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Facing FDA Inspections
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Facing FDA Inspections

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FDA inspections are stressful and worrisome. Failed FDA inspection costs include sales revenue loss, stock price decline, and public embarrassment from FDA warning letters and FDA-483 observations. ...

FDA inspections are stressful and worrisome. Failed FDA inspection costs include sales revenue loss, stock price decline, and public embarrassment from FDA warning letters and FDA-483 observations. It is good to recalibrate by looking at frequently asked questions when it comes to FDA inspections.

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Facing FDA Inspections Facing FDA Inspections Presentation Transcript

  • This presentation is compiled by “ Drug Regulations” a non profit organization which provides free online resource to the Pharmaceutical Professional. Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals. 1/6/2014 1
  • This presentation is compiled from freely available resources like the websites of FDA and other free websites.  “Drug Regulations” is a non profit organization which provides free online resource to the Pharmaceutical Professional.  Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals.  Drug Regulations : Online Resource for Latest Information 1/6/2014 2
  • ◦ FDA inspections are stressful and worrisome. ◦ Failed FDA inspection costs include sales revenue loss, stock price decline, and public embarrassment from FDA warning letters and FDA-483 observations. ◦ It is good to recalibrate by looking at frequently asked questions when it comes to FDA inspections. Drug Regulations : Online Resource for Latest Information 1/6/2014 3
  • ◦ Yes. ◦ The FDA is not blind to reality. ◦ FDA’s charter is to protect public safety. ◦ If people, through product liability litigation, are having to take matters into their own hands to go after companies for putting ineffective or unsafe products on the market, FDA could be seen as not performing its task. ◦ So yes, FDA pays very close attention to product liability litigation. Drug Regulations : Online Resource for Latest Information 1/6/2014 4
  •  Prior to an inspection, the investigator(s) will create an inspection plan that is largely based on the following information: ◦ Any previous establishment inspection reports (EIRs) ◦ Any previous FDA Form 483 observations, especially those that require follow-up ◦ Company responses (to FDA-483s) and commitments ◦ Firm’s website (including product literature, executive profiles, physical location profiles, recent press releases, etc.) ◦ Consumer complaints that have come in since the last inspection ◦ Adverse events that have come in since the last inspection ◦ Any recalls or other field activities that have occurred since the last inspection Drug Regulations : Online Resource for Latest Information 1/6/2014 5
  • ◦ Any product submissions and applications, specifically to find critical components or ingredients or processes that were of concern to FDA reviewers ◦ Online web research can be further broken into three main areas:  Online videos of your products in use (including if consumers have posted videos comparing/contrasting to other competing products, etc.)  Social media sites (especially for complaints about your product)  Searches for your company name or product name(s) along with key words (such as “review” or “fraud” or “FDA”).  An effective, independent FDA compliance gap analysis can help you pinpoint areas to strengthen in your compliance efforts before the FDA investigator arrives. Drug Regulations : Online Resource for Latest Information 1/6/2014 6
  • ◦ Yes. ◦ FDA investigators treat a closeout or follow-up inspection as a normal inspection. ◦ You can be cited for new or additional items. Drug Regulations : Online Resource for Latest Information 1/6/2014 7
  •  PAI inspections are Level 2 QSIT inspections by default.  FDA reviewers of a submission will identify areas of concern for the investigator to look at during the inspection (such as GCP data integrity controls).  PAI inspections may cover everything from ◦ Nonclinical supporting GLP-compliance, ◦ GCP compliance, ◦ GMP compliance, ◦ Even delve into how the company will monitor and control the product once it is approved and on the market. Drug Regulations : Online Resource for Latest Information 1/6/2014 8
  •  A level 2 QSIT inspection is a comprehensive inspection, covering all four major quality system subsystems ◦ Management controls, ◦ Development, ◦ CAPA, and ◦ Production and process controls Drug Regulations : Online Resource for Latest Information 1/6/2014 9
  •  It will also involve the remaining three subsystems ◦ Facilities ◦ Equipment controls, ◦ Materials and supplier controls, and records controls  These three subsystems cut across all four major subsystems.  Thus, 21 CFR 11 controls will be reviewed and inspected throughout the PAI, not just during review of the design and development (e.g., design control) subsystem. Drug Regulations : Online Resource for Latest Information 1/6/2014 10
  •  FDASIA 2012 expressly granted FDA the power to require supplier audit reports during regular inspections (see Title VII of FDASIA).  FDA discourages investigators from asking for the report in the hopes that this will encourage firms to be more candid and clear in supplier audits.  Unfortunately, as was painfully shown during the recent Heparin scandal, FDA’s hope has not panned out. Drug Regulations : Online Resource for Latest Information 1/6/2014 11
  •  Far too many firms conduct “meet and greet” supplier audits with little meaningful impact.  FDA investigators are now taking advantage of FDASIA’s new powers and requesting copies of supplier audit reports. Drug Regulations : Online Resource for Latest Information 1/6/2014 12
  •  FDA has always requested supplier audit reports ◦ FDA Compliance Policy Guide, section 130.300, ◦ FDA Access to Results of Quality Assurance Program Audits and Inspections ◦ During directed or “for cause” inspections of a sponsor or monitor of a clinical trial Drug Regulations : Online Resource for Latest Information 1/6/2014 13
  • ◦ In inspections where access to such records is authorized by statute (such as FDASIA) ◦ When public safety is at risk ◦ In litigation (or in support thereof) ◦ When executing a search warrant ◦ When a firm’s internal audit program is insufficient or otherwise deemed ineffective by FDA. Drug Regulations : Online Resource for Latest Information 1/6/2014 14
  •  This last point is often overlooked.  Technically, if the FDA investigator writes down a Form FDA-483 observation that a firm’s quality audit program is insufficient, the FDA investigator can then review the firm’s supplier audit reports.  It is thus in a firm’s interest to ensure that it has a robust, FDA supplier audit program that can withstand both FDA investigator and product liability litigator scrutiny.  Finally, always remember that FDA counts any corrective actions from supplier audits as CAPA documentation and freely open to review by any FDA investigator. Drug Regulations : Online Resource for Latest Information 1/6/2014 15
  •  As of the end of 2013, FDA’s special enforcement of 21 CFR 11 (e.g., "Part 11") is still ongoing.  Part 11 will come up throughout an inspection  It is a regulation that cuts across all quality system subsystems.  If records are used or kept in digital form, or if a computerized system is used to automate a regulated process (such as production, lab testing, etc.), then the FDA investigator will ask Part 11-relevant questions. Drug Regulations : Online Resource for Latest Information 1/6/2014 16
  •  FDA looks to see if you are verifying the functions that you use of a software or a computerized system in your environment, especially those functions related to data integrity.  For instance, with a spreadsheet macro, the FDA investigator will expect to see a simple verification of your use of the macro in your environment, documented with a validation protocol, document testing, and a summary report.  Do not validate Excel, just the use of the macro within your environment. Questions that the FDA investigator might ask include: ◦ How do you know the results of the macro are correct? ◦ Are complete? ◦ Did not drop off various data inputs? and so forth. ◦ These types of Part 11 validation are the ones to concentrate on. Drug Regulations : Online Resource for Latest Information 1/6/2014 17
  •  FDA treats all photographs, videos, documents, notes, etc. as confidential.  All such items go through FOIA to redact such sensitive information before they are released. Drug Regulations : Online Resource for Latest Information 1/6/2014 18
  •  Consider making sure to identify in your inspection notes what photographs the FDA investigator took  If possible, take a similar photograph.  In your response to the inspection, ◦ make sure to identify the photograph and ◦ any specific confidential or trade secret information that may have inadvertently been captured by the FDA photograph.  This will help FDA to redact the appropriate information  Provide you some degree of assurance that they understand and acknowledge the situation. Drug Regulations : Online Resource for Latest Information 1/6/2014 19
  •  FDASIA 2012 granted FDA the power to conduct remote and even online/virtual inspections.  FDA is currently not positioned to take advantage of this.  The agency is planning to start a pilot program wherein part of the inspection will be conducted remotely (e.g., remote document review) followed by a briefer onsite inspection portion. Drug Regulations : Online Resource for Latest Information 1/6/2014 20
  •  Keep in mind that at its core, FDA is a regulatory enforcement agency.  As such, during inspections, it is technically collecting evidence.  For companies doing all the right things, it is in their interest to have FDA investigators physically visit and see firsthand how well the company is doing.  For firms with more … “soft” …. approaches to compliance, a remote or online/virtual inspection has less of a chance to uncover gaps. Drug Regulations : Online Resource for Latest Information 1/6/2014 21
  •  FDA is well aware of this.  In order to address this, expect FDA over the next few years, to take a two-step approach to an inspection: ◦ Part one is a remote review of policies, SOPs, etc., (presumably through PDFs sent to the agency); ◦ This will then inform and shape part two, the onsite inspection. Drug Regulations : Online Resource for Latest Information 1/6/2014 22
  •  Management discussion items are non- compliance observations not written onto the Form FDA-483.  Management discussion items are compliance deviations that the FDA investigator believes to be of lesser significance than the documented 483s. Drug Regulations : Online Resource for Latest Information 1/6/2014 23
  •  Management discussion items can still end up as warning letter citations because the FDA district office or FDA head office believes they are more serious than originally assumed.  Thus, if you address management discussion items in your response to FDA, you may want to notify the district that you are working to resolve the items as well as the written 483 observations. Drug Regulations : Online Resource for Latest Information 1/6/2014 24
  •  Keep in mind that to FDA, as long as an observation of non-compliance was documented ◦ in the FDA investigator’s notes, ◦ written on a Form FDA-483, or ◦ spoken about to a firm's management,  FDA considers the observation “documented by FDA.”  FDA is, at its heart, an enforcement agency collecting evidence when it conducts an inspection. Drug Regulations : Online Resource for Latest Information 1/6/2014 25
  •  Management discussion items can be treated as repeat violations if found again in a follow-up or a second FDA inspection. Drug Regulations : Online Resource for Latest Information 1/6/2014 26
  •  Technically, up to 45 days after the inspection.  In reality, depending on the type, depth, and other FDA inspection conditions, it can be up to 3-6 months after the FDA investigator leaves.  Nonetheless, your FDA inspection response and remediation plan is still due to the agency within 15 business days after departure of the FDA investigator. Drug Regulations : Online Resource for Latest Information 1/6/2014 27
  •  This presentation was compiled from freely available resources like the websites of FDA and other free websites.  “Drug Regulations” is a non profit organization which provides free online resource to the Pharmaceutical Professional.  Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals. Drug Regulations : Online Resource for Latest Information 1/6/2014 28