October 12, 2016

Regulatory Limits – What Is the Role of the FDA in International Trade?

Contamination Control News

Black Spiders

Quick question: When are ‘highly purified phospholipids’ not highly purified phospholipids?

Short answer: Perhaps when they are manufactured by Nippon Fine Chemical of Hyogo, Japan.

There is much talk within the regulated industries of the critical importance of contamination control, purity, and sterility for pharmaceutical or food-related substances. Anything that eventually becomes part of our bodies – be it a 3D-printed pizza, pain management compounds, or the nanoparticles recently found in baby formula – must be subject to stringent regulation and control. This much is a given. But where does the oversight for such regulation come from? As we noted in our earlier article, the responsibility for managing the safety of these types of products comes from two different directions: self-regulation by manufacturers, per the guidelines outlined in the Federal Food, Drug, and Cosmetic Act (FD&C Act); and external pressure applied by the Federal Drug Administration (FDA). Outside of the industry, it is common to hear critique of the FDA – that the agency’s reach is too broad, that its guidelines are too stringent, and that the costs of compliance are too high. But as we have asked repeatedly (and rhetorically), what price do we set upon the value of public health and safety?

“…what price do we set upon the value of public health and safety?”

So when we learned this week of an FDA warning letter issued to a drug manufacturing facility in Japan we decided to broaden our focus and investigate what the agency is doing in terms of regulating international manufacturers. And what we found was troubling indeed.

In December 2015, inspectors from the FDA arrived in the Japanese Prefecture of Hyogo, an idyllic locale that boasts two outstanding coastlines and designates a full twenty percent of its landmass as National Parks. The population of Hyogo is mainly clustered in the Osaka-Kobe-Kyoto metropolitan area on the southern coast of the prefecture and, aside from the port activities in Kobe, Hyogo is economically reliant on a variety of heavy industries and medical research.

Standing at the gates of the Nippon Fine Chemical Co., Ltd in Takasago City, the U.S. FDA inspectors had little reason to assume their visit would be met with anything but professional courtesy and compliance. Unfortunately, this was not to be the case and in follow-up communications, the agency outlined the extraordinary ways in which the company failed inspection. Nippon Fine Chemical Co., Ltd has a long corporate history that stretches back to its 1918 founding as Nippon Camphor Co. Ltd. and had, during recent years, gained a handful of standardization and quality assurance certifications. Manufacturing, amongst other products, phospholipids for use in liposomal drugs and lung surfactants, this ISO-certified organization took it upon itself to impede and ultimately prevent FDA inspectors from completing their verification tasks. In a bizarre move, agents were physically barred from gaining access to the quality control laboratory as the manager instructed his employees to stand shoulder to shoulder to form a human shield around the equipment used to analyze drugs bound for the U.S. market. What could they possibly be trying to hide? The FDA moved in closer…

According to complaints already received from Japanese consumers the drugs had been found to contain ‘glass, hair, cardboard, metal, product discoloration, and a black spider.

Falling back to Plan B, the inspectors attempted to document conditions in the laboratory by taking evidential photos of the manufacturing apparatus. This should have been a relatively straightforward process were it not for the continued blocking efforts of the on-site QA manager who prevented the images from being captured. Frustrated by this childish non-compliance, the inspectors then turned to the question of documentation, requesting copies of prior complaint records. The equipment used by Nippon Fine Chemical Co. Ltd. created products for both Japanese and American customers, with the lots divided between the two market sectors. According to complaints already received from Japanese consumers the drugs had been found to contain ‘glass, hair, cardboard, metal, product discoloration, and a black spider.’(1) When asked for copies of these documents, the company again refused to comply, sending the inspectors away empty-handed.

“When asked for copies of these documents, the company again refused to comply, sending the inspectors away empty-handed.”

As a result of this outlandish behavior, Nippon Fine Chemical Co. Ltd. has been placed on an Import Alert 99-32, also known as ‘Detention Without Physical Examination of Products From Firms Refusing FDA Foreign Establishment Inspection.’(2) This adds the company to a so-called ‘Red List’ of foreign national firms that refuse to allow an inspection of their facilities where products are being manufactured for sale to the U.S. market. Also on this list is the Chinese manufacturer Xinxiang Tuoxin Biochemical Technology & Science Co. Ltd. which produces ‘chemical (sic) synthesized Nucleosides products (sic), including antivirus, nucleotide and nucleosides acid biochemical products.’ (3) Xinxiang Tuoxin Biochemical is now subject to a slightly different restriction – an Import Alert 66-40 – having failed an FDA inspection in September 2015. The Import Alert 66-40 now bars the company from exporting its products due to a failure to comply with Good Manufacturing Practices (GMPs). According to a warning letter issued on August 19 2015, FDA inspectors found ‘non-dedicated drug manufacturing equipment not properly maintained. Product contact surfaces and reactors contained product buildup and chipped paint.’(4)

Swarm of flies

But there was more.

In investigating the buildings where the active pharmaceutical ingredients (unlisted by the FDA) were produced, agents reported evidence of ‘[g]aps around windows and doors and holes in the ceilings [… and] flying insects in cleanrooms and on product transfer.’(5) That’s worth repeating: flying insects in cleanrooms. As a result of this investigation, the premises in Henan, China, were designated as ‘unsalvageable’ and the agency made a strong recommendation that Xinxiang Tuoxin Biochemical consult a third-party to evaluate their organization and help get back on track. Whether that will happen remains to be seen but, as it stands right now, the company is not permitted to export any drug and drug products for either human or veterinary use to the U.S.

So what are the lessons to learn from these two utterly flagrant violations of cleanroom protocols? Perhaps the obvious one is that contamination control is not a subject that can be taken lightly. When the importance of sterility and cleanliness is downgraded, corners are cut and abuse will occur. And as we have seen from our own domestic incidents of protocol evasion within the pharmaceutical cleanroom, the consequences for human and animal patients can be deadly.

And a second, perhaps the less obvious, conclusion is that we should reconsider our stance towards the role of the FDA. As a regulatory organization, the agency has a reputation as being a stickler and is seen by some as an obstacle to trade. But perhaps we should reframe our critique and, the next time we read a complaint about the FDA over-reaching its mandate, bear in mind the following. A full 43 companies from 7 different countries are currently red listed under Import Alert 99-32 (refusing inspection) and a further 152 others, in 30 countries, find themselves barred for non-compliance with Good Manufacturing Practices (Import Alert 66-40). Those numbers represent a huge number of potentially tainted products that could have been ‘manufactured, processed, or packed under insanitary conditions’ – but thanks to the stringency of the FDA, none of them have found their way to the U.S. consumer.(6)

“…but thanks to the stringency of the FDA, none of them have found their way to the U.S. consumer.”

Do you have thoughts about the FDA’s involvement with foreign national drug manufacturers? If so we’d love to hear them – please leave a comment below!


  5. Ibid


Share This!


  1. Wartrol Reviews

    Hi i’m new here. I found this site and I find it really helpful.

  2. Henrietta

    Great blog!

Submit a Comment


Cleanrooms, FDA

Show Buttons
Hide Buttons