FDA form 483 observations and warning letters - what is the difference

1. FDA form 483 observations and warning letters - what is the difference? USFDA uses the structured way of communicating to Pharmaceutical or medical device field entities to communicate their observation during audit. In Medical device field if firm deals in Class II or Class III categories then USFDA inspection is expected every two years. Inspector conveys his finding of non-compliance observation in the defined form called form 483. The observations are listed in order of most significant to less in that order. The investigator issues this along with EIR-Establishment investigation report. This is also discussed during closing meeting and firm can ask question, understand well observation,and try to resolve them if they find less significant and minor and some time show some evidence of action or completion of action before inspector leaves. The form 483 and EIR both are also studied at district level and higher level. If the district office or higher-level office find the one or more listed 483 observation as serious enough, a warning letter is issued which is more formal communication of genuine issue with firm requiring immediate action by firm including withdrawal of product from market if USFDA as well as firm agrees that issue described in Warning letter is present or potential significant issue with product. The warning letter is usually issued by higher ups in USFDA and not by investigator doing audit. Once form- 483 is issued its compliance is essential: Very first step is usually to respond to USFDA within 15 days maximum. The same is also applicable to warning letter.

2. Please understand that issuance of form 483 or Warning letter is not end of your product or company if you follow Form 483 compliance or form 483 remediation action. The same is applicable to warning letter also. If you are not so much familiar with all such issues, just do not start on your own way but approach experts who are well versed with such issues handling. Form 483 compliance and remediation: Once the form is issued, take those observations seriously. Issues observed by investigator those are questionable or negligible significance will not appear in form. (Though it is good practice to address those too internally.) All listed observations are not the final determination of your compliance, however not responding to them result into warning letter. Please also remember that product does not mean the physical object put in market, documentation associated with that also becomes product and its compliance is must. Like improper validation or slight lacunae in meeting the acceptance criteria may result into noncompliance and may be treated as potential risk to product. This may result the withdrawal of product. Following steps are recommended as general: Please ensure that you and investigator both understand the correct meaning of the same. Discuss and clarify if needed before he/she leaves the site. It is also important that Investigator got correct understanding of situation which you also agree. Ensure that text version of the observation is also correctly drafted. Once investigator leaves the site it will be almost impossible to get the text changed. Fix any observations which are possible to do in Investigator’s presence and provide objective evidence. Do not attempt to resolve everything and urge before investigator leaves the site. This will create an impression that firm does not want to put resource for investigating the issues. Make CAPA plan. Understanding of root cause and not cause, is especially important. Assess that issue with product impact. Take voluntary action if there is clear public safety risk. Hold current inventory which is not distributed yet. CAPA should investigate for identified and systemic issues. All actions which may even need update and generate procedure, conduct training as needed, conduct full internal audit and identify any other gap, gather all objective evidence. Ensure that test methods processes are revalidated if needed. Though for medical device companies are allowed to annotate the observations to provide context directly in the form 483, it is not advisable to do so as form 483 is going to go in public domain. Write and submit response which should be amazingly effective and presented in such a way that USFDA has no difficulty in going through your submission, references and attachments. Your submission should be aimed at your customer who is going to be USFDA. What it expects from you and accomplish all those documents. General Guideline on documentation submission.

3. 1.Cover letter. Do not forget to thank FDA for providing an opportunity for improvement. 2.Body: Restate each observation in the same text as given in form. Provide background about the observation. Include following for each observation. a.CAPA action. Immediate correction where possible with completion date (attach objective evidence) otherwise target date. b.Assessment of root cause suggested actions and target date. c.Preventive action (Particularly if any systemic issue found) d.Reference to objective evidence to be included as attachment.  Mention commitment to provide follow up response per specific date. List of attachments. Each one to be identified with some ID with reference described in above observation. They should be easy to locate, and reviewer should manage it very easily. Some important aspects for writing response. oBe clear and make it simple for it to understand easily. (If required get it verified) oAnswer to focus on key issues raised and provide accurate objective evidence anticipating answer to potential questions. oIf you feel strongly to dispute some observation, carefully manage it by providing factual objective evidence which should be convincing. Support all claims with facts and data. (“Just the facts sir/madame” start your sentence with each fact and data. (Third party experts may be hired) IZiel can help companies understand the gaps in their design and development process in a methodical and comprehensive manner. IZiel’s process-driven & outcome-based delivery approach, quick scalability of resources, sound project management and flexible onshore- offshore model throughout all phases of the remediation are the key enablers of success. IZiel can provide quick scalability of the skilled resources with knowledge of Design, Process Engineering & Validation, Systems Engineering, QMS and Regulatory to achieve outcome- based deliveries. The IZiel team comprises of experts in the Medical Device Industry and has a highly trained and experienced offshore team. This team not only consults but also helps in implementation of the solutions identified. The professional advice from experts will smoothen this process and save time. Go for it.