Posted: 18 Jun 2015 07:28 PM PDT
By Jay W. Cormier, David C. Gibbons & Roger C. Thies –
Having assisted clients with FDA inspections, 483 responses, and Warning Letter responses associated with cGMP for aseptic fill operations, we can imagine the nightmares many quality and manufacturing personnel would have with the observations in a recently, publicly-issued 483:
The answer is none. All of the above statements – and much, much, oh, so much more – can be read among the 17 detailed observations in the 483 issued to none other than the otherwise-esteemed National Institutes of Health (“NIH”) in Bethesda, Maryland.
Aseptic fill is a technically complex and resource intensive endeavor. Manufacturers of sterile products spend extraordinary time and treasure building, testing, and validating their fill lines in carefully monitored and controlled environments. To keep the drugs we rely on in plentiful supply, extensive training and retraining of personnel and constant vigilance is required. Every deviation requires investigation. Due to the patient risks involved with such products, it is not surprising that FDA keeps a close eye on these operations, and, as consumers of these products, we are thankful for that.
FDA inspected the NIH Pharmaceutical Development Section and Clinical Center Pharmacy for five days between May 19 and May 29, 2015, following a complaint about the facilities. FDA sent four individuals on the inspection – one compliance officer, two consumer safety officers, and one investigator – Tom Arista from the Baltimore District Office. The investigation closed on June 2, 2015, and on June 4th, NIH issued a press release disclosing the inspection results and stated that it would voluntarily suspend sterile product manufacturing at its facilities.
The NIH has said that the facility’s sterile product operations are currently involved in as many as 46 clinical studies – a significant number by any measure. It is too early to know how many study participants received potentially contaminated product, but, given NIH’s lack of an effective monitoring process in the first instance (at least according to FDA), such information is likely unknowable. What is known is that FDA says that NIH has no assurance that any of its “sterile” products is free from contamination. The impact on dozens of taxpayer-funded clinical studies and hundreds of individual patients is unknown.
Perhaps most of all, the 483 for the NIH facility raises a number of intriguing questions. Among them are:
As mentioned above, NIH has agreed to suspend its operations until the observations can be addressed. While voluntary compliance is typically a prudent course under these circumstances, it did get us wondering – what could FDA do if NIH, a sister agency within the Department of Health and Human Services, told FDA to go “pound sand”?
At bottom, we think the answer to this question may be: not much. While FDA now has, and may in the future, use informal advisory actions to gain cGMP compliance from its sister agency, it is certainly unclear if DOJ and FDA can or will sue NIH. Indeed, there may be constitutional limitations that may bar litigation by FDA against NIH.
We begin by reviewing FDA’s authority to conduct the inspection of NIH facilities in the first instance. FDA’s inspectional authority is found in section 704 of the Federal Food, Drug, and Cosmetic Act (“FD&C Act”). FDA inspectors are authorized to inspect “any factory, warehouse, or establishment” where drugs are manufactured, packaged, or stored. FD&C Act § 704(a)(1) (emphasis added). Upon the conclusion of the inspection, the FDA inspector typically provides a written report of conditions or practices that, in the inspector’s judgment, a drug is or may become adulterated, within the meaning of the FD&C Act, but such report does not constitute a conclusion that a violation has occurred. FDA Center staff then decides what to do about the inspectional observations.
The next rung on the FDA enforcement ladder is typically an advisory action, such as a Warning or Untitled Letter. FDA has stated that its “position is that Warning Letters are issued only for violations of regulatory significance. Significant violations are those violations that may lead to enforcement action if not promptly and adequately corrected. A Warning Letter is the agency's principal means of achieving prompt voluntary compliance with the [FD&C Act].” FDA, Regulatory Procedures Manual (“RPM”), Chapter 4, 2 (July 2012). (For additional background on Warning and Untitled Letters, see our recent post here.) We know FDA can issue these advisory notices to traditional pharmaceutical manufacturers, but can they issue such notices to a government agency? You betcha! In fact, FDA contemplates this and has developed policy around the issuance of Warning and Untitled Letters to government facilities. FDA’s RPM states:
To that point, the DC Circuit has stated, “judicial resolution of intra-Executive disputes [between traditional Executive branch agencies] is questionable under both Article II and Article III [of the federal Constitution]. . . . No one plausibly thinks, for example, that a federal court would resolve a dispute between the Department of Justice and, say, the Department of Defense or the Department of State.” Sec. and Exch. Comm’n v. Fed. Labor Relations Auth., 568 F.3d 990, 997 (D.C. Cir. 2009) (Kavanaugh, J., concurring).
In our case, where FDA may seek enforcement against NIH, the critical fact is that both FDA and NIH are controlled directly by the Secretary of Health and Human Services, who is in the proper, and best, position to resolve disputes arising between FDA and NIH.
Conclusion. Setting aside what we think are the very interesting legal implications of FDA inspecting NIH, and despite the political intrigue raised by the inspection and resultant 483, FDA likely won’t be taking the kinds of enforcement action it would take against commercial facilities with similar problems. Due to NIH’s decision to suspend sterile product manufacturing, sterile drug products from NIH won’t be used in study subjects until the facility has corrected the problems. We know from our experience that the road through remediation is long and expensive. This time, unfortunately, the “shareholders” who will be footing the bill, however, are all of us – the US taxpayers.
As NIH Director, Dr. Francis J. Collins, stated “The fact that patients may have been put in harm’s way because of a failure to follow standard operating procedures in the NIH Clinical Center’s Pharmaceutical Development Section is deeply troubling.” We couldn’t agree more.
Having assisted clients with FDA inspections, 483 responses, and Warning Letter responses associated with cGMP for aseptic fill operations, we can imagine the nightmares many quality and manufacturing personnel would have with the observations in a recently, publicly-issued 483:
- “Insects were observed in two (2) of five (5) ISO 7 cleanroom ceiling light bays . . . .”
- “Spore-forming organisms . . . were found in two released vials . . . .”
- “Gowning [] failed to fully cover [operators’] face and neck area.”
- “There are no media fill simulations to qualify the aseptic process and [operators].”
- “There is no GMP training program . . . .”
- “No [lyophilizer] sterilization cycle is performed . . . .”
- “Investigation into the sterility failure . . . did not establish a root cause.”
- “Three (3) vials were removed . . . for contamination with glass particles. . . . no root cause [was] identified, and no preventive actions [were] initiated to prevent recurrence.”
- “Container closure integrity testing is not performed for any sterile drug products.”
- “The cleaning and disinfection program for the ISO 5 hoods . . . does not include the use of a sporicidal agent.”
- “The quality unit is not involved in release of drug products . . . .”
The answer is none. All of the above statements – and much, much, oh, so much more – can be read among the 17 detailed observations in the 483 issued to none other than the otherwise-esteemed National Institutes of Health (“NIH”) in Bethesda, Maryland.
Aseptic fill is a technically complex and resource intensive endeavor. Manufacturers of sterile products spend extraordinary time and treasure building, testing, and validating their fill lines in carefully monitored and controlled environments. To keep the drugs we rely on in plentiful supply, extensive training and retraining of personnel and constant vigilance is required. Every deviation requires investigation. Due to the patient risks involved with such products, it is not surprising that FDA keeps a close eye on these operations, and, as consumers of these products, we are thankful for that.
FDA inspected the NIH Pharmaceutical Development Section and Clinical Center Pharmacy for five days between May 19 and May 29, 2015, following a complaint about the facilities. FDA sent four individuals on the inspection – one compliance officer, two consumer safety officers, and one investigator – Tom Arista from the Baltimore District Office. The investigation closed on June 2, 2015, and on June 4th, NIH issued a press release disclosing the inspection results and stated that it would voluntarily suspend sterile product manufacturing at its facilities.
The NIH has said that the facility’s sterile product operations are currently involved in as many as 46 clinical studies – a significant number by any measure. It is too early to know how many study participants received potentially contaminated product, but, given NIH’s lack of an effective monitoring process in the first instance (at least according to FDA), such information is likely unknowable. What is known is that FDA says that NIH has no assurance that any of its “sterile” products is free from contamination. The impact on dozens of taxpayer-funded clinical studies and hundreds of individual patients is unknown.
Perhaps most of all, the 483 for the NIH facility raises a number of intriguing questions. Among them are:
- What is the real story behind the formal inspection and 483?
- How long has FDA known of NIH’s alleged noncompliance with the basic tenets of aseptic processing and cGMPs?
- Did FDA know that NIH would release the 483 and did FDA consider notifying NIH of the inspection results without issuing a 483?
- What does FDA expect to do now that it has issued a 483 written in language that, under any other circumstance with a private company, would likely lead to a Warning Letter and perhaps an injunction action or import alert?
As mentioned above, NIH has agreed to suspend its operations until the observations can be addressed. While voluntary compliance is typically a prudent course under these circumstances, it did get us wondering – what could FDA do if NIH, a sister agency within the Department of Health and Human Services, told FDA to go “pound sand”?
At bottom, we think the answer to this question may be: not much. While FDA now has, and may in the future, use informal advisory actions to gain cGMP compliance from its sister agency, it is certainly unclear if DOJ and FDA can or will sue NIH. Indeed, there may be constitutional limitations that may bar litigation by FDA against NIH.
We begin by reviewing FDA’s authority to conduct the inspection of NIH facilities in the first instance. FDA’s inspectional authority is found in section 704 of the Federal Food, Drug, and Cosmetic Act (“FD&C Act”). FDA inspectors are authorized to inspect “any factory, warehouse, or establishment” where drugs are manufactured, packaged, or stored. FD&C Act § 704(a)(1) (emphasis added). Upon the conclusion of the inspection, the FDA inspector typically provides a written report of conditions or practices that, in the inspector’s judgment, a drug is or may become adulterated, within the meaning of the FD&C Act, but such report does not constitute a conclusion that a violation has occurred. FDA Center staff then decides what to do about the inspectional observations.
The next rung on the FDA enforcement ladder is typically an advisory action, such as a Warning or Untitled Letter. FDA has stated that its “position is that Warning Letters are issued only for violations of regulatory significance. Significant violations are those violations that may lead to enforcement action if not promptly and adequately corrected. A Warning Letter is the agency's principal means of achieving prompt voluntary compliance with the [FD&C Act].” FDA, Regulatory Procedures Manual (“RPM”), Chapter 4, 2 (July 2012). (For additional background on Warning and Untitled Letters, see our recent post here.) We know FDA can issue these advisory notices to traditional pharmaceutical manufacturers, but can they issue such notices to a government agency? You betcha! In fact, FDA contemplates this and has developed policy around the issuance of Warning and Untitled Letters to government facilities. FDA’s RPM states:
Government establishments should be held to the same standards as nongovernment establishments. The public health standards are identical; however, the method used to ensure compliance with these standards may vary. FDA believes that government establishments will achieve and maintain a higher rate of voluntary compliance with FDA regulations compared with nongovernment establishments. Efforts to obtain voluntary compliance should be made and documented before recommending the issuance of a Warning Letter. These efforts may include discussing the violations with the responsible government officials by phone or in a meeting, recommending an Untitled Letter, or requesting a written corrective action plan and periodic progress reports. The government establishment's progress should be monitored and a follow-up inspection should be scheduled, within a reasonable time consistent with the noted violations to confirm correction of the violations. Id. at 3-4.But, let’s say a Warning Letter is ineffective or exigent circumstances, such as a threat to public health, exist that warrant more immediate and aggressive enforcement action by FDA. Against traditional pharmaceutical manufacturers, FDA has, in its armamentarium, civil (e.g., TRO, seizure) and criminal (FD&C Act prosecution) judicial actions that can be initiated by the filing of a complaint in the name of the United States (i.e., by DOJ) in federal district court. See FD&C Act § 310(a) (all such proceedings for the enforcement, or to restrain violations, of this chapter shall be by and in the name of the United States). But what about vis-à-vis another government agency?
To that point, the DC Circuit has stated, “judicial resolution of intra-Executive disputes [between traditional Executive branch agencies] is questionable under both Article II and Article III [of the federal Constitution]. . . . No one plausibly thinks, for example, that a federal court would resolve a dispute between the Department of Justice and, say, the Department of Defense or the Department of State.” Sec. and Exch. Comm’n v. Fed. Labor Relations Auth., 568 F.3d 990, 997 (D.C. Cir. 2009) (Kavanaugh, J., concurring).
In our case, where FDA may seek enforcement against NIH, the critical fact is that both FDA and NIH are controlled directly by the Secretary of Health and Human Services, who is in the proper, and best, position to resolve disputes arising between FDA and NIH.
Conclusion. Setting aside what we think are the very interesting legal implications of FDA inspecting NIH, and despite the political intrigue raised by the inspection and resultant 483, FDA likely won’t be taking the kinds of enforcement action it would take against commercial facilities with similar problems. Due to NIH’s decision to suspend sterile product manufacturing, sterile drug products from NIH won’t be used in study subjects until the facility has corrected the problems. We know from our experience that the road through remediation is long and expensive. This time, unfortunately, the “shareholders” who will be footing the bill, however, are all of us – the US taxpayers.
As NIH Director, Dr. Francis J. Collins, stated “The fact that patients may have been put in harm’s way because of a failure to follow standard operating procedures in the NIH Clinical Center’s Pharmaceutical Development Section is deeply troubling.” We couldn’t agree more.
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