US FDA Form 483 and Warning Letter Analysis, Response, and Recovery

1. US FDA Form 483 and Warning Letter Analysis, Response, and Recovery Form 483 and warning letters are worry some or warning words for all those who are in Pharmaceutical and Medical device field. Those who deal with US FDA and doing business of Pharmaceuticals and Medical device in USA are most concerned when these two things appear. Even senior management gets concerned. Senior management may not get worried about some major observation in the internal audit which may be worth warning latter but gets worried for 483. Getting 483 is not so uncommon but passing the investigational audit without 483 becomes more prestigious than some other more important event of organisation. As we all know that 483 is issued at the end of investigational observation by investigator which is officially also called “Notice of inspectional Observation”. This observation is quality system deficiency observed by Investigator. Investigator also presents this 483 to his seniors. If the reply prepared for this 483 describing your approach for addressing this 483, is not found satisfactory, warning letter is issued. This becomes more serious action on the organisation. As not having 483 or warning letter becomes prestige for the organisation, having received warning letter becomes blot on the organisation and all who are in this world can read this warning letter. There are many other reasons to get warning letter like organisations do changes to their marketed devices and do not inform US FDA. When changes significance are not acceptable andwhen found by FDA, warning letter is issued. So now we all know that having received the 483 or warning letter, organisation’s first focus should be on how to address this issue so if 483 is issued, the firm becomes compliant to 483 and it does not get converted to warning letter. If warning letter is issued out of 483 or any other reasons, focus must be on how to analyse, respond so that you recover from this issue successfully. Primarily, action is to reply to FDA promptly with proper response to 483 or warning letter. The letter should clearly describe your action plan within US FDA defined timeline. Detailed answer to each observation and violation mentioned in 483 or warning letter is needed. The quality and promptness in response is key. If organisation feels that internal resource may not be an expert to address these issues, it is worth taking US FDA consultant’s support in review and drafting of reply so you become form 483 compliant and also address the warning letter effectively with 100 % success rate. It is quite likely that some time warning letter may result into recall. If this situation arises then apart from addressing this response, there are several actions may emerge out of recall. Such actions are surveillance, vigilance, field safety corrective actions and of course recall itself. Let us review actions internally before response, 1.Review 483 and/or warning letter and analyse each word of it. The content of violation can be on manufacturing condition including quality system, problems on claims product can do or incorrect directions of use. 2.Chart out course of action within organisation with detailed description and within.US FDA timeline. 3.Propose corrective plan for your quality system. For example, the violation is found with validation, it is not just to address issue of violation found in specific product but your action

2. plan must describe how you will work this validation issue in your quality system so this issue never arise for product in question or any other product. 4.Make an appropriate team with resources to implement corrective action plan. 5.This team with regulatory person/s should be available with priority time to address all questions from FDA during your course of action. FDA may issue close out letter for warning letter. (This applies to only warning letters issued after September 1,2009) This letter is issued by FDA only after learning that the firm has completed the corrective action satisfactorily. This way the firm comes out of warning letter issue. The closeout letter is not issued on representation of the firm that the action has been taken but it is verified by FDA. If the warning letter contains violations that are not correctable, then no close out letter will be issued. FDA will see in their future inspections about the adequacy and sustainability of such actions and if again some violation is observed during inspection or through other means, enforcement action may be taken without further notice. The FDA office that issued warning letter will issue close out letter also and that office will be the right source on any information concerned to warning letter.