FDA GMP Warning Letters Review: Foreign Drug Product Firms Hit Hard On GMP Basics

Many of the 30 drug product firms that received FDA warning letters in 2016 were foreign cosmetics and hygiene manufacturers that appeared to need education on US GMP requirements. Another major focus in letters to drug product firms last year was sterility assurance in the US and abroad.

The US FDA last year challenged foreign cosmetics and hygiene firms to start following basic US drug GMP requirements for products that the agency regulates as drugs.

Overseas consumer products firms that appeared to have little familiarity with US good manufacturing practices requirements accounted for a surprising share of the drug product manufacturers that got FDA warning letters in 2016.

Overall, drug product manufacturers accounted for a minority of warning letter recipients again last year, particularly on the domestic front. Thirty of last year’s 110 drug GMP warning letters went to drug product manufacturers – just 27% of the total – with nearly all the rest going to compounding pharmacies and active pharmaceutical ingredient firms.

As in recent years, the focus was on foreign rather than domestic drug product manufacturers. Only eight of the 30 drug product firms that got warning letters last year are in the US. The other 22 are in China, India, Europe, Brazil and Taiwan. In 2014, just three US-based drug product firms received warning letters. In 2015, there was only one. (Also see "FY 2015 Drug GMP Warning Letters Hit Compounders and Foreign Sites" - Pink Sheet, 29 Jan, 2016.)

Most warning letters had gone to US-based pharmaceutical companies until globalization sent most API and drug product manufacturing operations abroad over the past decade and, after the New England Compounding Center incident in 2012, compounding pharmacies came to dominate FDA’s domestic drug GMP inspection agenda.

The 30 drug product warning letters tended to focus on two main issue areas – basic GMP compliance abroad and aseptic processing in the US and abroad. A third focus area, data integrity, applied primarily to API firms last year, but three drug product firms also received data integrity warning letters. Two are in India; the third is in the Czech Republic.

It’s Not Like Making Car Care Products

Another trend last year is that many of the 30 drug product warning letter recipients were only tangentially involved in drug product manufacturing.

Eighteen don’t manufacture any prescription drugs; most of these are over-the-counter firms primarily focused on non-pharmaceutical types of consumer products. Some appeared completely unprepared for the rigors of US GMP requirements, and in some cases didn’t seem to realize they were producing FDA-regulated products. Several of the foreign manufacturers FDA cited told the agency they would opt out of the US market rather than try to achieve compliance.

Seven are cosmetics firms, five provide antiseptic wipes and other hygiene products for home and health care settings, and two focus on traditional Chinese medicines. One provides hotel amenities including toothpaste, another provides liquid cosmetics, dietary supplements and OTCs in single-use sachets. Yet another is a car care cleaning products company that expanded into other cleaning and sanitizing products.

Warning letters to hygiene products companies like China-based Huzhou Aupower Sanitary Commodity Co., Ltd., and Baoying County Fukang Medical Appliance Co., Ltd. may represent continued fallout from recalls of H&P Industries’ Triad Group Inc. microbiologically contaminated alcohol wipes and surgical prep pads in 2011. (Also see "Contamination Issues Drove Drug Recalls to Record Levels in 2011" - Pink Sheet, 28 Mar, 2012.)

Quality Control Abroad

The most prominent issues at drug product manufacturing facilities outside the US revolved around quality control, particularly in emerging economies:

Ko Da

For example, a May 27 warning letter to Ko Da Pharmaceutical Co. in Taoyuan City, Taiwan, focused on inaction of the quality unit, a lack of written procedures for process controls and a lack of timely release testing.

Rather than fix the problems, Ko Da told FDA it would stop distributing product to the US.

Laboratoire Sintyle

And a Sept. 29 warning letter to Laboratoire Sintyle SA of Geneva, Switzerland, focused on the company’s lack of an independent quality unit, its failure to conduct release testing and component testing or to properly clean and maintain certain equipment, or to perform process validation, or to conduct stability testing.

Sintyle told FDA it had stopped making the over-the-counter drug that was at issue. FDA urged the firm to retain a GMP consultant if it wants resume manufacturing for the US market.

Mappel Industria de Embalagens

In another case, FDA issued a warning letter on Sept. 12 to Mappel Industria de Embalagens SA of Sao Paulo, Brazil, after reaching similar findings regarding a lack of quality control, release testing, process control and batch record retention.

Mappel responded that “it did not fully comprehend” that certain products it was manufacturing “were regulated by the FDA as OTC drugs,” and that it would file a new drug establishment registration if it should ever decide to manufacture for the US market.

Yangzhou Hengyuan

Yangzhou Hengyuan Daily Chemical Plastic Co., Ltd., Yangzhou, China, which specializes in making tourist products like travel toothpaste and hotel shampoo, received a warning letter on Sept. 26 after FDA denied entry of a shipment that lacked any of the labeled API. The firm subsequently discovered it has added the wrong active ingredient. It turned out that Yangzhou had not been testing every batch for identity, strength and other specifications. (Also see "FDA Enforcement And Compliance In Brief" - Pink Sheet, 25 Oct, 2016.)

Intega Skin Sciences

Also worth noting is a Dec. 15 warning letter to Intega Skin Sciences Inc., Laval, Canada, which indicated the company lacked a functional quality unit. Intega failed to investigate positive microbial testing results, make sure equipment was cleaned frequently enough, or establish written procedures for complaint handling and process control. (Also see "Warning Letter Roundup: FDA Enforcement And Compliance In Brief" - Pink Sheet, 19 Jan, 2017.)

Nippon Fine Chemical

FDA cited a number of foreign API and drug product firms for refusing or limiting inspections, which under Section 707 of the July 2012 FDA Safety and Innovation Act renders all of the facility’s drug products adulterated.

But none of the others did it with the audacity of Nippon Fine Chemical Co., Ltd., of Takasago City, Japan. FDA said in a Sept. 26 warning letter that the firm’s “quality control manager directed employees to stand shoulder to shoulder, barring our investigator from accessing portions of the laboratory and the equipment used to analyze drugs for US distribution.”

Data Integrity Abroad

Data integrity has been a major theme of drug GMP warning letters in recent years, and 2016 was no exception.

However, just two of last year’s 12 data integrity-oriented warning letters went to drug product manufacturers; the rest went to API firms.

As in the past, nearly all recipients of data integrity warning letters were in India or China:

Sri Krisha

One drug product firm’s warning letter focused primarily on data integrity issues. An April 1 warning letter said that Sri Krishna Pharmaceuticals Ltd., Hyderabad, India, was conducting trial high-pressure liquid chromatography injections and storing the data separately from the reported test result data.

FDA also complained that Sri Krishna had given administrator privileges to its quality control analysts, which they used to change time and date settings, and overwrite and delete HPLC test data.

FDA’s investigator also discovered that Sri Krishna had been destroying batch records and backdating revised replacement pages.

Wockhardt

A Dec. 23 warning letter to Wockhardt Ltd. regarding its Ankleshwar, India, facility, hit all of last year’s main points of emphasis: sterility assurance and data integrity both for APIs and for drug products.

There were sterile API violations due to airflow disturbances and turbulence as well as breaches of aseptic technique in the ISO-5 area.

Plus, employees working in sterile areas were seen wearing gowns that had unraveled stitching, and therefore should have been discarded. FDA said Wockhardt was sterilizing its gowns too frequently, breaking down their fibers.

Our 2016 GMP Warning Letters Review

Related coverage already published:

• (Also see "FDA GMP Warning Letters Review: Rate Soared In 2016 On Sterility And Data Integrity Concerns" - Pink Sheet, 25 Apr, 2017.)
• (Also see "FDA GMP Warning Letters Review: API Supplier Warnings Surge On Data Integrity Concerns" - Pink Sheet, 26 Apr, 2017.)

Upcoming soon:

• FDA GMP Warning Letters Review: Compounding Pharmacies Drew Most Letters Again in 2016

And stay up to date with all our coverage on QA/QC and related issues with our manufacturing topics page.

There were also data integrity issues involving unreported gas chromatography results, including one that was out of specification for a raw material.

Workers in API areas failed to record activities contemporaneously, as required, and also incinerated GMP documentation.

Foreign Sterility Assurance

Seven of last year’s drug GMP warning letters focused on sterility assurance issues at injectables manufacturing operations.

One of these warning letters, issued Oct. 13 to Teva Pharmaceutical Works Private Ltd. Co., provided a stepwise agenda for addressing shortcomings in media fill operations like FDA investigators found when they inspected Teva’s Godollo, Hungary facility. (Also see "FDA’s Teva Warning Letter Sets Agenda For Investigating, Remedying Sterility Failures" - Pink Sheet, 26 Oct, 2016.)

In another case, FDA investigators had some problems with aseptic processing techniques they observed at Emcure Pharmaceuticals Ltd.’s plant in Hinjwadi, India, according to a March 3 warning letter.

The investigators saw one worker place a cup on the floor to collect water that operators later poured over the filling line’s piston drive. They saw operators crawling under the filling line on hands and knees, as well as one operator dropping a sterilized lid, then picking it up off the floor and placing it back on the container.

There were issues with the airflow along sterile filling lines at Antibioticos do Brasil in Sao Paulo, as well as with smoke studies that if done properly would have revealed the airflow problems, according to a Dec. 8 warning letter.

Domestic Sterility Assurance

For drug product firms in the US, the focus was mainly on sterility assurance and process control:

Horizon

FDA took a dim view in a Dec. 23 warning letter of what it termed a cursory investigation into microbial contamination of a purportedly sterile ophthalmic drug product at Horizon Pharmaceuticals Inc., a specialist in custom blow-fill-seal aseptic manufacturing located in Riviera Beach, Fla.

After sterility testing identified the spore-forming microbe Bacillus mycoides in three lots of its Saljet drug product, Horizon released all three lots based on a re-test, even though it hadn’t identified any error in the initial testing.

FDA was further troubled that the firm didn’t use sporicides in its cleaning and disinfection program and that it missed the possible connection between Bacillus mycoides found in cleanrooms during environmental monitoring in October 2014 and later in Saljet that it had manufactured at that time.

Chemolee

Chemolee Lab Corp., Irving, Texas, couldn’t find the root cause of too-numerous-to-count microbial specification failures, FDA said in a Feb. 23 warning letter, attributing the problem to insufficient cleaning of the transfer pump the first time and to “somewhere in the filling process” the second time.

Meanwhile, during the inspection that prompted the warning letter, FDA’s investigator learned that a reverse osmosis water system had been leaking for more than six months and that on occasion water sampled there also had too-numerous-to-count microbial contamination.

Chemolee replaced the gaskets of the reverse osmosis membrane housings during the inspection and the leaks stopped. But FDA wanted the firm to investigate whether the leaky gaskets were the sole cause of the contamination.

Burzynski

A June 13 warning letter cited S.R. Burzynski Manufacturing Facility, Stafford, Texas, for aseptic processing shortfalls reminiscent of those observed at many compounding pharmacies.

Inherent flaws in the design of the clinical supply manufacturing facility promoted the influx of poor quality air into the aseptic processing zone, FDA said.

The firm lacks written procedures for its “intensively manual” aseptic process and had not conducted a media fill since 2010, instead of at least twice yearly as it should have done.

There were shortfalls in cleaning and disinfection as well as environmental and personnel monitoring, and no evidence that high-efficiency particulate air filters were working properly. Workers’ clothing wasn’t appropriate for sterile processing and microbiological testing was inadequate.

Earlier warning letters had focused on the Burzynski Research Institute’s overly optimistic classification of some patients’ responses to antineoplastons in Phase II studies.

And a November 2014 complaint by the Texas Medical Board alleged that physician Stanislaw Burzynski had “created a medical practice model based on marketing his proprietary anti-cancer drugs, antineoplastons, to patients without adequate measures for patient safety and therapeutic value.”

Frontida

An Aug. 15 warning letter criticized the quality unit at Frontida BioPharm Inc. in Philadelphia for failing to carry out its basic responsibilities, an issue that arose more frequently abroad.

As a result of inspectional findings, an API supplier recalled one lot of potentially cross-contaminated clonidine API that Frontida had used in manufacturing 27 lots of clonidine hydrochloride tablets.

Frontida nevertheless released all 27 lots based on testing of clonidine API retain samples even though the contract laboratory warned that the test method was not validated to detect low-level cross-contamination and could not be used for batch release. Frontida recalled the 27 lots during the inspection that triggered the warning letter. (Also see "Enforcement Log, Dateline 08.25.16: College Pharmacy, Frontida BioPharm, Unimark, Huzhou Aupower, Cape Apothecary, Hospira" - Pink Sheet, 25 Aug, 2016.)

Noven

One of the rare brand firms to get a warning letter last year, Miami-based Noven Pharmaceuticals Inc. came under fire from FDA for failing to control the quality of its transdermal patches despite numerous customer complaints.

Complaints for the Minivelle patch had increased 50% in 2014 from the prior year, while 45% of the nearly 3,900 Daytrana patch complaints from the year before the July 2015 inspection that led to the warning letter were difficulty removing the liner.

Noven was using unsound testing methods that could be masking product failures, FDA said in an Aug. 5 warning letter.

Top CFR Cites

The top GMP provisions (published in Title 21 of the U.S. Code of Federal Regulations, Section 211) cited in warning letters to drug product firms last year reflect the predominance of firms that mainly manufacture non-pharmaceutical products.

The No. 1 citation for drug product firms is 21 CFR Section 211.34, which concerns hiring a GMP consultant. The other top five, 211.100 written procedures, 211.165 release testing, 211.160 laboratory controls, and 211.22 quality control unit responsibilities, are all about fulfilling fundamental quality control functions.

One of the top five cites for drug product firms, 211.160, also figures prominently where data integrity is an issue.

Last year’s top overall CFR cite, 211.113 control of microbiological contamination, merely ranks sixth for drug product firms. While microbiological contamination is an issue at many of these facilities, it’s not as central or widespread of an issue for them as for compounding pharmacies.

For a complete listing of warning letter CFR cites for drug product firms, see table below.

CFR Cites in Warning Letters to Drug Product Facilities
CFR	Description	Number *
34	Consultants	16
100	Written procedures; deviations	12
165	Testing and release for distribution	12
160	General requirements; laboratory controls	10
22	QC unit responsibilities	9
113	Control of microbiological contamination	9
67	Equipment cleaning and maintenance	7
84	Testing and approval or rejection of components	7
42	Design and construction features	6
166	Stability testing	6
192	Production record review	6
194	Laboratory records	5
68	Automatic, mechanical, and electronic equipment	4
137	Expiration dating	3
186	Master batch and control records	3
28	Personnel responsibilities	2
63	Equipment design, size and location	2
180	General requirements; records and reports	2
188	Batch production and control records	2
198	Complaint files	2
46	Ventilation and air filtration	1
52	Washing, toilet facilities	1
56	Sanitation	1
80	General requirements; control of components	1
101	Charge-in of components	1
103	Calculation of yield	1
* Number of warning letters that cite a specific 21 CFR 211 provision