Nucleic Acid Analysis with UV-vis and NMR - Spectroscopy

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24 Spectroscopy 24(11) November 2009 www.spectroscopyonline.com • “The agency must place greater emphasis on significant risks and violations, and use meaningful penalties to send a strong message to discourage future offenses.” The strong message coming through loud and clear is be compliant and remain compliant with the regulations — or else. You’ll now see that the tiger, far from being ready for the taxidermist, is starting to sharpen its teeth. Not only does this apply to the here-and-now but also, as noted in the final bullet point, the commissioner wants to discourage future offences. So why change the FDA approach to enforcement? One of the rationales for this was mentioned in the speech as the pathways for enforcement action can be too long and arduous when the public’s health is in jeopardy. So from this and the FDA, we must infer that the FDA will be increasing inspections while tightening up and speeding up enforcement actions. Thus. it was not surprising that the FDA announced in the Federal Register of August 11 (4) the trial of a new program entitled “Review of Post-Inspection Responses.” The purpose of this program is to facilitate the timely issuance of warning letters that started on September 15, 2009 and will run for 18 months (the tiger has just come back from the dentist and is feeling hungry — are you getting the message?). Issues with the Current Inspection Process Before we look in detail at the inspection goodies coming your way, I would just like to step back and review what happened before implementation of this new program. FDA inspections come in three flavors and will continue to do so: • Facility inspection: routine inspection of the facility and the six areas quality — however, we will just focus on the quality system and the laboratory in this column. • Preapproval inspection (PAI): inspection of the manufacturing facility for a new drug or a generic drug before licensing. • For cause inspection: either there is a public health issue that must be Late response Establishment Inspection Report (EIR) Regulatory action stopped Adequate response rapidly investigated or a whistleblower has alerted the agency. In either case, the first thing you’ll probably notice is the knock of the inspection team at the front door of your site. Regardless of the inspection type, the inspection follows the same format and begins with the inspectors FDA inspection 483 observations 15 days Response letter Inadequate response Warning letter 15 days Response letter Inspection follow-up Closeout letter Serious violations Figure 1: Process flow of the new FDA postinspection response program. Serious violations Further enforcement action presenting their credentials and a copy of FDA Form 482, which is the notice of inspection, at the opening meeting. During the inspection, they may notice noncompliances and these are documented on FDA Form 483 entitled “Inspectional Observations” (this is the dreaded 483!), which is given to the
www.spectroscopyonline.com November 2009 Spectroscopy 24(11) 25 company at the closing meeting of the inspection. Written on each page of Form 483 is the following wording: “This document lists observations made by the FDA representative during the inspection of your facility. They are inspectional observations, and do not represent a final agency determination regarding your compliance.” The company currently has 30 working days to respond to the 483 but what happens in practice is that a first response is presented within the time limit and then further letters are fed in over a few months for the more serious issues. If you read some of the warning letters on the FDA website, you’ll see if the inspection occurred in January, the warning letter finally emerges into the light 6–9 months later. The reason for this is that there has been protracted correspondence between the company and the FDA. This will stop under the new program. Warning letters are only issued for significant violations from the regulations. After the warning letter has been sent out to the company, a copy is hung on the “Wall of Shame” in the warning letter section of the FDA’s website. Here anyone can have a good laugh about the problems of another company while secretly hoping that they will not have a starring role in a future warning letter. The response time for the company to respond to a warning letter is 15 working days; in the new program, this also will be the response time for a 483. Regardless of whether you get a 483 or not, the FDA inspectors will write a detailed Establishment Inspection Report (EIR) of the inspection that details the people they had talks with and the procedures, systems, and records that were inspected; this document provides the agency with its elephant’s memory. Failure to correct the noncompliances outlined in a warning letter may lead to further enforcement action by the FDA, and ignoring a warning letter is not advisable. However, the agency has often issued further warning letters to companies in the past, a practice that will apparently stop with the new program. Further regulatory enforcement by the FDA can include a consent decree of permanent injunction, which will bind the company in perpetuity to comply with the regulations; this can cost a company millions of dollars or even its existence or withdrawing a product licence. For foreign companies, the FDA can ban import of its products. 483 Complaints Procedure Under the “GMP for the 21st Century” initiative, the FDA issued a guidance for industry with a delightful title of “Formal Dispute Resolution: Scientific and Technical Issues Related to Pharmaceutical CGMP” (5). In essence, this document encourages the company and the inspector to discuss and resolve everything while the inspection is still ongoing. However, if this is not possible, only with regard to observations where it is down to interpretation is a company allowed to appeal to the FDA in a formal, two-tiered response. For example, if you don’t keep complete records of a spectroscopic analysis, you will not have a leg to stand on as the regulations explicitly require you to do this. Here you are noncompliant and you have been caught — no discussion and no argument. In contrast, if the regulations are vague and it is down to differences of interpretation between the company and the inspector, then this is where the dispute procedure can be used. Postinspection Response Program So what has changed with this new program? Two changes that will impact laboratories is that a very short timeframe is being put around how quickly firms must respond to 483 observations, and the second is that there will be a formal close out of warning letters to demonstrate that the noncompliances listed there have been resolved. So let’s look in detail at what you have to do and you will now see that the tiger has sharp new teeth and that they will be sinking into your flesh. Figure 1 shows the process as a diagram and readers should look at this to put the text below into context.
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Nucleic Acid Analysis with UV-vis and NMR - Spectroscopy

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