No regulated business wants to receive an FDA Warning Letter (or Form-483) of Inspectional Observations. In such controlled industries as food, agriculture and pharmaceutical, receiving a list of deficiencies can feel like a heavy blow to your quality system. Worse, with the 2009 increase in enforcement staff (1) and the September 2009 change to the response time—now 15 days—the FDA appears to be ramping up its enforcement mandate (2).
The following article shows two excerpts from some of the more common “observations” noted in Warning Letters during 2008-2009. (The names have been left out in this article, but are a matter of public record) (3). Each of these deviations involved environmental conditions (temperature, humidity, etc.) in a variety of cGMP settings; they range from failure to properly monitor temperature at food processing facilities to a lack of temperature records in an aseptic processing area of a drug manufacturing facility. None of the deviations excerpted here are unique, but all are avoidable.
After the excerpts, we’ll outline some best practices of a 483 response, providing you with a 10-point checklist that should make that 15-day time limit more manageable, and some links for further research. Finally, we’ll look at ways to simplify and automate monitoring, alarming and reporting on FDA regulated environments. Options range from low-tech manual methods, to hybridized systems that combine written and electronic methods of documentation, to fully automated systems.
Sample Deviation #1 To a Food processing facility: “…your firm's HACCP plan for…this product… lists monitoring procedures and a frequency at the refrigerated storage CCP that is, not adequate to control histamines. 21 CFR 123.6(c)(4) Specifically, the HACCP plan for…this product… to control the hazard of histamines lists monitoring the temperature of the cooler by a, "Visual Wall Temperature Thermometer Check" at a frequency of [redacted] times per day, rather than continuous monitoring of the storage temperature with a continuous temperature monitoring and recording device, such as a recording thermometer or a digital time/temperature data logger.”
Sample Deviation #2 To a Seafood processing facility: “…your firm's HACCP plan for products 'Not Fully Cooked and Not Shelf Stable,' do not list the critical control point of refrigerated storage of cooked seafood ingredients for controlling the food safety hazard of pathogen growth and toxin formation. FDA recommends implementing controls which assure the product has not been exposed to temperatures above 40°F while in storage. These recommendations include monitoring the adequacy of the ice surrounding the product or continuous temperature monitoring of ambient temperature to control the growth of pathogens and toxin formation in cooked seafood products.”
10 ½ Tips for the Right Response
Your initial response must do three things: it must establish credibility, it must demonstrate acknowledgement of the observations and an understanding of the specific requirements referenced, and it must show that your facility is committed to corrective actions, any and all.
You can show commitment by working cross-departmentally; include a statement from all relevant department heads that briefly but specifically addresses each observation. Each observation needs to have a corrective action—either planned or accomplished—and it must be feasible and deliverable within a predetermined time-frame.
Here are some tips—some simple, some in depth—for responding appropriately to 483 letters:
1. Get your response in on time and in writing. You have 15 days, so ensure that final proofing and substantive editing is done at least by day 10.
2. In the first paragraph of the response letter, be explicit in your understanding of and desire to comply with FDA regulations.
3. Respond individually to each item that was addressed in the Warning letter. Be specific. Do not try to solve all issues in one paragraph or your response may be rejected, prompting further action from the FDA.
4. Respond by importance—that is, respond individually to items most likely to impact product quality.
5. Be detailed yet concise in each response. Outline how each deficiency will be corrected, and when, rather than how the deficiency came to be. Provide documentation of a corrective action commitment from the person responsible for it.
6. Use positive statements; avoid language that implies fault. Address each item in the form 483 as an opportunity to fine-tune the quality and compliance systems and personnel.
7. Include reference to how you will be forwarding evidence to support the correction. For example, "
8. If the inspector noted something that you feel was an isolated incident, document this fact and note it in your response. Be sure your data is complete and accurate. If you find some of the observations were in error after receiving the 483, there is a formal dispute resolution process outlined in the agency's "Guidance for Industry—Formal Dispute Resolution: Scientific and Technical Issues Related to Pharmaceutical CGMP (5)."
9. Be proactive. Reassess your internal compliance programs — Why were 483 deficiencies not detected internally? Mention this in your response letter, noting your commitment to QC/QA audit management. The definitive guide to what FDA inspectors are looking for (at least in theory) is the agency’s “Investigations Operations Manual” accessible at: http://www.fda.gov/ICECI/Inspections/IOM/default.htm
10. If you need clarification, seek it—in writing and from the correct party. Ideally, when the investigator gave you the Form 483 after the inspection you asked a lot of questions to clarify each observation. Try to be sure you are clear on each observation before the inspector leaves your facility and make notes while he/she is explaining the observations. If your questions involve policy, contact the FDA headquarters—don’t contact your local FDA because policy is set at HQ.
10.5. You may need an industry expert. There are many companies who specialize in creating and implementing regulatory strategy, whether from the ground up or from your existing quality and regulatory systems. If it’s worth doing, it may be worth hiring someone who knows how to do it really well. As regulatory compliance issues grow more complex, many companies have been created to provide solutions in common compliance areas like: response to agency queries and help with agency meetings, regulatory gap analysis & remediation, internal GLP/GMP auditing and pre-approval inspections.
Ideally, your regulated environments and equipment are always in full compliance with FDA regulations. An automated monitoring and alarming system providing high accuracy data at the point of measurement with back-up recording can make your QA/QC efficient, optimal and ready for any critical evaluation, internal or external. The continuous records that this type of system should provide could help be part of your detailed response to quality concerns outlined in a Form 483 letter.
For example, in the 483 excerpt of the food facility, which noted that “…monitoring procedures and a frequency at the refrigerated storage CCP that is, not adequate…” A continuous monitoring and alarming system would provide gap-free temperature data recording. Data loggers with long-life batteries (up to 10 years) can continue to record temperature at the point of measurement, rendering environ-mental data immune to network or power failures.
Regarding the seafood processing example, the rooms can be validated with the same equipment used to monitor. Self-contained data loggers with internal sensors, memory and battery can be equipped for “periodic testing” or mapping the temperature distribution of the containers.
Every monitoring system should have a detailed IQ/OQ change control document make validation a straightforward process.
In regard to the observations on the OTC Pharmaceutical manufacturer, the challenge of not having adequately documented temperature conditions would be solved by following the detailed IQ/OQ and SOPs provided with the monitoring, alarming and reporting system.
Some organizations compliant with GMP still use chart recorders or manual methods to track temperature and humidity. The issues with these methods are beyond the scope of this article, but as more facilities automate processes within quality assurance and regulatory compliance, relying on older technologies is and will continue to be problematic.
The FDA, with its “strong recommendations,” cannot insist that organizations upgrade to any given technology. But, a commitment to using industry-best instrumentation and systems in FDA-regulated storage, processing and critical manufacturing can stave off misgivings about a facility’s commitment to quality. It will also lower your financial risk of product damage, inspection costs and brand reputation when temperature- and humidity-sensitive products are at stake.
(1) Parts of this article were sourced, with permission, from two documents 1) “FDA 483 Responses—Compliance Considerations” by Richard Poska and Ballard Graham, as published in the Journal of Validation Technology, Winter 2010 ― available with subscription at: http://www.gxpandjvt.com/ivtnews/templates/IVTNews.aspx?articleid=1896&zoneid=27 and the FDA Presentation 2) “Writing An Effective 483 Response” presented by Anita Richardson, Associate Director for Policy, Office of Compliance & Biologics Quality at the 5th Annual FDA University RI Pharma Conference, January 2009 available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/UCM102921.pdf
(2) "FDA’s Enforcement Crackdown To Increase Inspections, Delays", Drug GMP Report - Issue No. 210, January 2010
(3) From the FDA’s Warning Letter web page: “Inspections, Compliance, Enforcement, and Criminal Investigations”