• Login
    • Join
  • FOLLOW:
  • Subscribe Free
    • Magazine
    • eNewsletter
    Checkout
    • Magazine
    • News
    • Manufacturing
    • Packaging
    • Development
    • Compliance
    • Top 20
    • Directory
    • Solution Center
    • Events
    • More
  • Magazine
  • News
  • Manufacturing
  • Packaging
  • Development
  • Compliance
  • Top 20
  • Directory
  • Solution Center
  • Events
  • Current / Back Issue
    Features
    Editorial
    Columns
    Digital Edition
    eNewsletter Archive
    Our Team
    Editorial Guidelines
    Subscribe Now
    Advertise Now
    Top Features
    Amorphous Solid Dispersions for Bioavailability Enhancement

    Dietary Supplement Quality Assurance Programs Critical to Natural Products Industry Success

    Manufacturing Dietary Supplements in Economic Uncertainty

    2023 Contract Manufacturing Survey

    New Possibilities for Small Batch Manufacturing
    Breaking News
    Online Exclusives
    Industry News
    Collaborations & Alliances
    Promotions & Moves
    Trials & Filings
    Financial Reports
    Bio News & Views
    Custom Sourcing News
    Packaging & Tracking
    CRO News
    Live From Shows
    Top News
    Adragos Pharma Acquires Clinigen's Development Unit, Lamda Laboratories

    Vantage Nutrition Acquires ComboCap

    Secarna, SciNeuro Enter Research Agreement for CNS Diseases

    BioNTech Revenues Slide with Waning Demand for COVID-19 Vaccines

    Codiak BioSciences to File for Chapter 11
    APIs
    Aseptic Processing
    Cleaning Validation
    Clinical Trial Materials
    Cytotoxics and High Potency Manufacturing
    Equipment
    Excipients
    Extractables and Leachables
    Facilities
    Fill/Finish
    Lyophilization
    Parenterals
    Process Development
    Process Validation
    Risk Management
    Scale-up/ Technology Transfer
    Solid Dosage/ Creams/ Ointments

    PharmaBlock Opens New R&D Facility in Pennsylvania

    Macfarlan Smith Annan Facility Marked for Closure  

    Northwest Bio, Advent BioServices Gain MHRA License for Commercial Manufacturing

    Willow, Suanfarma Complete Manufacturing Process for Cannabigerol

    Harm Reduction Therapeutics, Catalent Ink Naloxone Commercial Supply Pact
    Capsules
    Cold Chain Management
    Injectables
    Logistics
    Serialization
    Solid Dosage / Semi-solids
    Supply Chain
    Vials

    Adare Pharma Solutions Chooses Vantage to Lead Packaging Facility Upgrade

    This is Sofgen Pharmaceuticals

    Why Sofgen Pharmaceuticals?

    Stevanato, Recipharm Partner to Develop Pre-fillable Syringes for Soft Mist Inhaler

    Chewgels™ - An Explosive Experience with Innovative Technology
    Analytical Services
    Bioanalytical Services
    Bioassay Developement
    Biologics, Proteins, Vaccines
    Biosimilars
    Chemistry
    Clinical Trials
    Drug Delivery
    Drug Development
    Drug Discovery
    Formulation Development
    Information Technology
    Laboratory Testing
    Methods Development
    Microbiology
    Preclinical Outsourcing
    R&D
    Toxicology

    Adragos Pharma Acquires Clinigen's Development Unit, Lamda Laboratories

    Secarna, SciNeuro Enter Research Agreement for CNS Diseases

    Pharming Gets FDA Nod for Joenja

    PharmaBlock Opens New R&D Facility in Pennsylvania

    Catalent Licenses Formulation Technology to Deliver High-Concentration Biologics
    Filtration & Purification
    GMPs/GCPs
    Inspections
    QA/QC
    Regulatory Affairs
    Validation

    Grand River Aseptic Manufacturing Receives Zero Observations from FDA Inspection

    Sofgen's Center for Pharmaceutical Excellence (CPhE)

    Dietary Supplement Quality Assurance Programs Critical to Natural Products Industry Success

    What Does the Future of Gene Therapy Hold?

    Automated Regulatory Electronic Publishing: How is It Changing the Industry?
    Companies
    Categories
    Corporate Capabilities
    Add New Company
    Contract Service Directory Companies
    INCOG BioPharma Services

    U.S. Pharmacopeia (USP)

    TaiMed Biologics

    Alcami

    Quotient Sciences
    Companies
    News Releases
    Posters
    Brochures
    Services
    Videos
    Case Study
    White Papers
    Jobs
    Contract Service Directory Companies
    INCOG BioPharma Services

    U.S. Pharmacopeia (USP)

    TaiMed Biologics

    Alcami

    Quotient Sciences
    Webinars
    Live From Shows
    • Magazine
      • Current / Back Issue
      • Features
      • Editorial
      • Columns
      • Editorial Guidelines
      • Subscribe Now
      • Advertise Now
      • Enewsletter Archive
      • Digital Edition
    • Directory
      • Companies
      • Categories
      • Corporate Capabilities
      • Add Your Company
    • Manufacturing
      • APIs
      • Aseptic Processing
      • Cleaning Validation
      • Clinical Trial Materials
      • Cytotoxics and High Potency Manufacturing
      • Equipment
      • Excipients
      • Extractables and Leachables
      • Facilities
      • Fill/Finish
      • Lyophilization
      • Parenterals
      • Process Development
      • Process Validation
      • Risk Management
      • Scale-up/ Technology Transfer
      • Solid Dosage/ Creams/ Ointments
      • cGMP Manufacture
    • Packaging
      • Capsules
      • Cold Chain Management
      • Injectables
      • Logistics
      • Serialization
      • Solid Dosage / Semi-solids
      • Supply Chain
      • Vials
    • Development
      • Analytical Services
      • Bioanalytical Services
      • Bioassay Developement
      • Biologics, Proteins, Vaccines
      • Biosimilars
      • Chemistry
      • Clinical Trials
      • Drug Delivery
      • Drug Development
      • Drug Discovery
      • Formulation Development
      • Information Technology
      • Laboratory Testing
      • Methods Development
      • Microbiology
      • Preclinical Outsourcing
      • R&D
      • Toxicology
    • Compliance
      • Filtration & Purification
      • GMPs/GCPs
      • Inspections
      • QA/QC
      • Regulatory Affairs
      • Validation
    • Top 25 Pharma & BioPharma
    • Contract Pharma Direct
    • Breaking News
    • Online Exclusives
    • Slideshows
    • Experts Opinions
    • Surveys
      • Outsourcing Survey
      • Salary Survey
    • Glossary
    • Videos
    • White Papers
    • Podcasts
    • Infographics
    • Microsites
      • Companies
      • News Releases
      • Posters
      • Brochures
      • Services
      • Videos
      • Case Study
      • White Papers
    • Contract Pharma Conference
      • Contract Pharma Conference
      • Speakers
      • Exhibitors
      • Conference Sessions
    • eBook
    • Webinars
    • Events
      • Industry Events
      • Live from Show Events
      • Webinars
    • Classifieds / Job Bank
      • Classifieds
      • Job Bank
    • About Us
      • About Us
      • Contact Us
      • Advertise With Us
      • Privacy Policy
      • Terms of Use
    FDA Watch

    Warning Letters & Close-out Letters

    Why does it take so long to get a close-out letter?

    06.06.17
    One of the enforcement tools that FDA has in its toolbox is the Warning Letter. Most people in the pharmaceutical industry are quite familiar with Warning Letters. For all Warning Letters issued on or after September 1, 2009, FDA will issue a close-out letter for Warning Letters when all observations have been appropriately resolved, which basically states that the FDA is satisfied with a company’s response, corrective actions, and subsequent actions. This was intended to give industry clarity about the status of their sites, and to provide consumers, buyers, and potential partners insight into the state of compliance of manufacturers. In theory, it is possible to aggressively manage remediation and to satisfy FDA to get the Warning Letter lifted in an expeditious manner; however, a quick review of available data shows that this isn’t always the case.

    I’ve reviewed Warning Letters and close-out letters for the last several years, and find that the length of time to achieve close-out can be two plus years. For example, in 2014, there were 16 Warning Letters issued for drug facilities, but only 11 have subsequently received close-out letters. For Warning Letters issued in 2014, which have been closed-out, the average time for API facilities from issuance of a Warning Letter to close-out was 795 days, and the average time for finished dosage form facilities was 555 days. Add to those numbers the fact that there are 5 Warning Letters from 2014 that still haven’t been closed-out. If these Warning Letters are lifted, those statistics will climb. Similarly, in 2015 there were 20 Warning Letters issued, with only 3 closed-out to date. In 2016, there were 44 Warning Letters issued, with only 3 closed-out to date. Average time to closure with respect to Warning Letters issued in both 2015 and 2016 is currently much lower than those issued in 2014, but there is also a much lower percentage of close-outs relative to the total amount of Warning Letters issued, so average close-out time for Warning Letters issued in 2015 and 2016 is likely to rise if and when more close-outs occur.

    The time from receipt of a 483 to issuance of a Warning Letter has also risen over the last several years, with many Warning Letters being issued over a year after the 483 was issued. This adds to the overall time that companies are in limbo, without a clear direction as to their compliance status in the eyes of FDA.

    What are some of the possible reasons that it is taking so long for companies to resolve Warning Letters to FDA’s satisfaction? We believe it is attributable to any one (or a combination) of the following factors:

    Inadequate initial response to the Warning Letter
    When FDA issues a Warning Letter, generally it is because they have some concerns over the firm’s response to one or more 483s. However, at times, companies make the mistake of just reiterating the responses they gave in the initial 483 response when responding to a Warning Letter. Just restating the same thing isn’t going to change FDA’s mind. It’s very unlikely that FDA missed something in your initial response that would change its mind. Companies need to break down the Warning Letter citations to determine where they went wrong with the initial response, and try to rectify it.

    Another issue that makes companies’ responses inadequate in FDA’s eyes is when they are very narrow. If the FDA cited something in one system, or for one product, the firm needs to assess similar situations for other products or systems. Good responses look at overall systems, across the entire product line, site, and even across sites. This lets FDA know that you are serious about examining your entire systems and operations.

    Another pitfall that companies make is not implementing interim controls. If you have determined that an effective corrective action is going to take a year to implement, and you haven’t implemented an interim control in that year, you are still manufacturing product under the same objectionable conditions that FDA observed and cited, and that will erode FDA’s confidence in your company. Closely related to this failure is not assessing the impact of the Warning Letter citations on product currently on the market. Remember that FDA’s mission is to protect public health, and a response that doesn’t take this into consideration will be seen by FDA as inadequate.

    Not providing periodic updates
    Unless everything that you have committed to do has been completed prior to sending in your Warning Letter response, it’s important to keep FDA updated regularly. We’ve seen examples of companies that have committed to periodic updates and haven’t submitted them, haven’t had any dialogue with FDA, and then are surprised when FDA hasn’t scheduled a re-inspection because of this uncertainty. In a similar vein, letting FDA know when you have completed all the corrective actions is crucial, particularly with foreign sites. This lets FDA know that you are ready for a re-inspection.

    Thinking that the Warning Letter citations are all inclusive
    FDA states that the violations listed in a Warning Letter are not all inclusive; however, we frequently hear companies state that, because a certain system wasn’t listed on the Warning Letter or 483 with any observations, it must be acceptable. When it comes to 483s, the investigator may not have focused on a specific area and therefore had no observations. With Warning Letters, the content of the response may have led FDA to accept the response to a specific item, but on re-inspection, the field investigator may find some additional violations. Nothing is off limits.

    When FDA comes to re-inspect
    A lot of times companies think that when FDA comes to re-inspect, they are only going to look at the systems that were cited in the Warning Letter. Many companies fall into this trap thinking that when FDA comes back, they are only going to verify corrective actions. This is just not true. FDA will focus some of the inspection on the corrective actions, but will also, generally, perform a full inspection. The issues identified in the Warning Letter may have been corrected, but new potential issues may be noted. While some of the issues may not warrant additional action, they may lead to a delay in lifting the Warning Letter.

    Some companies aren’t interested in getting the Warning Letter lifted
    Some Warning Letters may not be lifted simply because the company has either abandoned the U.S. market, or has gone out of business.  A small percentage of Warning Letters simply go unanswered, particularly when there isn’t any product on the U.S. market. Other companies, particularly when an Import Alert is in place, may make an initial response, but then discontinue products, move facilities, etc., with the result being no opportunity for the Warning Letter to be lifted. We have no way of knowing how many of the open letters fall into that category.

    Warning Letters are FDA’s practice to allow for firms to take voluntary and prompt corrective actions before initiating a drastic enforcement action such as a seizure or injunction. It goes without saying that firms should demonstrate to FDA their willingness to address the issues raised in the letter in as short of a time frame as is possible, not only to get their Warning Letters lifted as soon as possible, but also to minimize disruption of supply of products to patients. Many companies who have received a Warning Letter have expressed that they desire to have it lifted in a year or less.
    Given the data, this would be an aggressive exception to recent close-out timeframes. While it is theoretically possible to do so in such a short interval, the likelihood of this happening is not high. In addition, because it is critical to demonstrate to FDA that the issues raised in the Waning Letter are being handled, a superficial fix by a firm to reduce time frames could lead to escalated regulatory action by FDA.


    Linda Evans O’Connor
    Lachman Consultants

    Linda Evans O’Connor is head of business processes and regulatory at Lachman Consultants. Ms. Evans O’Connor delivers project oversight/management, work planning and work flow
    analysis, and quality assurance. She can be reached at lcs@lachmanconsultants.com or visit www.lachmanconsultants.com.
    Related Searches
    • API
    • Manufacturing
    • it
    • Dosage
    Suggested For You
    Roberto Almodóvar Febles Joins Pii as Head of Aseptic Operations Roberto Almodóvar Febles Joins Pii as Head of Aseptic Operations
    Pii Names Head of Aseptic Operations Pii Names Head of Aseptic Operations
    Mogene Mogene
    Know the Challenges of Biosimilar Manufacturing Know the Challenges of Biosimilar Manufacturing
    Will Immunotherapy Knock Out Cancer? Will Immunotherapy Knock Out Cancer?
    Tapemark Passes Regulatory Hurdle Tapemark Passes Regulatory Hurdle
    BioPharma Services Completes 3 FDA Inspections BioPharma Services Completes 3 FDA Inspections
    Synthetic Genomics Launches cGMP Synthetic Biology Suite  Synthetic Genomics Launches cGMP Synthetic Biology Suite
    Frontida BioPharm Launches Expansion Efforts Frontida BioPharm Launches Expansion Efforts
    The FDA and Metrics The FDA and Metrics
    Advaxis Appoints CBO Advaxis Appoints CBO
    Establishments, Identifications, Submissions and Beyond Establishments, Identifications, Submissions and Beyond
    Generic Drug Trends Generic Drug Trends
    Challenges and Advantages of International Regulatory Inspections Challenges and Advantages of International Regulatory Inspections
    LSNE Completes Two FDA Inspections LSNE Completes Two FDA Inspections

    Related Breaking News

    • Aseptic Processing | Breaking News | Industry News | Promotions & Moves
      Roberto Almodóvar Febles Joins Pii as Head of Aseptic Operations

      Roberto Almodóvar Febles Joins Pii as Head of Aseptic Operations

      Will oversee and manage day-to-day aseptic manufacturing.
      09.03.21

    • Aseptic Processing | Breaking News | cGMP Manufacture | Promotions & Moves
      Pii Names Head of Aseptic Operations

      Pii Names Head of Aseptic Operations

      Roberto Almodóvar Febles will oversee and manage day-to-day aseptic manufacturing.
      08.31.21

    • Mogene

      ...
      Craig Morley, CEO 11.17.20


    • Bio News | Biosimilars
      Know the Challenges of Biosimilar Manufacturing

      Know the Challenges of Biosimilar Manufacturing

      Best Practices for a Competitive Market
      Jerry Martin, Pharmaceutical and Life Sciences Consultant to PMMI, and, Dr. Michiel Ultee, Principal, Ulteemit BioConsulting, LLC 04.11.18

    • Biologics, Proteins, Vaccines
      Will Immunotherapy Knock Out Cancer?

      Will Immunotherapy Knock Out Cancer?

      Innovative immunotherapy companies discuss with WuXi AppTec what’s next for this rapidly developing field ahead of BIO 2017.
      06.14.17

    Loading, Please Wait..
    Trending
    • Merck KGaA Secures Exclusive Worldwide Rights To Bavencio
    • Codiak BioSciences To File For Chapter 11
    • BioNTech Revenues Slide With Waning Demand For COVID-19 Vaccines
    • How Industry 5.0 Might Benefit Pharmaceutical Manufacturing
    • Jubilant HollisterStier Appoints Chris Preti President
    Breaking News
    • Adragos Pharma Acquires Clinigen's Development Unit, Lamda Laboratories
    • Vantage Nutrition Acquires ComboCap
    • Secarna, SciNeuro Enter Research Agreement for CNS Diseases
    • BioNTech Revenues Slide with Waning Demand for COVID-19 Vaccines
    • Codiak BioSciences to File for Chapter 11
    View Breaking News >
    CURRENT ISSUE

    March 2023

    • Amorphous Solid Dispersions for Bioavailability Enhancement
    • Dietary Supplement Quality Assurance Programs Critical to Natural Products Industry Success
    • Manufacturing Dietary Supplements in Economic Uncertainty
    • 2023 Contract Manufacturing Survey
    • New Possibilities for Small Batch Manufacturing
    • Supply Chain Risk Management
    • 3 Ways Pharma Can Outsmart Talent Challenges in 2023
    • Nutraceutical Dosage Trends: Functional Gummies Offer Alternative to Tablets and Capsules
    • View More >

    Cookies help us to provide you with an excellent service. By using our website, you declare yourself in agreement with our use of cookies.
    You can obtain detailed information about the use of cookies on our website by clicking on "More information”.

    • About Us
    • Privacy Policy
    • Terms And Conditions
    • Contact Us

    follow us

    Subscribe
    Nutraceuticals World

    Latest Breaking News From Nutraceuticals World

    Melodea Launches New Plastic-Free Packaging Solution
    GOED and NASC Announce Strategic Partnership
    NPA: ‘Major Victory’ in Colorado After Amendment to Eating Disorder Bill
    Coatings World

    Latest Breaking News From Coatings World

    HOFFMANN MINERAL to Focus on Comprehensive Sustainability Strategy
    HMG and Prodrive Renew Technical Partnership
    Eastern Coatings Show Sets Schedule for Technical Papers
    Medical Product Outsourcing

    Latest Breaking News From Medical Product Outsourcing

    FDA OKs FemDx Medsystems' FalloView Device
    FDA Clears NeuroRPM Parkinson's Disease Monitoring Tech
    Vaporox Earns FDA Nod for VHT-200 Wound Care Device
    Contract Pharma

    Latest Breaking News From Contract Pharma

    Adragos Pharma Acquires Clinigen's Development Unit, Lamda Laboratories
    Vantage Nutrition Acquires ComboCap
    Secarna, SciNeuro Enter Research Agreement for CNS Diseases
    Beauty Packaging

    Latest Breaking News From Beauty Packaging

    Thread Beauty Expands Cosmetics Line at Target
    The Body Shop Expands its Refill Program in Canada
    Clinique Introduces Digital Retail Concept—Clinique Lab
    Happi

    Latest Breaking News From Happi

    Arbonne Welcomes New Executives
    Total Sales for Naples Soap Company in 2022 Increase 2% Despite Inflation, Supply Chain Issues
    IBA Supports FDA in the MoCRA Rulemaking and Implementation Process
    Ink World

    Latest Breaking News From Ink World

    hubergroup Print Solutions Presents Sustainable Portfolio at PAMEX 2023
    Weekly Recap: Packaging Inks, Toyo Ink Top This Week’s Stories
    Eastern Coatings Show Announces Schedule for Technical Papers
    Label & Narrow Web

    Latest Breaking News From Label & Narrow Web

    eProductivity Software acquires Tharstern Group
    Imageworx details new facility, Avery Dennison tackles recycling and more
    TLMI announces 2022 Eugene Singer Award winners
    Nonwovens Industry

    Latest Breaking News From Nonwovens Industry

    Period Care Brand August Launches in Target Stores
    Albany International Announced CEO Succession Plan
    Ahlström Partners to Make Sustainable Butter, Margarine Packaging
    Orthopedic Design & Technology

    Latest Breaking News From Orthopedic Design & Technology

    Exactech Boosts AI Expertise with Licensing Deal, Team of Scientists
    Anchor Harvey Celebrates 100th Anniversary in 2023
    Arjun Ishwar Joins Miach Orthopaedics as Sales and Marketing VP
    Printed Electronics Now

    Latest Breaking News From Printed Electronics Now

    onsemi Honored with Supplier of the Year 2022 Award by Hyundai Motor Group 
    Weekly Recap: Dave Rahami, Zebra, Dracula Technologies Top This Week’s Stories
    Midsummer, UCLA Collaborate on Perovskite-CIGS Tandem Solar Cells

    Copyright © 2023 Rodman Media. All rights reserved. Use of this constitutes acceptance of our privacy policy The material on this site may not be reproduced, distributed, transmitted, or otherwise used, except with the prior written permission of Rodman Media.

    AD BLOCKER DETECTED

    Our website is made possible by displaying online advertisements to our visitors.
    Please consider supporting us by disabling your ad blocker.


    FREE SUBSCRIPTION Already a subscriber? Login