FDA Warning letter

FDA WARNING LETTER IS A OFFICIAL LETTER FROM USFDA TO A MANUFACTURING FIRM TO NOTICE THE SERIOUS VIOLATION FOUND AT THE FDA INSPECTION AT FIRM AND THE CORRECTIVE ACTION SHOULD TO TAKEN BY FIRM TO OVERCOME THE VIOLATION FOR FDA APPROVAL

1. FDA WARNING LETTER Presented By:- Sridhar S 1 st M.Pharmacy Pharmaceutical Regulatory Affairs JSS College Of Pharmacy Mysuru-15

2. DEFINITION An FDA warning letter is an official message from the United states Food & Drugs Administration (FDA) that it has found that a manufacturer has violated some rule in a regulated activity. While the FDA generally determines violations through its own inspections, they can also issue one based on evidence from state personnel  the FDA does not consider a warning letter a final action on which it can be issued

3. The FDA defines an FDA warning letter as:- “A correspondence that notifies regulated industry about violations that FDA has documented during its  inspections or investigations. Typically, a Warning Letter notifies a responsible individual or firm that the Agency considers one or more products, practices, processes, or other activities to be in violation of the Federal Food, Drug, and Cosmetic Act (the Act), its implementing regulations and other federal statutes. Warning Letters should only be issued for violations of regulatory significance, i.e., those that may actually lead to an enforcement action if the documented violations are not promptly and adequately corrected. A Warning Letter is one of the Agency’s principal means of achieving prompt voluntary compliance with the Act.

4. The agency has a computer application called the Compliance Management System (CMS) that district offices use to electronically submit warning letter recommendations to FDA Centers. All district office must use the CMS to submit the warning letter recommendation, the  Form FDA 483  that supports the alleged violations, the Establishment Inspection Report (EIR), and any written response from the firm .

5. WHY FDA COMES FOR INSPECTION The person who involved in the manufacturing of bulk API or involved in the formulation of product are willing to sale or market there product in the regions of the united states The dossier is submitted according NDA for new product and ANDA for generic drug and 502(f)(1) for an API or bulk chemical

6. After the dossier or application is accepted by the USFDA and send a reply for the inspection of the premises FDA FORM 482- Notice Of Inspection It is an official notice of FDA for inspection signed by the FDA officials. It is produced by the inspector and has the authority to inspect the manufacturing facility Inspection coordinator will receive the notice and manage the inspection accordingly

7. Coordinator should ask for notice, if it is not presented by the FDA inspector A copy of this shall be attached with the inspection file FORM 482 shows that inspector has authorization from FDA to inspect the facility An inspector can ask for the manufacturing records of the regulated product and can enter in the area where the product is being manufactured .

8. He can review online records, collect samples and interview the personnel working in area An inspector cant review the product price list, financial data of firm, product marketing data, research documents and employee data excluding the training records. These documents are considered as firms confidential documents

9. FDA FORM 483 – Observations of inspection Inspector shall provide the list of his observations about inspection on FORM 483 It has all the points noticed by the FDA inspectors. An observation made in previous inspection or as mentioned in the GMP are not followed or corrected can be added in 483 The original copy of the FDA Form 483 is presented to the form management, generally to the person who had received the notice of inspection

10. FDA Form 484- recipient of Samples During the inspection if FDA inspectors want to take any sample they have to issue a receipt of those samples on Form 484 It has a quantity of simple with the lot number of the product sampled Form 484 is used for samples only but not for promotional material, labels, photographs or any record taken by FDA investigators

11. TYPES OF WARNING LETTERS General FDA Warning Letters Tobacco Retailer Warning Letters Drug Marketing and Advertising Warning Letters (and Untitled Letters to Pharmaceutical Companies)

12. General FDA Warning Letters When FDA finds that a manufacturer has significantly violated FDA regulations, FDA notifies the manufacturer. This notification is often in the form of a Warning Letter.  The Warning Letter identifies the violation, such as poor manufacturing practices, problems with claims for what a product can do, or incorrect directions for use.  The letter also makes clear that the company must correct the problem and provides directions and a timeframe for the company to inform FDA of its plans for correction.

13.   FDA then checks to ensure that the company’s corrections are adequate.  Matters described in FDA warning letters may have been subject to subsequent interaction between FDA and the recipient of the letter that may have changed the regulatory status of the issues discussed in the letter .

14. Tobacco Retail Warning Letters Compliance check inspections of tobacco retailers occur periodically, and are conducted to determine a retail establishment’s compliance with the Federal Food, Drug, and Cosmetic Act, as amended by the Family Smoking Prevention and Tobacco Control Act (Tobacco Control Act) and its regulations in effect such as the Regulations Restricting the Sale and Distribution of Cigarettes and Smokeless Tobacco to Protect Children and Adolescents, found at Title 21 of the Code of Federal Regulations, Part 1140

15. 21 C.F.R. Part 1140 CIGARETTES, SMOKELESS TOBACCO, AND COVERED TOBACCO PRODUCTS Prohibition of sale and distribution to the persons younger then 18yrs of age and  Format and content requirements for labeling and advertising. Tobacco products covered in compliance check inspections of tobacco retailers include cigarettes and smokeless tobacco. All other Warning Letters issued by CTP for violations of the Federal Food, Drug, and Cosmetic Act, as amended by the Tobacco Control Act and its applicable regulations, can be found at FDA’s main Warning Letter page at the Inspections, Compliance, Enforcement, and Criminal Investigations - Warning Letters page.

16. Drug Marketing and Advertising Warning Letters These letters are supplied by the CDER Freedom of  Information Office (FOI).  This page only covers letters issued by Headquarters and the Office of Prescription Drug Promotion (formerly the Division of Drug Marketing, Advertising, and Communications). "Cyber" letters are sent electronically via the Internet to web sites that offer to sell online prescription drugs that may be illegal.  The letters warn these web site operators that they may be engaged in illegal activities and informs them of the laws that govern prescription drug sales.  

17. Warning Letter Close-Out Letter Program (Applies to letters issued on or after Sept. 1, 2009) FDA may issue a Warning Letter close-out letter ("close-out letter") once the Agency has completed an evaluation of corrective actions undertaken by a firm in response to a Warning Letter. A close-out letter may issue when, based on FDA’s evaluation, the firm has taken corrective action to address the violations contained in the Warning Letter. This procedure applies to Warning Letters issued on or after September 1, 2009.

18. A close-out letter will not be issued based on representations that some action will or has been taken. The corrective actions must actually have been made and verified by FDA. If the Warning Letter contains violations that by their nature are not correctable, then no close-out letter will issue. Future FDA inspections and regulatory activities may further assess the adequacy and sustainability of these corrections. Should violations be observed during a subsequent inspection or through other means, enforcement action may be taken without further notice

19. HOW TO BROWSE WARNING LETTERS Use any of these "Browse " functions: Browse Warning Letters by Company Browse Warning Letters by Issuing Office Browse Warning Letters by Subject Browse Warning Letters with Response Letters Browse Warning Letters with Closeout Letters

20. REFERENCE https://en.wikipedia.org/wiki/Form_FDA_483 http://www.pharmaguideline.com/2014/11/fda-forms-issued-in-inspections.html https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm278624.htm https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=1140