It seems like it was yesterday when all of the heparin issues starting flowing out of China like the Mississippi River in the springtime. Now granted, FDA has no legal standing in China; however, for device and pharma companies wishing to sell their products into the United States, compliance with the statutory and regulatory requirements imposed by FDA are not optional. Simply stated; “Our sandbox, our rules.”

Unfortunately, a Chinese biotech establishment failed to grant our friends from the agency full access to their facility for the purpose of pursuing an inspection. Now couple the access issue with evidence of using an approved supplier currently on FDA’s Import Alert List (FDA Import Alert 55-03) with the annotation of “Detention without Physical Examination” and bad thing are bound to happen to this offending foreign establishment. In an effort to maintain political correctness, no doubt the investigators had to employ a “sotto voce” (look-it-up) delivery to inform this establishment that there is not a chance in hades their products were going to gain entry into the United States market. In fact, FDA has clearly stated that this week’s offending established has been awarded with three Import Alerts, a failure to accept threat, and a stern warning that all of this establishment’s new applications will not be reviewed. Enjoy.

Warning Letter – 29 September 2014

Folks, before you decide to crucify Dr. D, the old doctor recognizes that the recipient of this week’s FDA warning letter prize is essentially a pharma company. However, the use of heparin, as a component in finished medical devices, is a well-known application, especially when employed in catheter technology. Additionally, the failure to allow an agency inspection always makes for good industry drama. Besides, for foreign inspections it is not like FDA just arrives at an establishment’s front door. Some serious advanced planning is required before the inspectors jump on a flight, in this case to China. If an establishment is not going to grant FDA access, please have the common courtesy to let the agency know in advance so they can save the American taxpayers some money and just proceed directly to the product detention process.

Now if this offending establishment really wants to make a lasting impression they can decide not to respond to the warning letter. Failure to respond will definitely ingratiate this establishment with FDA.

Warning letter excerpts

Excerpt One: “FDA investigators documented that your firm limited and/or refused an FDA inspection. Under the Food and Drug Administration Safety and Innovation Act (FDASIA), Section 707, your drugs are adulterated within the meaning of Section 501(j) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 351(j), in that they have been manufactured, processed, packed, or held in an establishment where the owner or operator has limited inspection and/or refused inspection.”

Excerpt Two: “You barred the investigators access to the production area and other parts of the manufacturing facility. In several instances, the investigators requested to inspect the facility, but were repeatedly denied access to the production area. Your firm also limited FDA access to certain requested records. For example, the FDA investigators requested batch production records for review, but were refused access to these records repeatedly.”

Excerpt Three: “Furthermore, during the review of a list of your suppliers, one of the few documents you did provide, we noted that you are supplied by (b)(4), which research indicates has the same physical address as, and is thus an alias of, the (b)(4), a firm that is currently on FDA Import Alert 55-03, “Detention Without Physical Examination of Different Forms of Heparin and Heparin-Related Products.”” 

Excerpt Four: “Your firm was placed on Import Alert 55-03, Import Alert 66-40, and Import Alert 99-32 on July 22, 2014.”

Excerpt Five: “Until FDA is permitted to inspect your facility and confirms compliance with CGMP, this office may recommend withholding approval of any new applications or supplements listing your firm as a drug manufacturer. In addition, shipments of articles manufactured at Beijing Shunxin Meihua Bio-technical Co., Ltd, Beijing, China into the United States are subject to refusal of admission pursuant to Section 801(a)(3) of the Act, 21 U.S.C. 381(a)(3).”

Compliance for Dummies

Regardless of an establishment being categorized as foreign or domestic, failure to grant FDA access for the purposes of a cup of coffee and an inspection is always going to be a bad thing resulting in additional enforcement activity coming from the agency. For some reason, device and pharma establishments occasionally become delusional and think that warning letters are easy to clear once the violations have been corrected. Folks regardless of your beliefs; that is just not how it works in regards to clearing a warning letter. In the case of failure to grant entry for an inspection, the offending establishment will need to find its way back onto the agency’s calendar. If it is a device that is already being serviced adequately by your competitors, it may take another two to three years before they show up for a re-inspection. By the way, if you have not figured it out yet, detention holds and refusal to accept will become the norm until the warning letter is lifted. That sound like a whole bunch of Yuan being lost due to no products being given entry into the good ole US of A. Ouch!

The best advice the doctor can give is to establish (define, document, and implement) a Quality Management System (QMS) that meets the intent of 21 CFR, Part 820 for devices or Part 201 and 211 for pharma. If you currently do not have a compliant QMS you can purchase one of Dr. D’s compliance books and get some stellar advice as to what is required. If your organization does not have a fully compliant QMS, chances are good the FDA investigator(s) will find the gaps during an inspection. However, failing to grant the FDA access is just plain crazy. Why? If you have to ask that question, just maybe you are in the wrong industry.

Takeaways

For this week’s guidance, the doctor is going to leave the readers with just one takeaway. Not granting the agency full access for the purpose of conducting an inspection is going to end badly for the offending establishment. Outside of the United States: (a) Import Alerts; (b) product detention; and (c) failure to accept for importation; are all viable outcomes for offending establishments, including the failure to accept/review new device/drug applications. In the United State, product seizures and injunctions are viable tools employed by FDA to grab the attention of offending device establishments. The staunch reality of failing to grant FDA access for an inspection is free admission to regulatory purgatory until as such time access is granted and a re-inspection performed. Please keep in mind if the offending establishment has an epiphany and decides to grant FDA full access, the agency is not going to be there tomorrow. In fact, FDA is going to take their sweet time in an effort to reinforce their message of compliance.

In closing, thank you again for joining Dr. D and I hope you find value in the guidance provided. Until the next installment of DG – cheers from Dr. D. and best wishes for continued professional success.

References: 

1. Code of Federal Regulation. (2013, April) Title 21 Part 820: Quality system regulation. Washington, D.C.: U.S. Government Printing Office.
2. Devine, C. (2011). Devine guidance for complying with the FDA’s quality system regulation – 21 CFR, Part 820. Charleston, SC: Amazon.
3. Devine, C. (2013). Devine guidance for managing key attributes of a FDA-compliant quality management system – 21 CFR, Part 820 Compliance. Charleston, SC: Amazon.
4. FDA’s enforcement page. (2014, September). FDA.gov Website. Retrieved October 20, 2014, from http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2014/ucm418141.htm.