How to Respond to (and Avoid) FDA Form 483s for Controlled Environments

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No cGMP manufacturer wants to receive a Form 483 letter. In such stringently controlled industries as pharmaceutical/biotechnical development, manufacturing and warehousing, receiving a list of deficiencies can feel like a heavy blow to your quality system. Worse, with the recent increase in enforcement staff¹ and the September 2009 change to the response time—now 15 days—the FDA appears to be ramping up its enforcement mandate² .

The following article features four excerpts from some of the more common observations noted in Form 483 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 validate containers for Human Cell & Tissue Products to a lack of temperature records in an aseptic processing area of a drug manufacturing facility.

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 documenting 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 Contract Pharma manufacturer:

Records showing periodic validation/mapping of an environment can be as important as your continuous monitoring records.

Requirements for stability testing of drug products are not being met. For example, you do not have, as part of the storage condition, any documentation that stability samples are maintained at the designated temperature [21 CFR 211.166(a)(2)]; and you do not have appropriate stability data to support the 4 year expiration date for the product. [21 CFR 211.166(b)]”

Sample Deviation #2

To a Medical Device Manufacturer:

“Procedures for the control of manufacturing and storage areas where environmental conditions could be reasonably expected to have an adverse effect on product quality were not adequately followed [21 CFR 820.70(c). Relative Humidity readings of 19% and 20% -- which fall below your specified limits...were disclosed in your failure investigations work area...”

Sample Deviation #3

To a blood bank:

Failure to have quality control procedures and follow those procedures for periodic tests of containers to maintain proper temperature...as required by 21 CFR 606.160(b)(5)(iv)...

Sample Deviation #4

To a manufacturer of OTC Pharmaceuticals:

Failure to establish and maintain procedures to adequately control environmental conditions, as required by 21 CFR 820.70(c). Specifically, temperature conditions within the aseptic processing area are not being documented to ensure such conditions are consistently within established specifications...

For example, during the inspection we observed that your firm was recording the relative humidity (RH) in the processing room, but not in the sterilization chamber. We also observed that your firm was not maintaining or reviewing the temperature recorder charts generated during your sterilization process of [product x]...”

None of the deviations excerpted here are unique, but all are avoidable. There is no regulatory requirement to respond to a 483. According to the agency, they are merely “…inspectional observations, and do not represent a final agency determination regarding your compliance.” Sort of like an offer to help you with your compliance concerns. However, not responding quickly and carefully will most likely result in further investigation. In addition, all Warning Letters are posted on the FDA's site⁴ in html format and are indexed by search engines. Once you receive a 483, all anyone needs to do is type [Your Company Name] + FDA (or 483) into the search box, and there you are.

A long list of ORA postings of 483s, some of which may note "recurrent observations" will likely initiate more frequent visits from investigators and may degrade the trust of client companies and other stakeholders. The only way to ensure that doesn't happen is a fast response showing a definitive outline of corrective actions. If receiving a 483 can initiate a quality system overhaul, then your response can be simplest way to start the planning process. Format your response as much for your own benefit as to mitigate further action from the FDA.

How to Formulate the Right Response

Customize your reports to the level of detail that auditors and enforcement staff expect. Search the FDA's Investigations Operations Manual to learn what inspectors are looking for.

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 a bit more complex — 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. These items may not be the first on the form, but they should be first in your response.
   
   
5. Be detailed yet concise, but provide support documents to accompany your cover letter. Outline how and when each deficiency will be corrected (rather than how you feel the deficiency came to be), and provide documentation of a corrective action commitment from the person responsible for it.
   
   
6. Use positive statements; avoid language that implies fault. Make it clear in your tone that you regard each item in the 483 as an opportunity to fine-tune your quality and compliance systems.
   
   
7. Include reference to how you will be forwarding evidence to support the correction. For example, “<Your Company>will use a validated monitoring and alarming system to provide reports on temperature recordings taken at 10 minute intervals month-by-month.” Product specifications and protocols of applications you use to create records can be provided in your support documents to accompany your corrective action plan.
   
   
8. If the inspector noted something that you feel was an isolated incident, note it in your response. However, be 100% certain that you can back this up and that your data is complete and accurate. If you find some of the observations were in error, 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 (see below)
   
   
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. If you need to fine-tune your quality systems, a good place to start is the guide to what FDA inspectors are looking for, which is contained in the agency's Investigations Operations Manual.⁶
   
   
10. If you need clarification, seek it—in writing and from the correct party. Ideally, when the investigator handed you the Form 483 after the inspection you asked a lot of questions to clarify each observation. Try to be sure you understand each deviation before the inspector leaves your facility and make notes while he/she is explaining their observation. If your questions involve policy, contact the FDA headquarters — don't contact your local FDA because policy is set at HQ.

And... 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.

Avoiding 483s with Continuous, Automated Monitoring

Once you customize and configure reports, keep them consistent for future inspections and audits.

Ideally, your regulated environments and equipment are always in full compliance with FDA regulations. A continuous monitoring system that provides a gap-free audit train can keep your facility ready for any critical evaluation, internal or external. The continuous records that this type of system provides can also serve as part of your support documents in responding to quality concerns outlined in a Form 483 letter. If the records are secure, showing all interactions with the system and conditions within each monitored environment over a given time-frame, you have easily retrievable documentation for any inspector.

For example, one 483 issued to a CMO noted that they were lacking “documentation that stability samples are maintained at the designated temperature." The reason for such gaps in data can include facility downtime due to network or power failures, periods with no personnel to check a recording instrument or fill in a manual log.

A simple solution can be sensor-equipped data loggers with long-life batteries (up to 10 years) to record temperatures continuously at the point of measurement. If the logger includes a large memory that is independent of the facility infrastructure (network, power) the data is essentially immune and will be available when you download the logger.

In the above 483 issued to a blood bank, the storage units could have been validated with the same data loggers used to monitor. Self-contained data loggers with internal sensors, memory and battery can be equipped for periodic mapping to record the temperature distribution of the containers.

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.

Every monitoring system should have a detailed IQ/OQ change control document make validation a straightforward process.

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 cannot insist that organizations upgrade to any given technology. But, a commitment to using industry-best instrumentation and systems in FDA-regulated manufacturing processes and environments can stave off misgivings about your facility's commitment to quality.

Vaisala's Continuous Monitoring System

For information on keeping your regulated environments inspection proof and audit ready with Vaisala's continuous monitoring solution, call 800-683-8374, or email veriteqinfo@vaisala.com.