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:

Particular targets of warning letters, including over-the-counter (OTC) and homeopathic drug products, API manufacturers, and Human Cell Therapy Product (HCT/P) manufacturers.
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!]

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:

Cord blood products (Stemell, Cord for Life, and Genetech)
Amniotic membrane patch allograft (Stratus Biosystems)
Adipose tissue harvested and modified for autologous use (StemGenex Biological Laboratories)
Advanced stem cell allografts (Human Biologics of Texas/Globus Medical)

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!