Sunday, 13 November 2011

FDA Form 483

Here is a post on Form-483, which is dreaded by managements of pharmaceutical companies!

What is Form-483?
The U.S. Food and Drug Administration (FDA) is authorized to perform inspections under the Federal Food, Drug, and Cosmetic Act, "Factory Inspection".  FDA Form 483 “Inspectional Observations,” is a form used by the FDA to document and communicate concerns discovered during these inspections. It is also referred to as "Form 483 or merely 483.
 In simple words- “It is a form which consists of all the objectionable observations by a FDA inspector during his/her inspection of manufacturing facility (Pharmaceuticals manufacturing facility in the present context)”

When is a FDA Form 483 issued?  
An FDA Form 483 is issued to firm management at the conclusion of an inspection when an investigator(s) has observed any conditions that in their judgement may constitute violations of the Food Drug and Cosmetic (FD&C) Act and related Acts. FDA investigators are trained to ensure that each observation noted on the FDA Form 483 is clear, specific and significant. Observations are made when in the investigator’s judgement, conditions or practices observed would indicate that any food, drug, device or cosmetic has been adulterated or is being prepared, packed, or held under conditions whereby it may become adulterated or rendered injurious to health.

 What is the purpose of an FDA Form 483?  
The FDA Form 483 notifies the company’s management of objectionable conditions.  At the conclusion of an inspection, the FDA Form 483 is presented and discussed with the company’s senior management.  Companies are encouraged to respond to the FDA Form 483 in writing with their corrective action plan and then implement that corrective action plan expeditiously.

Is the FDA Form 483 intended to be an all-inclusive list of every possible deviation from law and regulation?
No, it’s not. The FDA Form 483 is a report which does not include observations of questionable or unknown significance at the time of the inspection. There may be other objectionable conditions that exist at the firm that are not cited on the FDA Form 483. FDA investigators are instructed to note only what they saw during the course of the inspection.  Companies are responsible to take corrective action to address the cited objectionable conditions and any related non-cited objectionable conditions that might exist.
What are the implications of the FDA Form 483 for agency enforcement and what happens next?
The FDA Form 483 does not constitute a final Agency determination of whether any condition is in violation of the FD&C Act or any of its relevant regulations.  The FDA Form 483 is considered, along with a written report called an Establishment Inspection Report, all evidence or documentation collected on-site, and any responses made by the company.   The Agency considers all of this information and then determines what further action, if any, is appropriate to protect public health.

Disclaimers in form 483-
"This document lists observations made by the FDA representative(s) during the inspection of your facility. They are inspectional observations, and do not represent a final Agency determination regarding your compliance. If you have an objection regarding an observation, or have implemented, or plan to implement, corrective action in response to an observation, you may discuss the objection or action with the FDA representative(s) during the inspection or submit this information to FDA at the address above. If you have any questions, please contact FDA at the phone number and address above.”

"The observations noted in this Form FDA-483 [sic] are not an exhaustive listing of objectionable conditions. Under the law, your firm is responsible for conducting internal self-audits to identify and correct any and all violations of the quality system requirements."

Recent trends in form-483-
From 2002 to 2009, the dominant problem area documented on Form FDA 483 was Investigations, which are integral to good CAPA programs. Investigations accounted for 27% of the observations in 2009. The next most problematic areas were Equipment/Facilities/Operations at 11% (2009) and Validation at 10% (2009).
The FDA issued 9,910 483s in 2010, which is at least a 10-year high based on available data. Among these, the top three issues were quality unit deficiencies, inadequate batch failure investigations, and lack of follow-up procedures. For international inspections, the top three were deficient laboratory controls, quality unit deficiencies, and deficient procedures.


Thursday, 3 November 2011

Effective Dossier Management

Importance of effective dossier management-
  • The registration dossier for medicines is an important document which is submitted for review to regulatory agencies by pharma companies for approval to market their medicines.
  •  Utmost care should be taken during its compilation and filing as it plays a direct role in earliest possible availability of medicines in the market which in turn translates into business for the company.
  • Of course, regulatory affairs professionals need to ensure the safety, quality and efficacy of  the medicines for which they are filing registration dossier.
Note : The dossiers could be anything among DMF, ASMF, ANDA, NDA or MAA.

From my experience I could possibly think of 3 important aspects which play an important role in effective dossier management-

1. Planning aspects
2. Formatting and compilation aspects
3. Review aspects

1. Planning aspects-
  • Deadline-It is important to know the deadline for filing the dossier and action plan should be prepared so as to meet the deadline.
  • Understanding the registration requirements of respective agencies- Although most of the regulatory agencies accept the CTD format for registration dossier,  the requirements for approving  marketing applications may vary for individual agencies. For example- USFDA requires Batch Manufacturing Records to be provided, while it is not necessary for approval by European regulatory agencies. Hence it is necessary to completely read and understand the guidance document of each regulatory agency before going ahead with filing registration dossier with them. 
  • Requirements Listing- Listing down all the requirements for preparing the registration dossier, for example in the preparation of section 3.2.S.1 of a DMF I need to have all the information on nomenclature, structure and general properties (like pH, Pka, solubility, partition coefficient, stereochemistry etc ) of drug substance. Similarly Listing down all the requirements for preparation of all the modules and their respective sections is an important aspect.
  • Sending the requirements list to respective departments-Preparing an individual requirement list and sending them to each respective department. For example I need to have all the information regarding the general properties, synthetic scheme, manufacturing process development of drug from R & D department and finalised specification & test procedures, Batch manufacturing sheets from Quality assurance department.

2. Formatting and Compilation Aspects-


As per the ICH's M4 guideline the following are recommended-
  • The display of information should be unambiguous and transparent, in order to facilitate the review of the basic data and to help a reviewer become quickly oriented to the application contents.
  • Text and tables should be prepared using margins that allow the document to be printed on both A4 and 8.5 x 11” paper (For Europe and Japan regions A4 paper is recommended and 8.5 x 11” paper for USA).
  • Times New Roman, 12-point font is recommended for narrative text.
  • The left-hand margin should be sufficiently large that information is not obscured by the method of binding.
  • Font sizes for text and tables should be of a style and size that are large enough to be easily legible, even after photocopying.
  • Every page should be numbered, according to the granularity document (refer pages 6 to 14 of M4 guideline).
  • Acronyms and abbreviations should be defined the first time they are used in each module.
  • References should be cited in accordance with the current edition of the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, International Committee of Medical Journal Editors (ICMJE).
  • All pages of a document should include a unique header or footer that briefly identifies its subject matter.
Note: For any person who is new/relatively new to the field of RA it is important to read and understand CTD guidelines of ICH (M4, M4Q,M4S, M4E) before starting to compile any dossier. (Refer the post CTD in my blog)


The following compilation aspects are important-
  • The information should be specific, clear, precise and accurate.
  • Typographical and grammatical errors should be avoided.
  • The information should be arranged in a sequential order in computer. Each module could have a separate folder and in turn each section of a module could have a separate folder. This kind of orderly arrangement will help in easy access of information and help in taking printouts of finalized copy conveniently.
  • The line spacing should be preferably single.
  • All the documents received from other departments should be cross-checked so as to ensure that they are free from errors.
  • Ensuring the specifications & test procedures are designed in accordance with ICH guidelines Q3A, Q3B, Q3C, Q6A and Q6B. Stability Protocols are designed as per ICH guidelines Q1A through Q1E . Similarly ensuring that various documents are designed as per ICH guidelines. This can be ensured during drafting stages of preparation of various documents.
  • After the finalized soft copy is ready, printouts should be taken using a good quality printer and arranged sequentially in a module and section wise manner. 
  • As per the note given in the website of  EMA-"All Microsoft Office documents submitted to the European Medicines Agency must be in a format compatible with MS Office 2003. Office 2007 and Office 2010 formats cannot currently be accepted".

3.Review Aspects
  • .Every human being is prone to make mistakes; hence it is important to re check the information in the dossier before filing it with regulatory agencies. 
  • It is also important that a dossier meant to be filed with a regulatory agency should be cross verified by a person other than the one who has complied the dossier.
  • It is very useful to have a check list so as to ensure that all the required information is present in the dossier before submission to regulatory agency.
  • The USFDA has a check list which is very useful while filing an ANDA- ANDA checklist
  • The module 1 of CTD in most of the cases is completely different for various agencies hence care should be taken in compiling this section.

Avoiding Deficiencies-
You can learn without necessarily making mistakes. EDQM has compiled a list of top 10 deficiencies of CEP dossier which will go a long way in preventing you from making the same mistakes.

Key software skills for effective dossier management-
  • Proficiency in MS office (Yes, I know that most of you are proficient! ).
  • Proficiency in Adobe Acrobat tools. (Especially useful in preparing NeeS dossier and eCTD ).
  • Proficiency in ISIS draw or Chem sketch softwares, which are useful in drawing chemical structures.
  • Since we generally receive number of mails on a daily basis, we could sort the emails by using labels based on the sources. This will make your job easy while accessing mails.
  • eCTD is mandatory for the centralised procedures in Europe and it could be made mandatory for the other procedures as well in the future. Hence it is important to undergo training in the use of eCTD software.(My fellow Indian countrymen, let me know if there are any institutes which are offering training in the use of eCTD software back here in India)


1. This article is mainly intended to provide guidance for the  preparation of  paper format of registration dossier, but not eCTD or NeeS format.

2. I have posted this article based on my experiences. There could be other key aspects which are to be considered in preparation of registration dossier for medicines.

Keywords- registration dossier, planning aspects, formatting and compilation aspects, review aspects,  M4, M4Q, ANDA check list.

References :

Orange Book


What is Orange Book?
  • It is the commonly used name for the book “Approved Drug Products with Therapeutic Equivalence Evaluations”, which is published by USFDA.
  • It contains the list of drug products, approved on the basis of safety and effectiveness by the Food and Drug Administration (FDA) under the Federal Food, Drug, and Cosmetic Act.
  • FDA was required to publish orange book under Drug, Price and Competition Act (1984) which is also known as Hatch-Waxman Act

Orange book doesn’t cover-
  • Drugs on the market approved only on the basis of safety (covered by the ongoing Drug Efficacy Study Implementation [DESI] review [e.g., Donnatal Tablets and  Librax Capsules]
  • Pre-1938 drugs [e.g., Phenobarbital Tablets]) are not included in this publication. 

Other important facts-
  • The main criterion for the inclusion of any product is that the product is the subject of an application with an effective approval that has not been withdrawn for safety or efficacy reasons.
  • Inclusion of products on the List is independent of any current regulatory action through administrative or judicial means against a drug product.
  • The List contains therapeutic equivalence evaluations for approved multisource prescription drug products. These evaluations have been prepared to serve as public information and advice to state health agencies, prescribers, and pharmacists to promote public education in the area of drug product selection and to foster containment of health care costs.
  • Therapeutic equivalence evaluations in this publication are not official FDA actions affecting the legal status of products under the Act.

We can search all the orange book listed approved drug products in the FDA’s website by using any of the following search options
  • Search by Active Ingredient
  • Search by Applicant Holder
  • Search by Proprietary Name
  • Search by Application Number
  • Search by Patent

Keywords: Approved Drug Products with Therapeutic Equivalence Evaluations, Orange Book, Drug, Price and Competition Act or Hatch-Waxman Act, DESI.