Wednesday 20 January 2016

eCTD Issues for ANDA Submissions

Post the implementation of GDUFA, in the current year 4 cohort of FY 2016, there has been a very significant positive change with respect to ANDA review timelines. The initial screening deficiencies/ information requests or acceptance letters are generally being issued within 1 month of filing ANDAs. The most important screening deficiency/information request issued by USFDA is related to eCTD aspects, which in general is given least importance. RA professionals generally ensure to meet the requirements of ANDA Filing Checklist, which doesn’t summarize the eCTD requirements in detail, but gives a link to USFDA website where we get all the guidelines and eCTD requirements details.

In this post, the below listed eCTD aspects will be discussed in detail, as they are important for avoiding eCTD related deficiencies.
  • PDF Document Properties
  • Fonts and Font Sizes
  • Embedding of Non –Standard Fonts
  • Bookmarks  and Hyper Linking
  • Requirements of Scanned Documents
  • Leaf Title Naming (for eCTD XML)

PDF Document Properties
  • The file name is to be given in abbreviated form with the use of small letters.”Hyphens (-)” should be  used in place of spaces.”Full Stops (.)”, should not be used.
  • The title is generally not given under document properties.
  • The acceptable PDF Versions are 1.4 to 1.7. Irrespective of the version of Adobe Acrobat, PDF Version should be anything from 1.4 to 1.7 only.
  • There should not be any security passwords for opening the document
  • “Fast Web View”, should be yes. If “Fast Web View” option is being displayed as “no” it has to be changed to “Yes” as per following procedure - go to “File” option in the menu bar of PDF File, go to “Save As Other”, then “Reduced Size PDF”. Under “Make Compatible with” option “Acrobat 5.0 and later” or “Acrobat 6.0 and later” should ideally be selected. Next “Ok” should be selected. Finally, the file in which this correction is being done, should be replaced (We get a message – “The file already exists. Replace existing file”. We should select “Yes” option). After this procedure, we should ensure PDF version is anything from 1.4 to 1.7 only.
  • For Submissions to USFDA, Pages size should be 8.50 x 11.00 in.
  • Under Initial View tab - Navigation tab should be set to “page only”, if the numbers of pages are less than 5 and there are no bookmarks. Any PDF file with more than 5 pages should be bookmarked in which case; navigation tab should be set to “Bookmarks Panel and Page”. Page Layout and Magnification should be set to “Default”.
  •  The maximum length of the filename should be 64 characters.
  • The leaf element path length should not exceed 230 characters.

Fonts and Font Sizes
  • Times New Roman 12-point font, is recommended and should be preferred for narrative text.
  • Point sizes 9-10 are recommended for tables; smaller point sizes should be avoided.
  •  Point Size 10 is recommended for footnotes.

Embedding of Non –Standard Fonts
  • All the non – standard fonts should be embedded. PDF viewing software, substitutes non-standard fonts if the font used to create the text is unavailable on the reviewer’s computer.
  • In some cases, substitution of standard fonts like Helvetica or Times is done by PDF viewing software.
  • Font substitution can affect a document’s appearance and structure, and in some cases it can affect the information conveyed by a document. Hence, embedding of fonts should be ensured.
  • However, embedding of font should be avoided for labels and electronically signed documents.
  • The table with list of standard fonts are provided below.

     Image Courtesy: Portable document format specifications guidance of USFDA
Note: There are multiple procedures for “embedding font”. You could Google it and follow. If you are facing any difficulty, I’ll be happy to help out.

Bookmarks and Hyper Linking
  • There should be appropriate number of bookmarks in the document. The number of bookmarks should be neither less nor more.
  • The number of sub heading trees within book marks should be limited to 3 or 4.
  • If there is table of contents in the document, the bookmarks should exactly match with the table of contents (naming and number of bookmarks).
  • The trick for giving bookmarks using Adobe Acrobat – Go to the page where bookmark is to be given, select the hand tool and go exactly to the title where the bookmark is to be given (it is to ensured that, no text is visible above bookmark title) and select the text, press control + B, the title automatically appears in the bookmark panel (if there are errors in bookmark title due to misreading of software, correct it manually), right click on title and press set destination, finally click on all the bookmarks and check whether they are going to exact destination.
  • Hyper linking of texts to the destination is to be ensured, wherever applicable.

Requirements of Scanned Documents
  • It commonly happens that, clarity of documents is not checked before submitting to the Agency. If we are not able to read a document due to lack of clarity, we definitely cannot expect the reviewer to read the document.
  • The probability of Plant Layouts lacking clarity is more. Hence, clearly scanned Plant Layouts should be submitted.
  • Please refer the below table for scanning resolution requirements –

     Image Courtesy: Portable document format specifications guidance of USFDA
    Leaf Title Naming (for eCTD XML)
  • The Leaf Title should be elaborate, considering ICH M4, M4Q guidelines, without the use of hyphens (-), full stops (.).
  • Abbreviations should not be used.
  • Examples of Correct and Incorrect Naming of eCTD Leaf Titles are provided below –Correct Naming – Description and Composition of the Drug Product                 Incorrect Naming – desc-comp-dp
Note –
  • The above post could also be considered for NDA submissions.
  • I have listed the most important aspects which are to be considered to avoid eCTD Deficiencies. Please refer the below references for complete information related to eCTD.
  • For submissions with clinical data, “Study Tagging Files” requirements are also to be considered.


Sunday 3 March 2013


History and background of GDUFA:
  • The one hundred twelfth congress of the United States of America at the second session on 3rd January,  2012, amended the Federal Food, Drug, and Cosmetic Act to revise and extend the user-fee programs for prescription drugs and medical devices, to establish user-fee programs for generic drugs and biosimilars and for other purposes.
  •  This act may be cited as the “Food and Drug Administration Safety and Innovation Act”.
  •  The amendment is referred to as Generic Drug User Fee Amendments of 2012 (GDUFA).
  •  On July 9, 2012, the Generic Drug User Fee Amendments of 2012 (GDUFA) was signed into law. 
  •  On Oct. 1, 2012, FDA implemented the Generic Drug User Fee Amendments of 2012 (GDUFA) 

What is GDUFA and why was it implemented by FDA?
  • GDUFA is Generic Drug User Fee Amendments of 2012 (GDUFA). GDUFA was implemented to speed the delivery of safe and effective generic drugs to the public and reduce costs to industry.
  • Under GDUFA, certain facilities, sites, and organizations must self-identify and may be Subject to user fees.
  • GDUFA requires industry to pay user fees, which will supplement the costs of reviewing generic drug applications and inspecting facilities.
  • The money earned by FDA through GDUFA will help FDA to reduce a current backlog of pending applications, cut the average time required to review generic drug applications for safety, and increase risk- based inspections.
  • GDUFA is designed to build on the success of the Prescription Drug User Fee Act (PDUFA).  Over the past 20 years, PDUFA has ensured a more predictable, consistent, and streamlined premarket program for industry and helped speed access to new, safe and effective prescription drugs for patients.  
  •  GDUFA will also enhance global supply chain safety by requiring that generic drug facilities and sites around the world self-identify. 

Self-Identification:  All the facilities which manufacture, or intend to manufacture, human generic drug APIs or FDFs, or both are required to self-identify. Under GDUFA, Self-identification is necessary to determine the universe of facilities required to pay user fees, and is a central component of an effort to promote global supply chain transparency. This information will enable quick, accurate, and reliable surveillance of generic drugs and facilitate inspections and compliance.

The Facilities/ Entities/Sites/ Organizations which are not required to pay annual facility fee -
  • Generic entities that solely manufacture positron emission tomography (PET) drugs
  • Clinical bioequivalence or bioavailability study sites
  • In vitro bioequivalence testing or bioanalytical testing sites
  • Active pharmaceutical ingredient (API)/finished dosage form (FDF) analytical testing sites
  • Packagers and repackagers.

Penalty for failure to self-identify: All FDFs (Finished dosage forms) or APIs (Active Pharmaceutical Ingredients) manufactured in the facility, and all FDFs containing APIs manufactured in the facility will be deemed misbranded. This means that it will be a violation of federal law to ship these products in interstate commerce or to import them into the United States.

As stated in the earlier section of this post, user fees have to be paid by the industry to supplement costs of reviewing generic drug applications and inspecting facilities.

The various types of GDUFA fees, which were effective on October 1st 2012, are listed below-
Back log Fee- The ANDA, that has not been withdrawn, which has been under review, got tentative approval, that was submitted as on September 28th, 2012 is considered for back log fee. The FDA calculated the fee as $17,434.

DMF Fee- The Type II active pharmaceutical ingredient (API) DMF that is referenced, on or after Oct. 1, 2012, in a generic drug submission by an initial letter of authorization (LOA) is considered for DMF fee. The DMF fee For Year 2013 is calculated as $21,340. It is a one-time fee for each individual DMF, incurred on first reference of the DMF on or after Oct. 1, 2012..

ANDA and PAS Fee- The ANDA which is filed with FDA on or after October 1st, 2012 is considered for ANDA fee. The ANDA fee for year 2013 is calculated as $51,520. PAS fee is considered for any approved ANDA for which Prior Approval Supplement (PAS) [PAS is filed to notify and seek approval of FDA for any major change in an approved ANDA] is filed. The PAS fee for year 2013 is calculated as $25,760. The PAS fee is half the fee of new ANDA

FDA’s Refuse to File Policy with respect to GDUFA
  • GDUFA adds a new requirement to FDA’s existing refuse to receive policy with respect to payment of fees and the time of receipt of an ANDA.
  •  Failure to pay an ANDA fee within 20 calendar days of the applicable due date will result in the ANDA not being received.
  • Failure to pay the fee for a DMF referenced in the ANDA within 20 calendar days of the date that FDA provides notification of that failure will result in the ANDA not being received.
  • Failure to pay a facility fee for any facility referenced in the ANDA within 20 calendar days of the date that FDA provides notification of that failure will result in the ANDA not being received.
  • If an application is substantially complete except for failure to pay the ANDA fee, or the failure to pay the facility fee within 20 days of notification, the application will be deemed received as of the date the fee is paid.

My Take on GDUFA:
The landmark Hatch and Waxman act paved the way for fast track approval of generics in USA, which resulted in large scale entry of generic players into the market over a period of time.  The presence of generics was kind of, win-win situation for Government, Insurance companies and patients alike, as generics resulted in saving billions of dollars to them.

The numbers of ANDAs filed are rapidly growing, which were around 900 in the year 2011. The numbers of ANDAs pending for review were about 2600 in the year 2011. So, obviously it made the job tough for FDA. Hence, the fees earned will help the FDA to increase its resources and expedite the approval process of ANDAs.

The GDUFA may superficially seem to be burdensome for generic companies. However, for the generic companies which are serious to have their ANDA approval in the fact track and gain market share as soon as possible, the GDUFA is positive news.

Five years down the line after implementation of GDUFA, the FDA has given commitment that, it will review and act on 90 percent of complete electronic ANDAs within 10 months after the date of submission. This is fantastic news, as the generic companies could get their ANDAs approved within 10 months of their filing for conventional generic drugs.

References –

Rajesh Yelugoila