How to Respond to 483 Letters?

Here are some tips — some simple, some a bit more complex — for responding appropriately to 483 letters:

[b][COLOR=“blue”]-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.

-In the first paragraph of the response letter, be explicit in your understanding of and desire to comply with FDA regulations.

-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.

-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.

-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.

-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.

-Include reference to how you will be forwarding evidence to support the correction. For example, “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.

-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.

-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.

-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. [/color][/b]

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.

Hi Druga prasad

Lot of info you have been giveing on validations and Thank you very much.

For recent devlopments and any presentation in prcess validation pl suggest me some sites


You are welcome.
I think most of the free sites do not have the information you get in this site.
Some of the paid membership sites are
these are important.
Along with these FDA, TGA , ICH,WHO & EUDRA sites are very important


Some good points here. From my expereience, be sure to clarify in each item the exact or estimated completion date–item by item-- as to when each item will be completed/established. Mind you, you need to have your CEO or his/her deputy to sign off on the CAPA plan. The agency holds management with executive responsibility accountable for making the plan happen. Keep in mind that lack of diligence and follow-through on any comittments outlined you run the risk of the agency escalating the issue to a warning letter or possible other sanctions. Timely follow through and a well thought out plan is paramount. In case the 483 mentioned product issues, be sure to conduct a risk mitigation of all product up stream and down stream and address your remedial CAPA/activities in your response. As the agency’s charter is to protect the public health from adulterated or misbranded product, they expect you to demonstrate in writing that you’ve investigated thoroughly any concerns identified in their report.

Jerome Council
Quality Compliance Specialist.

Yes, your points are all valid and they infact true. Thanks for posting comments. Iam writing soon in my next post how to write CAPA & Risk mitigation due to an event when 483 were issued.

Form 483
This form with the eponymous number 483 is used by the investigator conducting the investigation (FDA investigator) in order to document his findings. It is delivered directly at the end of the inspection and should be answered officially. The answer is expected within 15 working days after issuing Form 483. This is the only way to ensure that the response is taken into account when a warning letter (see below) is issued. However not in every inspection a Form 483 is issued.

EIR: Establishment Investigation Report

The EIR is issued by the investigator in addition to Form 483. This should be done within 30 working days. The EIR will then be reviewed by the competent FDA centre. The following statuses are assigned:

NAI: No Action Indicated - there were no objectionable conditions found during the inspection.

VAI: Voluntary Action Indicated - there were objectionable conditions found but the authorities do not need to take any measures. All measures (CAPAs) by the company are taken on a voluntary basis.

OAI: Official Action Indicated - there were objectionable conditions found and further regulatory action is initiated.

The EIR is made available to the inspected company, but it can also be requested by other companies under the so-called “Freedom of Information Act”. Experience has shown however that it can take quite a long time until an external EIR is transferred.

Warning Letter

A Warning Letter is issued especially in the case of serious findings or if the response to Form 483 is classified as inadequate. After the review by the competent centre, the District Offices issue the warning letters and not the investigator himself. The company is obliged to comment in due time and explain in detail how the failure will be corrected and its recurrence prevented (CAPA).


ORCA_Presentation_May18_2010.pdf (309.5 KB)