across all of your sites

INSPECTIONS Complete list of FDA inspections by date, company, category, and country

Get Complete Access to the Redica Systems Platform

Please submit your email address and one of our team members will contact you shortly to answer all of your questions and get you started with the new Enforcement Analytics platform.

Experience the Power of Redica Systems

Complete the form and one of our experts will reach out to you to schedule a demo and answer questions about our subscription options.

INDEX INFORMATION  Redica consolidates regulatory data in real-time on the single largest database for quality, safety, and compliance intelligence.

STRENGTHEN DATASETS Redica machine intelligence algorithms identify and triage risk signals to derive meaning from vast amounts of private and public data.

ANALYZE & INTERPRET PATTERNS Redica instantly models the customer-specific regulatory risks, trends, and opportunities that stand to fundamentally change compliance operations.

Redica Systems Enforcement Analytics

Upgrade your inspection strategy.

Enter your email address and someone will contact you shortly to get the reports and analysis you need.

Impact of the Global Pandemic on Recent Data Integrity and Regulatory Non-compliance Trends

Webinar: Impact of the Global Pandemic on Recent Data Integrity and Regulatory Non-compliance Trends

Presented by Paul Smith, Agilent Technologies on Aug. 26, 2020

What you will learn:

  • Examples of essential laboratory actions to remain compliant during the pandemic
  • Recent data integrity non-compliance findings and trends
  • Essential strategies to find, understand, and leverage regulatory non-compliance data

Get the scoop on recent data integrity 483 observations!

  • FY 2020 Data Integrity 483 Observations
  • Data Integrity Observations for Human Drugs
  • Observations Falling Under GMP
  •  

Past, Present, and Future of Quality Culture

Presented by Regulatory Compliance Associates Distinguished Fellow Susan Schniepp

What you will learn:

  • How the 2014 FDA quality metrics initiative led to greater focus on quality culture
  • New quality culture tools and standards under development by PDA and other organizations
  • Best practices for quality culture, including case studies with lessons learned

Changing Medical Device Regulations

Presented by Redica Systems 

What you will learn:

  • The latest developments regarding the EU MDR
  • Quality Systems requirements for medical devices
  • Regulatory updates affecting medical devices

Download the Special Report

Combination Product Report

What You Will Learn from This Report:

The latest U.S. and European regulatory developments

The impact of smart combination products

How the EU MDR impacts drug-device combination products

Download the Special Report

5 GMP Case Studies Report

What You Will Learn from This Report:

In-depth analysis of the findings

Lessons learned

How companies can avoid similar shortcomings.

Experience the Power of Redica Systems

Redica Systems Expert Jerry Chapman to Present at SQA Annual Meeting

Index Information Redica consolidates regulatory data in real-time on the single largest database for quality, safety, and compliance intelligence.

Strengthen Datasets Redica machine intelligence algorithms identify and triage risk signals to derive meaning from vast amounts of private and public data.

Analyze & Interpret Patterns Redica instantly models the customer-specific regulatory risks, trends, and opportunities that stand to fundamentally change compliance operations.

Download the 510(k) Sample

What You Will Learn from This Sample:

See how a 510(k) submission is structured

Find out what information to include

Review correspondence between sponsor and FDA

Redica Systems Enforcement Analytics

Unlimited Access to Reports and Data

Enter your email address and someone will contact you shortly.

Download the Special Report

5 GMP Case Studies Report

What You Will Learn from This Report:

The first countrywide import alert issued by FDA

An inadequate deviation investigation

An inadequate product specifications and a product recall

Process validation issues at a CMO

A different perspective on process validation and the culpability of the quality unit

 

A.I. for Quality and Compliance Teams

August 3 webinar

Presented by Redica Systems Senior GMP Quality Expert Jerry Chapman

What you will learn:

  • A basic understanding of data sources, machine learning, NLP, and A.I. tools
  • Building and applying Expert Models
  • Two case studies, one on sterile manufacturing/503B and one on data integrity

Human Factors – Compliance and Applications

June webinar

Presented by Alison Sathe, Founder, Regulatory Mark & Valerie Fenster, Director of Insights and  Human Factors, Kaleidoscope Innovation 

What you will learn:

  • Human factors strategies from simple drug products to complex surgical devices
  • Primary and secondary labeling development and evaluation for usability
  • Human factors activities from product development to post-market
  • International strategies: expectations for human factors in regulatory submissions in international markets

Experience the Power of Redica Systems

Redica Systems Enforcement Analytics

Sign up for your FREE account today and get instant access to Enforcement Analytics.

Experience the Power of Redica Systems

Redica Systems Enforcement Analytics

Let us know who you are and we’ll be in touch to answer all of your questions and get you started.

Redica Systems Enforcement Analytics

Keep up with the latest Regulatory Developments on Clinical Trials

Enter your email address and someone will contact you shortly. 

Redica Systems Enforcement Analytics

Save your team valuable time when using External Monitoring.

Enter your email address and someone will contact you shortly. 

Redica Systems Enforcement Analytics

Save time and Resources when using External Monitoring.

Enter your email address and someone will contact you shortly. 

Redica Systems Enforcement Analytics

Get immediate access to the news that matters to your sites.

Enter your email address and someone will contact you shortly. 

Redica Systems Enforcement Analytics

See how we can help you eliminate yet another spreadsheet.

Enter your email address and someone will contact you shortly. 

Redica Systems Enforcement Analytics

Stay ahead of changing regulations.

Enter your email address and someone will contact you shortly to get the data and analysis you need.

Redica Systems Enforcement Analytics

Upgrade your CDMO monitoring strategy.

Enter your email address and someone will contact you shortly to get the data and analysis you need.

Redica Systems Enforcement Analytics

Upgrade your CDMO management strategy.

Enter your email address and someone will contact you shortly to get the reports and analysis you need.

Discover the power of the most comprehensive database of 483s in existence.

Our database of over 20,000 483s is retyped and tagged, making it easy to create an Observation Report in seconds.

Eliminate days of work and get your FREE personalized 483 Observation Report.