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Drug Master Files (DMFs) and it submission

Pharmaceutical Guidanace October 12, 2020 QA & QC , Quality Assurance Comments Off on Drug Master Files (DMFs) and it submission 2,802 Views

Drug master files (DMFs) are submissions to FDA used to provide confidential, detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of human drug products. They:

• Allow parties to reference material without disclosing DMF contents to those parties.
• Are not required by statute or regulation.
• Are neither approved nor disapproved. Instead, FDA reviews the technical contents of DMFs in connection with the review of applications that reference them (e.g., NDAs, ANDAs, INDs, BLAs)

(a) A drug master file is a submission of information to the Food and Drug Administration by a person (the drug master file holder) who intends it to be used for one of the following purposes: To permit the holder to incorporate the information by reference when the holder submits an investigational new drug application under part 312 or submits an application or an abbreviated application or an amendment or supplement to them under this part, or to permit the holder to authorize other persons to rely on the information to support a submission to FDA without the holder having to disclose the information to the person.

FDA ordinarily neither independently reviews drug master files nor approves or disapproves submissions to a drug master file. Instead, the agency customarily reviews the information only in the context of an application under part 312 or this part.

A drug master file may contain information of the kind required for any submission to the agency, including information about the following: (1) [Reserved] (2) Drug substance, drug substance intermediate, and materials used in their preparation, or drug product; (3) Packaging materials; (4) Excipient, colorant, flavor, essence, or materials used in their preparation; (5) FDA-accepted reference information. (A person wishing to submit information and supporting data in a drug master file (DMF) that is not covered by Types II through IV DMF’s must first submit a letter of intent to the Drug Master File Staff, Food and Drug Administration, 5901–B Ammendale Rd., Beltsville, MD 20705– 1266.)

FDA will then contact the person to discuss the proposed submission.

(b) An investigational new drug application or an application, abbreviated application, amendment, or supplement may incorporate by reference all or part of the contents of any drug master file in support of the submission if the holder authorizes the incorporation in writing. Each incorporation by reference is required to describe the incorporated material by name, reference number, volume, and page number of the drug master file.

(c) A drug master file is required to be submitted in two copies. The agency has prepared guidance that provides information about how to prepare a well organized drug master file. If the drug master file holder adds, changes, or deletes any information in the file, the holder shall notify in writing, each person authorized to reference that information. Any addition, change, or deletion of information in a drug master file (except the list required under paragraph

(d) of this section) is required to be submitted in two copies and to describe by name, reference number, volume, and page number the information affected in the drug master file.

(d) The drug master file is required to contain a complete list of each person currently authorized to incorporate by reference any information in the file, identifying by name, reference number, volume, and page number the information that each person is authorized to incorporate. If the holder restricts the authorization to particular drug products, the list is required to include the name of each drug product and the application number, if known, to which the authorization applies.

(e) The public availability of data and information in a drug master file,including the availability of data and information in the file to a person authorized to reference the file, is determined under part 20 and §314.430.

Types of Drug Master Files (DMFs)

Type ii drug substance, drug substance intermediate, and material used in their preparation; or drug product, type iii packaging material, type iv excipient, colorant, flavor, essence, or material used in their preparation, type v fda-accepted reference information.

The  Generic Drug User Fee Amendments (GDUFA)  include provisions for DMF fees, a completeness assessment, and communications with DMF holders for Type II DMFs for drug substances (active pharmaceutical ingredients (APIs)) used to support ANDAs. These provisions do not apply to other types of DMFs or to Type II DMFs used to exclusively support NDAs or INDs. For more information about GDUFA as it relates to Type II DMFs, see:

• DMF enhancements under GDUFA II
• Completeness Assessments for Type II API DMFs Under GDUFA (guidance for industry) A completeness assessment is a series of questions that must be satisfied for a DMF to be made publicly available on FDA’s website. It does not replace the full scientific review to determine the adequacy of a DMF to support an ANDA regulatory action. Send inquiries concerning the status of a DMF that is being reviewed for a completeness assessment to  [email protected] .
• List of Type II DMFs Available for Reference A list of DMFs that have passed the completeness assessment and are available for reference by ANDAs under GDUFA.

For submissions of sterility assurance information, see:

• MAPP 5040.1 Product Quality Microbiology Information in the Common Technical Document—Quality (CTD-Q)
• Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products (guidance for industry)

Additional Resources

• Q1A(R2) Stability Testing of New Drug Substances and Products (ICH guidance for industry)
• Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (ICH guidance for industry; see also Q7 Questions and Answers)
• Q11 Development and Manufacture of Drug Substances  (ICH guidance for industry; see also Q11 Questions and Answers)

FDA does not require that packaging information be submitted in a DMF. NDA, ANDA, or BLA applicants or IND sponsors who receive information from the manufacturer of a packaging component or material of construction may include that information directly in the application. If, however, the manufacturer does not wish to share information with the applicant or sponsor (i.e., because it is considered proprietary), it may be placed in a Type III DMF and incorporated into the application by a manufacturer’s letter authorizing reference to the DMF.

For submission requirements related to Type III DMFs, see guidance for industry Providing Regulatory Submissions in Electronic Format—Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (Rev.6).  Revision 7 of this guidance has been issued as a draft for public comment and includes a proposed exemption for Type III DMFs. When final, this guidance will represent FDA’s current thinking on this topic.

Additional Resource

• Container Closure Systems for Packaging Human Drugs and Biologics:  Chemistry, Manufacturing, and Controls Documentation (guidance for industry; see also Questions and Answers)

Each additive should be identified and characterized by its method of manufacture, release specifications, and testing methods.

• Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients (guidance for industry)
• Use of a Drug Master File for Shared System REMS Submissions (draft guidance for industry)
• Type V DMFs for CDER-Led Combination Products Using Device Constituent Parts With Electronics or Software  (draft guidance for industry)

List of Drug Master Files (DMFs)

The list of DMFs, which is updated quarterly, contains DMFs  received  by June 30, 2020, for which acknowledgment letters were sent before June 9, 2020. The list is current through DMF 034984. Changes to the DMF activity status (A=active; I=inactive), DMF type, holder name, and subject (title) made since the last update of March 31, 2020, are included.

• 2Q2020 – All – Excel (XLS)
• 2Q2020 – All – Text (TXT)

Drug Master File (DMF) Templates

The following templates recommend elements to include in certain DMF submissions:

• Cover Letter: Original Submissions
• Cover Letter: Subsequent Submissions
• Letter of Authorization
• Annual Report Template
• Agent Appointment Letter
• DMF Holder Name Change Letter
• DMF Holder Transfer Letter
• New Holder Acceptance Letter
• Request for Closure Letter
• Withdrawal of LOA Letter

In these letters, list the submission type and, if applicable, the amendment type as laid out below:

DMF Submission and Amendment Types

Tags Aberdeen Aberdeenshire Abu Dhabi Abu Dhalouf Abu Hamour Abu Samra ABUJA ACCRA Acre Ad Dawhah al Jadidah ADDIS ABABA Adelaide AFGHANISTAN Agra Agrigento Ahmedabad Aïn Beïda Ain Khaled Ain Sinan Ajman Ajman and Ra’s al-Khaimah Ajmer Al Ain Al Aziziya Al Bidda Al Daayen Al Dafna Al Ebb Al Egla Al Gharrafa Al Ghuwariyah Al Hilal Al Jasrah Al Jeryan Al Karaana Al Kharaitiyat Al Kharayej Al Kharrara Al Kheesa Al Khor Al Khulaifat Al Luqta Al Mamoura Al Mansoura Al Markhiyah Al Mashaf Al Masrouhiya Al Mearad Al Messila Al Mirqab Al Najada Al Nasraniya Al Qassar Al Rufaa Al Sadd Al Sailiya Al Sakhama Al Seej Al Shagub Al Souq Al Tarfa Al Thakhira Al Themaid Al Thumama (Al Wakrah) Al Thumama (Doha) Al Utouriya Al Waab Al Wajba Al Wakrah Al Wukair Al Zubarah Al-Shahaniya Alagoas ALBANIA Alberta Alessandria ALGERIA Algiers Aligarh Allahabad Allerdale Amapa Amazonas Amber Valley Amersham AMMAN Ampthill Amravati Amritsar Amsterdam Amur Ancona and Craigavon and Down ANDORRA ANDORRA LA VELLA ANGOLA Angus ANKARA Annaba ANTANANARIVO ANTIGUA & BARBUDA Antrim and Newtownabbey Antwerp Aosta APIA Ar Ru'ays Ards and North Down ARGENTINA Argyll and Bute Arkhangelsk Arlington Armagh ARMENIA As Salatah Ascoli Piceno Ashbourne ASHGABAT ashington Ashland Ashmore and Cartier Islands ASMARA Asti Astrakhan ASUNCIÓN Athens Auckland Aurangabad australia Australian Antarctic Territory Australian Capital Territory Austria Avellino Aylesbury Aylesbury Vale AZERBAIJAN Baaya BAGHDAD BAHAMAS Bahia BAHRAIN BAKU BAMAKO Banbridge BANDAR SERI BEGAWAN Bangalore BANGKOK Bangladesh Bangor BANGUI Bani Hajer BANJUL Barahat Al Jufairi BARBADOS Barcelona Bareilly Bari Barletta-Andria-Trani Barrow-in-Furness BASSETERRE Bath Batna Bavaria Beaconsfield Béchar Bedford BEIJING BEIRUT Béjaïa Belarus Belfast Belgium Belgorod Belgrade BELIZE Belluno BELMOPAN Belper Benevento BENIN Bergamo Berlin BERN Bhavnagar Bhilai Nagar Bhiwandi Bhopal Bhubaneswar Salem BHUTAN Biella Bikaner Birmingham Birmingham (West Midlands) BISHKEK Biskra BISSAU Blackburn with Darwen Blackpool Blaenau Gwent Blida BLOEMFONTEIN Bloomsbury Bodmin BOGOTÁ BOLIVIA Bologna Bolsover Bordj Bou Arreridj BOSNIA & HERZEGOVINA BOTSWANA Bou Saâda Bournemouth Bracknell Forest Bradford BRASILIA BRATISLAVA brazil BRAZZAVILLE Bremen Brescia Bridgend BRIDGETOWN Brighton Brighton and Hove Brindisi Brisbane Bristol British Columbia BRUNEI BRUSSELS Brussels-Capital Region Bryansk Bu Fasseela Bu Samra Bu Sidra Bucharest Buckinghamshire Budapest BUENOS AIRES BUJUMBURA Bulgaria BURKINA FASO Burlington BURUNDI Buxton CABO VERDE Caerphilly Cagliari CAIRO Caltanissetta CAMBODIA Cambridge Cambridgeshire Camden CAMEROON Campobasso canada Canberra Canterbury CAPE TOWN Cardiff Carlisle Carmarthenshire Caserta CASTRIES Catania Catanzaro Causeway Coast and Glens Ceara Centerville CENTRAL AFRICAN REPUBLIC Central Bedfordshire Ceredigion CHAD Chalfont St. Giles Chandigarh Charlottetown Chelmsford Chelyabinsk Chennai Cheshire East Cheshire West and Chester Chester Chesterfield Chichester Chieti CHILE Chiltern China Chlef Christmas Island City of London Clackmannanshire Clayton Cleveland Clinton Clydebank Coatbridge Cockermouth Cocos (Keeling) Islands Coimbatore Coldstream colombia COLOMBO Como COMOROS CONAKRY Congleton CONGO Constantine Conwy Copeland Copenhagen Coral Sea Islands Cornwall Cosenza COSTA RICA CÔTE D'IVOIRE(Ivory Coast) Coventry Cremona Crewe CROATIA Cromarty Crotone CUBA Cumbernauld Cumbria Cuneo Cuttack CYPRUS Czech Republic CZECH REPUBLIC (Czechia) Dahl Al Hamam DAKAR Dalkeith DAMASCUS Darlington Darwin Dayton Dehradun Garhwali Delhi Denbighshire denmark Derby Derbyshire Derbyshire Dales Derry Derry and Strabane Devon DHAKA Djelfa DJIBOUTI DJIBOUTI (CITY) DODOMA Doha Dombivali DOMINICA DOMINICAN REPUBLIC Donetsk Dorset Dover dubai Dublin Duhail Dukhan Dumfries and Galloway Dunbar Dundee Dunkeld Duns Dunstable Durgapur Asansol Durham DUSHANBE East Ayrshire East Devon East Dunbartonshire EAST JERUSALEM East Lothian East Midlands East of England East Renfrewshire East Riding of Yorkshire East Sussex ECUADOR Eden Edinburgh Edmonton Egypt El Eulma El Oued EL SALVADOR Elgin Ely England Enna EQUATORIAL GUINEA Erewash ERITREA Espirito Santo Essex estado estados ESTONIA ESWATINI (formerly Swaziland) ETHIOPIA Exeter Fairview Falkirk Falmouth Faridabad Fenland Fereej Abdel Aziz Fereej Al Amir Fereej Al Asiri Fereej Al Asmakh Fereej Al Manaseer Fereej Al Murra Fereej Al Nasr Fereej Al Soudan Fereej Al Zaeem Fereej Bin Durham Fereej Bin Mahmoud Fereej Bin Omran Fereej Kulaib Fereej Mohammed Bin Jassim Fermanagh and Omagh Fermo Ferrara Fife FIJI Finland Firozabad Flintshire Florence Foggia Forlì-Cesena Forres Fort William Fowey france Frankfurt Rhine-Main Region Franklin Fredericton FREETOWN SINGAPORE Frosinone Fujairah FUNAFUTI Fuwayrit GABON GABORONE Galashiels GAMBIA Genoa Georgetown Georgia Germany GHANA Gharrafat Al Rayyan Ghaziabad Glasgow Gloucester Gloucestershire Goias Gorakhpur Gorizia Grasmere Greater Glasgow Greater London Greater Manchester greece Greenock Greenville GRENADA Grosseto GUATEMALA GUATEMALA CITY Guelma GUINEA GUINEA-BISSAU Gujarati Gulbarga Guntur Gurgaon Guwahati GUYANA Gwalior Gwynedd Haddington HAITI Halifax Halton Hamad Medical City Hamburg Hampshire Haora HARARE Hartlepool HAVANA Hawick Hawke's Bay Hazm Al Markhiya Heard Island and McDonald Islands Helsinki Helston Hereford Herefordshire Hertfordshire Hesse High Peak High Wycombe Highland Hobart HONDURAS HONIARA Hove Hubli and Dharwad Hudson Hungary Huntingdon Huntingdonshire hyderabad ICELAND Imperia Indonesia Indore Inverclyde Invergordon Inverness Iqaluit Iran Iraq ireland Irkutsk Irvine Isernia ISLAMABAD Isle of Anglesey Isle of Wight Isles of Scilly ISRAEL Istanbul Italy Ivanovo Izghawa (Al Rayyan) Izghawa (Umm Salal) Jabal Thuaileb Jabalpur Jackson Jaipur JAKARTA Jalandhar jamaica Jammu Jamnagar Jamshedpur japan Jelaiah JERUSALEM Jervis Bay Territory Jeryan Jenaihat Jeryan Nejaima Jhansi Jijel Jodhpur jordan JUBA KABUL Kaliningrad Kaluga Kalyan KAMPALA Kanpur KATHMANDU Katowice urban area KAZAKHSTAN Kazan Kemerovo Kendal Kent KENYA Keswick Kharkiv KHARTOUM Khawr al Udayd Kiev KIGALI Kingston Kingston upon Hull KINGSTOWN Kinross KINSHASA KIRIBATI Kirkintilloch Kirkwall Kirov Knutsford Kochi Kolkata KOSOVO Kostroma Kota Kraków KUALA LUMPUR Kurgan Kursk kuwait KUWAIT CITY KYRGYZSTAN L'Aquila La Spezia Laghouat Lancashire Lancaster LAOS Latina LATVIA Launceston Leabaib Lebanon Lebday Lecce Lecco Leeds Leicester Leicestershire Lejbailat Lekhwair Leningrad Leqtaifiya (West Bay Lagoon) LESOTHO Lexington LIBERIA LIBREVILLE LIBYA Lichfield LIECHTENSTEIN Lijmiliya Lille–Kortrijk–Tournai France/ Belgium LILONGWE LIMA Lincoln Lincolnshire Lipetsk Lisbon Lisburn Lisburn and Castlereagh LITHUANIA Liverpool Livorno LJUBLJANA LOMÉ london Loni Looe Lossiemouth Lostwithiel Luaib LUANDA Lucca Lucknow Ludhian Lusail LUSAKA Luton LUXEMBOURG M'Sila Macclesfield Macerata MADAGASCAR Madinat Al Kaaban Madinat ash Shamal Madinat Khalifa North Madinat Khalifa South Madison Madrid Madurai Magadan Moscow Maghnia MAJURO MALABO malawi Malaysia MALDIVES MALE MALI MALTA MANAGUA MANAMA Manchester MANILA Manitoba Mantua Maranhao Marlborough Marlow Marseille Mascara MASERU Massa and Carrara Matera Matlock Mato Grosso Mato Grosso do Sul MAURITANIA mauritius MBABANE Mebaireek Médéa Medway Meerut Mehairja Melbourne Merseyside Merthyr Tydfil Mesaieed Mesaimeer Messina Mexico MEXICO CITY Mid and East Antrim Mid Ulster Middlesbrough Midlothian Milan Milford Milngavie Milton Milton Keynes Minas Gerais Minsk Modena MOGADISHU Monmouthshire MONROVIA MONTEVIDEO Monza and Brianza Moradabad Moray MORONI Moscow Mostaganem Motherwell and Wishaw Mount Vernon Mourne Muaither Mumbai Muraikh Murmansk MUSCAT Mushayrib Mysore N'DJAMENA Nagpur NAIROBI Najma NAMIBIA WINDHOEK Nanded Kolapur Nantwich Naples Nashik NASSAU NAURU Navi Mumbai Neath Port Talbot Nellore Nelson Nepal Netherlands New Al Hitmi New Al Mirqab New Al Rayyan New Brunswick New Fereej Al Ghanim New Fereej Al Khulaifat New Plymouth New Salata New South Wales new Zealand Newfoundland and Labrador Newport NewportAuburn Newquay Newry NGERULMUD NIAMEY NICARAGUA NICOSIA NIGER Nigeria Nizhniy Novgorod Nizhny Noida Norfolk Norfolk Island North Ayrshire North East North East Derbyshire North East Lincolnshire NORTH KOREA North Lanarkshire North Lincolnshire NORTH MACEDONIA North Somerset North West North Yorkshire Northamptonshire Northern Ireland Northern Territory Northumberland Northwest Territories Northwich Norway Norwich Nottingham Nottinghamshire NOUAKCHOTT Nova Scotia Novara Novgorod Novosibirsk Nu`ayjah Nunavut Nuoro NUR-SULTAN Nuremberg Oakland Old Al Ghanim Old Al Hitmi Old Al Rayyan oman Omsk Onaiza Ontario OntarioToronto Oran Orenburg Oristano Orkney Islands Oryol OSLO Otago Ottawa OUAGADOUGOU Ouargla Oxford Oxfordshire Padua Paisley Pakistan PALAU Palermo PALESTINE PANAMA PANAMA CITY PAPUA NEW GUINEA Para PARAGUAY Paraiba PARAMARIBO Parana Paris Parma Patna Pavia Pembrokeshire Penrith Penryn Penza Penzance Pernambuco Perth Perth and Kinross peru Perugia Pesaro and Urbino Pescara Peterborough Philippines PHNOM PENH Piacenza Piaui Pimpri Pisa Pistoia Plymouth Poland Poole Pordenone PORT LOUIS PORT MORESBY PORT OF SPAIN PORT VILA PORT-AU-PRINCE Porto Portugal PORTO-NOVO Portsmouth portugal Potenza Powys Prague PRAIA Prato Preston PRETORIA Prince Edward Island PRISTINA Pskov Pune PYONGYANG Qatar Quebec Quebec City Queensland QUITO Ragusa Raipur Rajkot Ramsey Ranchi Ras Abu Aboud Ras Al Khaimah Ras Lafan Ravenna Rawdat Al Hamama Rawdat Al Khail Rawdat Egdaim Rawdat Rashed Reading Redcar and Cleveland Reggio Calabria Reggio Emilia Regina Relizane Renfrew Renfrewshire Repton REYKJAVIK Rhondda Cynon Taf Rieti RIGA Rimini Rio de Janeiro Rio Grande Ripon Riverside RIYADH Romania Rome ROSEAU Rostov Rotterdam Rovigo Rumeilah Russia Rutland RWANDA Ryazan Saharanpur Saïda SAINT GEORGE'S SAINT JOHN'S SAINT KITTS & NEVIS SAINT LUCIA Saint Petersburg SAINT VINCENT & THE GRENADINES Sakhalin Salem Salerno Salford Salisbury Saltash Samara SAMOA SAN JOSE SAN MARINO SAN SALVADOR Sandhurst SANTIAGO SANTO DOMINGO SÃO TOMÉ & PRÍNCIPE SÃO TOMÉ SAUDI ARABIA SARAJEVO Saratov Saskatchewan Sassari Savona Sawda Natheel Saxony Scotland Scottish Borders SENEGAL SEOUL Serbia Sétif Seville SEYCHELLES Shagra Sharjah Sheffield Shetland Islands Shropshire Sidi bel Abbès Siena SIERRA LEONE Siliguri Simaisma singular Skikda SKOPJE Slough SLOVAKIA SLOVENIA Smolensk Sofia Solapur SOLOMON ISLANDS SOMALIA Somerset Sondrio Souk Ahras SOUTH AFRICA South Australia South Ayrshire South Bucks South Cambridgeshire South Derbyshire South East South Gloucestershire SOUTH KOREA South Lakeland South Lanarkshire South Sardinia SOUTH SUDAN SOUTH TARAWA South Tyrol South West South Yorkshire Southampton Southend-on-Sea Southland spain Springfield SRI JAYAWARDENEPURA KOTTE Sri Lanka Srinagar St Albans St Asaph St Davids St. Austell St. Ives St. John's Staffordshire Stirling STOCKHOLM Stockton-on-Tees Stoke Poges Stoke-on-Trent Stuttgart SUCRE sudan Suffolk Sunderland Surat SURINAME Surrey SUVA Sverdlovsk Swansea Sweden Swindon switzerland Sydney Syracuse SYRIA TAJIKISTAN TALLINN Tambov TANZANIA Taranto TASHKENT Tasmania TBILISI Tébessa TEGUCIGALPA TEHRAN Telford Telford and Wrekin Teramo Terni Thailand Thane The Hague The Pearl THIMPHU Thiruvananthapuram Thuringia Thurrock Thurso Tiaret TIMOR-LESTE DILI Tintagel TIRANA Tiruchirappalli Tizi Ouzou Tlemcen TOGO TOKYO Tomsk TONGA NUKUʻALOFA Torbay Trapani Trento Treviso Trieste TRINIDAD & TOBAGO TRIPOLI Truro Tula TUNIS TUNISIA Turin turkey TURKMENISTAN TUVALU Tver Tyne and Wear Tyumen Udine UGANDA Ujjain Ukraine Ukraine. Dnipropetrovsk Ulhasnagar Ulyanovsk Umm al-Qaiwain Umm al-Quwain Umm Bab Umm Birka Umm Ghuwailina Umm Lekhba Umm Qarn Umm Salal Ali Umm Salal Mohammed United arab emirates UNITED ARAB EMIRATES (UAE) united Kingdom UNITED KINGDOM* (UK) United States UNITED STATES OF AMERICA (USA) URUGUAY UZBEKISTAN Vadodara VADUZ Vale of Glamorgan Valencia VALLETTA MARSHALL ISLANDS VANUATU Varanasi Varese Vasai Virar VATICAN CITY VATICAN CITY (Holy See) VENEZUELA CARACAS Venice Verbano-Cusio-Ossola Vercelli Verona Vibo Valentia Vicenza Victoria Vienna VIENTIANE VIETNAM HANOI Vijayawada VILNIUS Visakhapatnam Viterbo Vladimir Volgograd Vologda Voronezh Wadi Al Banat Wadi Al Sail Wadi Al Wasaah Wadi Lusail Wakefield Wales Warrington Warsaw Warwickshire Washington Wellington Wells West Berkshire West Dunbartonshire West Lothian West Midlands West Sussex West Yorkshire West Yorkshire (Bradford–Leeds) Western Australia Western Isles Westland Whitehaven Whitehorse Wick Wiltshire Winchester Windsor and Maidenhead Winnipeg Wisbech Wokingham Wolverhampton Worcester Worcestershire Workington Wrexham Wycombe YAMOUSSOUKRO YAOUNDE YAREN DISTRICT Yaroslavl Yellowknife YEMEN SANA'A ZAMBIA YEREVAN York Yorkshire and the Humber Yukon ZAGREB ZIMBABWE Zürich

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Drug Master File

Drug master file, types of us fda dmf, us agent & consultants, benefits of dmf number, drug master file (dmf) guidance.

Drug Master File (DMF) is a submission to the US FDA that may be used to provide confidential detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs.

Typically, a US DMF is filed when two or more firms work in partnership on developing or manufacturing a drug product. The DMF filing allows a firm to protect its intellectual property from its partner while complying with regulatory requirements for disclosing processing details.

The information contained in the Drug Master File may be used to support an Investigational New Drug Application (IND), a New Drug Application (NDA), an Abbreviated New Drug Application (ANDA), another DMF, an Export Application or amendments and supplements to any of these.

The US DMF contains factual and complete information on a drug product’s chemistry, manufacture, stability, purity, impurity profile, packaging, and the cGMP status of any human drug product.

Types of Drug Master File

We provide our service to firms that focus on developing drug master files with the United States Food & Drug Administration (FDA).

More information about the Drug Master File can be found on the FDA website .

Role of US Agents and Consultants

The major roles and responsibilities are defined below.

Option 01: Documentation and Technical Consultancy

• Provide a checklist containing documents to be provided by the client to the consultant for the DMP Preparation.
• Preparation of Drug Master File for submission. (Exclusive feature)
• Identification of records, reports, chemistry needs to furnish in the submission file(for type II DMF and III DMF).
• Edit and organize DMF information as per FDA required format.
• Completed FDA DMF for review and acceptance by the client.
• Guidance on GMP.

Option 02: U.S Agent Service

• Submitting DMF to FDA.( electronic or paper form)
• Communicating with FDA on behalf of our client.
• Assisting clients to issue LOA (letter of authorization) to FDA.
• Annual Maintenance for the submitted Drug Master File.

Option 03: Full Service Package including eCTD conversion

• eCTD converion

Annual Drug Master File Maintenance service includes:

• Respond to FDA concerns about USDMF submitted by the client.
• Notify in advance if any changes in the submitted US FDA DMF.
• Provide DMF changes, additions, and deletions to the FDA.
• Submit any additional letters of authorization to the FDA.
• Assist in the closure of a DMF on file with the U.S. FDA, as required.
• Assistance with DMF Annual report submission to FDA.
• Assistance in DMF Closure request submission to FDA.
• Assistance in DMF Reactivation request submission to FDA. (for closed DMF)

Benefits of Drug Master File Number

The following are the major benefits

Gives you an edge over your competitors.

 Adds prestige to your company and product

Confidence building with customers

Improve sales anywhere in the world

Penetrating high entry barrier US market.

DMF Pricing

Service available from Bangalore, India and Chicago, USA.

• GMP GAP analysis and Implementation will be separately invoiced as per the agreed terms and conditions.
• Travelling and Lodging additional.
• eCTD conversion charges depending on the number of pages (for ex;100 pages 500 USD
• Payment – 50 % advance and balance after submission.
• Method of communication – Telephone & Skype
• Documentation by using an external Cloud server.
• Minimum Timeline – 30 Days.
• Tax’s Applicable as per Govt. rules.

Quick Contact

+1 630 290 5772 (USA) +44 75 8147 1399 (UK) +91 99 4591 2081 (INDIA) +84 98 499 0992 (VIETNAM) +60 12 429 0417 (MALAYSIA) +49 2161 990 8831 (GERMANY)

[email protected]

Our Social Activities

Under GDUFA, Type II API DMF holders are required to pay a one-time DMF fee when first authorizing the reference of their DMF in a generic drug submission.

• In order to pay the DMF fee you must have a DMF number
• DMF fees may be paid at any time, including before a LOA is requested

When submitting a DMF, the DMF holder should also submit Form FDA 3794, the Generic Drug User Fee Cover Sheet.

Partner with Us

Talk to our experts, drug master file (dmf) submissions, drug master file (dmf) submissions - overview.

Drug Master File Submission (DMF submission) is not mandatory for the US FDA, as DMFs are neither approved nor disapproved. However, to maintain confidentiality in multiple DMFs, manufacturers/DMF holders file independent DMF submissions for drug substances/excipients/packaging materials.

To be compliant with the Generic Drug User Fee Act (GDUFA) II and Initial Completeness Assessment (ICA) requirements of the US FDA, DMF holders must ensure that their DMF is compliant with the FDA prerequisites. It is critical to get approval for the DMF application as it will enable the DMF holder to provide access to multiple applications such as IND/NDA/ANDA through a Letter of Access (LoA).

Freyr boasts of a highly skilled and committed Regulatory team that specializes in FDA Drug Master File (DMF) filing. Our team possesses extensive expertise in DMF submission and managing DMF for various components such as drug substances, excipients, and packaging materials in the US FDA.

DMF Submission - Freyr Expertise

• Drug Master File type II: Drug substance and drug substance intermediate.
• Drug Master File type III: Packaging materials.
• Drug Master File type IV: Excipient, colorant, flavor, essence, or material used in their preparation.
• Regulatory support in identifying the starting material.
• Guidance in the selection of the route of synthesis for the drug substance.
• Support for designing the limits for impurities in starting materials, intermediates, and their carry-over to Active Pharmaceutical Ingredients.
• Support in setting the strategy and limits for genotoxic impurities and elemental impurities in intermediates or drug substances.
• Review support in the finalization of the development report with Quality by Design (QbD).
• Guidance on designing the protocols for stability studies, process validation, hold-time study, and forced degradation studies for DMF submission.
• Review of executed batch manufacturing records for adequacy.
• DMF/Drug Master Files submission and DMF preparation in line with the GDUFA and ICA requirements for drug substances.
• Guidance for the GDUFA fee compliance.
• Publishing US DMFs in the eCTD format as per the current US FDA guidelines and requirements.
• Regulatory strategy, preparation, and submission of amendments and annual reports for registered Drug Master Files.
• Regulatory strategy, preparation, and submission of responses to Health Authority queries.

DMF Submission - Freyr Advantages

• DMF Filing Expertise.
• Creation of Drug Master File Template.
• DMF Preparation.
• Active Pharmaceutical Ingredient submission.
• Support in publishing US DMF.

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• v.16(5); 2014 Sep

Completeness Assessment of Type II Active Pharmaceutical Ingredient Drug Master Files under Generic Drug User Fee Amendment: Review Metrics and Common Incomplete Items

Office of Pharmaceutical Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland USA

Diandian Shen

David skanchy, robert a. lionberger, susan m. rosencrance, lawrence x. yu.

Under the Generic Drug User Fee Amendments (GDUFA) of 2012, Type II active pharmaceutical ingredient (API) drug master files (DMFs) must pay a user fee and pass a Completeness Assessment (CA) before they can be referenced in an Abbreviated New Drug Application (ANDA), ANDA amendment, or ANDA prior approval supplement (PAS). During the first year of GDUFA implementation, from October 1, 2012 to September 30, 2013, approximately 1,500 Type II API DMFs received at least one cycle of CA review and more than 1,100 Type II DMFs were deemed complete and published on FDA’s “Available for Reference List”. The data from CA reviews were analyzed for factors that influenced the CA review process and metrics, as well as the areas of DMF submissions which most frequently led to an incomplete CA status. The metrics analysis revealed that electronic DMFs appear to improve the completeness of submission and shorten both the review and response times. Utilizing the CA checklist to compile and proactively update the DMFs improves the chance for the DMFs to pass the CA in the first cycle. However, given that the majority of DMFs require at least two cycles of CA before being deemed complete, it is recommended that DMF fees are paid 6 months in advance of the ANDA submissions in order to avoid negatively impacting the filling status of the ANDAs.

INTRODUCTION

On July 9, 2012, the Food and Drug Administration Safety and Innovation Act (FDASIA) ( 1 ) was signed into law (Public Law No. 112–144, 126 Stat. 993, 2012). This law reauthorizes and amends the existing user fee statute for drugs, the Prescription Drug User Fee Act (PDUFA), and establishes two new statutes, the Generic Drug User Fee Amendments (GDUFA) and the Biosimilar User Fee Amendments (BsUFA), which set out fee structures for generic drugs and biosimilars, respectively.

One provision in GDUFA specific to Type II drug master files (DMFs) for active pharmaceutical ingredients (APIs) established a one-time user fee when such a DMF is referenced in an Abbreviated New Drug Application ( 2 ) submitted after October 1, 2012. In addition, GDUFA requires Type II API DMFs to undergo an initial completeness assessment (CA) ( 3 ) to ensure that the DMF contains sufficient information for a full scientific review. DMFs that have paid the fee and been found complete in accordance with the criteria set forth for an initial CA are identified on FDA’s public website as available for reference ( 4 ) in support of a generic drug submission. GDUFA establishes that submissions which make reference to DMFs which are not “Available for Reference” will not be received by the Agency. If the DMF fee has not been paid, the Abbreviated New Drug Application (ANDA) applicant will receive a notification and given 20 calendar days to pay the fee. After 20 days, the ANDA submission will be refuse-to-receive (RTR) and the application fee for the referencing ANDA submission will be forfeited. If the DMF has not passed the initial completeness assessment, the ANDA will be refuse-to-receive and a 75% refund of the ANDA submission fee can be granted.

On October 1, 2012, the U. S. Food and Drug Administration (FDA) launched the GDUFA. The Completeness Assessment of Type II API DMFs was among a few GDUFA initiatives that required full implementation at the start and the draft guidance for industry entitled “Initial Completeness Assessments for Type II API DMFs Under GDUFA” ( 5 ) was published on September 28, 2012, to clarify the criteria that FDA will use in the initial completeness assessment. On October 25, 2012, the FDA issued notices in the Federal Register releasing the fiscal year (FY) 2013 fee amounts ( 6 ). For example, the DMF fee for FY 2013 (October 1, 2012 to September 30, 2013) was set at US$21,340. This fee very specifically applies only to Type II API DMFs referenced by generic drug submissions ( 7 ) under GDUFA (upon the first reference on or after October 1, 2012). This fee should not be confused with the facility fee associated with the API manufacturing facility. It is paid only once during the DMF lifecycle and can be paid independently from an ANDA reference (i.e., no Letter of Authorization to an ANDA applicant is necessary to pay the fee). Once the DMF fee is received and processed by the FDA, the DMF is placed in queue to receive the completeness assessment ( 8 ).

COMPLETENESS ASSESSMENT PROCESS OVERVIEW

GDUFA requires Type II API DMFs to undergo an initial CA to ensure that the DMF contains all information required for a full scientific review; therefore, the scope of the review in a “Completeness Assessment” is higher than the administrative criteria used in the Central Document Room for accepting the DMF submission; however, the initial CA does not replace the full scientific review, which is performed to determine the adequacy or inadequacy of the information contained in the DMF to support an ANDA regulatory action, i.e., a “Complete” DMF is not a guarantee it will support an ANDA’s approval, rather it only supports an ANDA’s filing.

The draft CA Guidance establishes two types of CA with different levels of scrutiny that a DMF may receive. A DMF may receive an “administrative CA” review or a “full CA” review depending on the previous review history of the particular DMF. If the DMF has been previously reviewed for chemistry, manufacture, and control (CMC) after November 30, 2007, the DMF will receive the administrative CA review and be considered to have passed the initial CA without further assessment provided that the current DMF status is “active” ( 9 ) and the payment status has been verified. If the DMF has not previously been reviewed or the most recent review on record is prior to the November 30, 2007 cutoff date, the DMF will receive a full CA review using the entire CA checklist ( 10 ).

Once assigned to a reviewer for full CA, the process follows the general work flow and timeline outlined in Scheme  1 . For paper DMFs, the reviewer must request the jackets from the Central Document Room (CDR) and wait 1 to 3 days for delivery before starting the CA review. After the primary review and secondary review are concluded, the finalized review document is checked into the archival system and any incomplete comments are communicated to the DMF holder. A process of notifying the ANDA applicant who references this DMF was implemented in 2013 to promote the active communication between the DMF holder and the ANDA applicant in order to avoid potential refuse-to-receive (RTR) of the referencing ANDA. When the DMF is found incomplete, the ANDA applicant will be notified via email of the DMF status (not the actual incomplete comments) and be reminded to follow up with the DMF holder in a few days.

Process flow for the completeness assessment

The “Incomplete Comment” letters list deficiencies by the checklist item number along with recommendations on how to address these items. The DMF holder would address these issues as an amendment to the DMF, clearly identified as a “DMF AMENDMENT FOR GDUFA INCOMPLETE” in the cover letter. Per the instruction in the Incomplete Comment letter, the DMF holder also needs to notify the DMF Review Team by e-mail to [email protected] that the amendment to address the incomplete comments has been submitted. This notification will help to avoid any delays in the process with respect to subsequent completeness assessments. Once the DMF is deemed complete, the DMF number, the DMF subject, the DMF holder name, and the date when the DMF was deemed complete are published on FDA’s public website of Available for Reference Type II DMFs for APIs, which is updated on a weekly basis. This list is the mechanism by which the complete status is communicated by the Agency as individual letters are not issued.

As shown in Fig.  1 , a very large overall number of DMF payments was received during the first year of the program at a level about 2.5 times the projected number ( 11 ). Furthermore, a large bolus of payments was received initially in the first 2 months immediately after the fee schedule was published, creating a challenge to the limited review resources available in the DMF Review Staff ( 12 ). In order to efficiently process the high number of CAs received over the first year and reduce the risk to applicant’s having their ANDA’s “Refuse to Receive” due to a DMF that had not passed the CA, a three-tiered prioritization system based on the referencing ANDA priority, referencing ANDA status, and the payment date was adopted during the first year (see Table  I ) to determine the order of CA assignments for those DMFs needing a “full CA”.

Numbers of paid DMFs by month during GDUFA year 1

CA Assignment Priority Scheme

ANDA abbreviated new drug application, DMFs drug master files, OGD office of generic, GDUFA generic drug user fee amendments

a Numbers of DMFs at a given priority during first 6 months of GDUFA year 1

Over the first year, the stratified risk-based prioritization scheme outlined in Table  I was extremely effective in reducing the risk to an ANDA applicant of receiving an RTR due to the DMF not passing the CA. Under this scheme, the highest priority is given to DMFs referenced by an expedited ANDA which is in queue for filing review (two common reasons for expedited review are drug shortage and Paragraph IV certifications under GDUFA). These DMFs are at highest risk for causing an RTR because the filing review window is much shorter due to the expedited status, leaving less time for the CA to be completed. A DMF referenced by an ANDA without an expedited status which is in queue for filing review is given the second tier priority due to the longer filing window. DMFs which have not been referenced by a GDUFA submission, thus posing no risk for an RTR, are given the normal priority. Within each priority tier, the DMFs are assigned by the DMF fee payment date with the earliest being assigned first. The status of each DMF in the queue is updated weekly so that newly expedited or newly referenced DMFs can move into the higher priority tiers when appropriate.

By September 30, 2013, the end of the first year under GDUFA, 1,797 DMF user fees had been paid, 1, 432 DMFs had received at least one CA review cycle with an additional 137 DMFs assigned but pending CA review. A total of 1,164 DMFs were deemed complete and published on the “Available for Reference List”. The small CA backlog is primarily made up of DMFs with no risk of causing an RTR of a referencing ANDA due to the effectiveness of the prioritization scheme. Of the 184 backlogged CAs in the queue on September 30, 2013, 176 or 96%, were not associated with an ANDA submission; only 8 (4%) were associated with a non-expedited ANDA submission undergoing filing review and none were associated with an expedited ANDA submission undergoing filing review. The three-tiered priority scheme remains in place for all DMFs which pay the fee by December 31, 2013. DMFs which pay the fee after that date are prioritized using a two-tier scheme which retains the top tier for DMFs that are referenced by expedited ANDAs, but which eliminates the middle tier (referenced by non-expedited ANDAs). CA assignment within the two tiers will remain based on payment date. Under the two-tiered scheme, DMF holders and ANDA applicants will take more responsibility for planning a viable submission strategy.

A critical issue impacting the risk of receiving an RTR because of the CA is the timing of the DMF payment and the ANDA submission ( 13 ). The time frame between the date of submission of a Type II API DMF and the ANDA submission making reference to it was analyzed for approximately 75 NCE-1 ( 14 ) submissions. Only 30% of these DMF payments were submitted more than 60 days prior to the ANDA submission, and 38% were submitted within 30 days of the ANDA submission. Of the 38% submitted 30 days or less prior to ANDA submission, nearly 43% were submitted within 10 days of the ANDA submission. Clearly, DMF fee payment and ANDA submission timelines such as these do not allow sufficient time for a CA to be completed even under the most favorable circumstances and indicate that ANDA applicants and DMF holders need to plan viable submission strategies under GDUFA.

Another issue observed over the first year of GDUFA was the low rate at which DMFs were complete upon the initial CA cycle. Only about 20% of all DMFs undergoing a CA were found “complete” on the first cycle. Although the requirement for an initial CA for Type II API DMFs is new, the elements of the initial CA have been used previously by the FDA to evaluate DMFs during the full scientific review and the information requirements should not have come as a complete surprise. Hopefully as GDUFA continues, more DMFs will be prepared using the draft CA guidance and first cycle complete rates will gradually improve. Subsequent cycles of CA do decrease the efficiency of the process and increase the risk for an RTR for the ANDA applicant and are a major reason for recommending that a Type II API DMF payment should ideally be submitted at least 6 months in advance of the ANDA ( 11 , 13 ).

The objective of this metrics investigation is to identify the common incomplete items leading to DMF incomplete status, and to provide clarification on how to address these items in order for the DMFs to become complete in subsequent cycles. It is hoped that the information provided from this study will assist industry in preparing high quality DMF submissions so that these issues may be prevented from reoccurring in the future, thus facilitating approval of high quality, safe, and effective generic drugs.

COMPLETENESS ASSESSMENT METRICS ( 15 )

The CA reviews performed during the first 6 months after publication of the DMF fee were selected for this analysis. The first DMF fee payment was received on October 25, 2012, and the last DMF payment date for inclusion in the analysis was April 15, 2013 ( 16 ). During this time period, a total 1,049 DMF user fee payments were received. Figure  2 shows the numbers of paid DMFs by month which roughly correspond to the period covered by the study.

Numbers of paid DMFs by month during first 6 months of GDUFA

These 1,049 DMF user fee payments were received from 300 DMF holders and covered 481 distinct APIs. Approximately half of the DMF holders (144) paid for only one DMF; nearly 40% of the holders (115) paid for between two and five DMFs; about 10% of the DMF holders (41) have more than six paid DMFs each (see Fig.  3 ).

Numbers of paid DMFs by companies

The majority of DMF payments received over the first 6 months were for paper submissions, with a small percentage of the DMFs in mixed format (i.e., submitted in paper initially and amended electronically later). Less than 20% of the DMFs were submitted in eCTD (or completely converted to eCTD). Figure  4 shows the distribution of submission types.

Numbers of paid DMFs by submission types

About half of these DMFs (539 DMFs) had been reviewed for CMC (chemistry, manufacture, and controls) after November 30, 2007, and thus received the administrative CA review. The average time from payment to completion of an administrative CA was just 19 days. The remaining half (510 DMFs), which consisted of DMFs that had never received a scientific review or those where the most recent review was prior to the cutoff date, received the full CA review utilizing the entire checklist. Among the DMFs which need full CA reviews, approximately half of these DMFs had been through the first cycle (243 DMFs) at the end of this 6-month period; the rest were either pending assignment (unassigned, 176 DMFs) or assigned but pending review (uncompleted, 91 DMFs); only 10% of them were deemed complete (50 DMFs) and published on the Available for Reference List after one cycle of CA review (see Fig.  5 ).

CA metrics chart

The time to completion of the first cycle CA from the time the payment is made is an important metric for DMF holders and ANDA applicants who are trying to coordinate the ANDA submission to the CA status of the DMF. Over the first 6 months, the average time from payment to completion of the first cycle for a full CA was about 3 months with 2 months spent in the queue pending assignment to a reviewer. As shown in Fig.  6 , queue times doubled for expedited CAs and more than tripled for non-expedited CAs in the January through April time frame. The long queue times were primarily the result of the large bolus of payments received initially in the first 2 months and the limited review resources available since the majority of GDUFA hires had not arrived. As discussed previously, the priority scheme was introduced at the beginning of 2013 in order to reduce the risk to the ANDA applicant for an RTR of an ANDA due to the DMF not being “available for reference”. Though it did not reduce assignment duration for the DMFs with references from expedited ANDAs (the review resource had not been improved much yet at that time and the expedited queue were also backed up), the prioritization scheme allowed the limited resources to concentrate on the “high risk” DMFs with the net effect that “low risk” DMFs had to wait longer in the queue before they could be assigned. As the trend in DMF fee payments decreased after the first 2 months, the initial bolus was cleared, and additional review resources arrived, the “low risk” DMFs with normal priority were cleared gradually with improving queue times.

Average assignment and review durations. Asterisk “Expedited” and “Referenced” DMFs are bundled together for this analysis. See Table  I for priority scheme in detail. Number sign the duration was back-calculated for the period when priority scheme was not introduced yet. Circumflex accent review duration was calculated for the CA reviews completed during this 6-month period

An additional factor that seemed to have an impact on CA review times and success rates on the first cycle CA review was the DMF submission format. The average review time from the time the assignment was made to the completion of the review cycle was 1 week shorter for electronic DMFs than for paper submissions. This is likely due to the additional time spent on requesting, locating, delivering, and transferring the paper DMFs to the reviewer, when compared to an electronic DMF which is available immediately. It was also observed that DMF holders were able to respond 1 week faster on average to the Incomplete Comments for electronic DMFs versus their paper DMF counterparts (see Fig.  7 ). This 2-week reduction in the overall timeline may not seem significant when the queue time was several months; however, it may become critical when the Guidance, ANDA Submissions―Refuse-to-Receive Standards ( 17 ), is implemented and GDUFA goal dates become official in the third fiscal year of 2015. By October 1, 2014, the ANDA will be RTR if the referenced Type II API DMF is not on FDA’s “Available for Reference List” at the time of submission.

Review and response time impacted by submission types

It was also observed close to 40% of electronic DMFs were deemed complete on the first cycle, while only 12% of paper DMFs passed on the initial CA cycle (see Fig.  8 ). For those DMFs deemed incomplete, electronic DMFs were also identified with fewer incomplete items than the paper ones. One possible reason that electronic submissions fared better than paper submissions is that electronic DMFs were submitted more recently and tend to reflect the DMF holders’ awareness of evolving regulatory standards. Another reason could be that the eCTD format provides the backbone for the submission which serves as a guide for what to include and where to place information. Though there is no requirement to file DMFs in electronic format, and paper DMFs will continue to be accepted, electronic DMFs appear to improve the completeness of submission and gain valuable review and response time. The Draft Guidance, Providing Regulatory Submissions in Electronic Format—Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications ( 18 ), published in January 2013 highly encourages all DMF holders to submit their DMFs in electronic format ( 19 ), including updating current paper DMFs.

Submission quality impacted by submission types

COMMON INCOMPLETE ITEMS OBSERVED IN COMPLETENESS ASSESSMENT ( 20 , 21 )

The full CA reviews completed during the first 6 months were analyzed to profile the incomplete items most frequently cited. Figure  9 shows the overall profile of incomplete items which resulted in DMF incomplete status. It is obvious from the profile that some items are more commonly missing or incomplete than others.

Overall profile of incomplete items leading to DMF incomplete status

The items were categorized and analyzed according to the appropriate CTD section, consistent with the structure of the CA checklist as follows:

• Administrative/General Information (Item #1–12)
• 3.2.S.1 General Information (Item # 13–15)
• 3.2.S.2 Manufacture (Item # 16–36)
• 3.2.S.3 Characterization (Item # 37–40)
• 3.2.S.4 Control of Drug Substance (Item # 41–45)
• 3.2.S.5 Reference Standards or Materials (Item # 46–51)
• 3.2.S.6 Container Closure System (Item # 52–54)
• 3.2.S.7 Stability (Item # 55–58)
• 3.2 R Regional info (Item # 59–62)

The most commonly cited items in incomplete letters from each section are highlighted and discussed in more detail below.

Item 1 , “ Subject of the DMF is a single drug substance produced by one manufacturing process ”, appears to be fully in compliance in Fig.  9 ; however, this is only because non-compliance with this item stops the CA review and the DMF holder is immediately contacted to resolve the issue. This is because resolution of this issue usually requires changes to DMF fee payments (i.e., additional payments or refunds) and there have been several instances where DMFs have failed this critical item. A single manufacturing process refers to a single synthetic route with permissible alternatives or minor variations. Some examples of the alternative or variation observed in the submissions include validated reprocess/rework procedures governed by the same control strategy for the routine process, additional micronization leading to different particle sizes of the same API, or minor process variation that is the same chemical transformation with little risk to the impurity profile. Multiple manufacturing sites for a single drug substance in the same DMF would not cause a citation of this item as long as the process utilized at each site is the same.

For the purposes of facility self-identification and payment of fees, GDUFA defines API differently from the way it has been defined historically. The definition of API in GDUFA allows a mixture to be an API “when the substance is unstable or cannot be transported on its own”. In this special case, the DMF for the mixture can pay the fee, undergo a CA, and appear on the Available for Reference List. GDUFA also states that “any combination of an active pharmaceutical ingredient (as defined in the statute) with another component of a drug product for purposes of production of a drug product” is defined as a finished dosage form (FDF). Therefore, a DMF which solely describes the mixing of the API with excipient(s) or the mixture of two or more APIs and that does not qualify as an API under the special case described above is considered an FDF DMF under GDUFA and no fee is due ( 22 ).

Item 2 , “ For previously submitted DMFs, the DMF holder needs to submit a complete update ”, was cited for more than 10% of the incomplete DMFs. This is the only item for which the answer of “Yes” would result in the DMF incomplete status. Because DMFs with numerous amendments make it difficult to determine the current state of the information in the DMF, the draft guidance on CA ( 5 ) establishes that a complete update is needed if it has been more than 5 years or there are more than five amendments to the DMF since the original submission or last complete update. Though the DMF guideline ( 23 ) states all changes must be reported as amendments and annual reports are not to be used to report changes in the DMF, it is observed that many annual reports were filed with technical information and process changes. If this occurred, an “annual report” would also be counted in the general guide of five amendments for a complete update. The complete update should reflect the current status of the process and not require reference to any previous submission for information. The requirement for complete update does not apply to the DMF if the entire DMF is in eCTD format because the eCTD format always presents the current state of the DMF. However, if the DMF was originally submitted in paper, and only the later amendments are submitted in eCTD, then the complete update may still be needed. A DMF submission for a complete update should clearly state “Complete Update” in the cover letter for clarity. The subsequent CA cycle will be based solely on the information contained in the complete update.

Item 8 , “ Contains label with storage conditions and expiry/retest date ”, was the most common incomplete item in this section. Some DMFs simply did not submit a copy of the container label; other DMFs missed necessary information on the label, particularly the retest date and storage conditions which are specified in the check list. The storage condition is preferably a numerical temperature range based on the stability studies but using USP terminology associated with a defined temperature limit or range such as “USP Controlled Room Temperature” is also acceptable. Undefined general terms, such as “room temperature” may result in a citation for this item. Having a retest date on the container label is consistent with current compliance recommendations ( 24 ). The 21 CFR 201.122 also recommends a caution statement, such as “Caution: for manufacturing, processing, or repacking” and prescription sign “Rx” to be on the label ( 25 ).

Item 15, “ General Properties: Should contain basic information regarding the general properties of the drug substance ”, was by far the most common item cited for incomplete DMFs in S.1 section. A list of the common general properties for a drug substance was presented at the recent GPhA/FDA Fall Technical Conference/API Workshop ( 26 ). Polymorphism (polymorph, amorphous, solvate, hydrate), solubility characteristics (in aqueous and organic solvents), and hygroscopicity were among the most common missing information.

Though Item 23 , “ Certificate of Analysis (COA) of the starting material from supplier(s) ”, item 24 , “ COA from the DMF Holder ”, and item 27 , “ Representative COAs for Reagents/Solvents ” have been cited for more than one quarter of the incomplete DMFs they are easily amendable.

Item 17 , “ If API is synthetic, complete Synthetic Scheme from appropriately supported starting materials. Scheme includes structural representation with reagents, reaction conditions, etc. ” is cited for more than one fifth of incomplete DMFs. The requirements for the synthetic scheme were generally met. Occasionally observed missing reaction conditions, reagents or solvents can be easily amended. The emphasis of this item, however, is on the justification of the starting material designation which should be in agreement with the general principles outlined in ICH Q11 ( 27 ). This can include, if applicable, manufacturer information (name, address, and contact information, etc. ), process information (e.g., flow diagram, description, synthetic route, etc. ), discussion on impurities (organic, inorganic, residual solvents, etc. ), any spike/purge studies to support the proposed specification for each starting material, and the ability of the analytical methods to ensure the quality of starting materials for their intended purpose. Alternatively, referencing another DMF for such information using an appropriate Letter of Authorization (LOA) is an option. Sometimes, the quality control strategy for the starting material is specific to a given process, the holder may commit to re-evaluate the impact due to changes of manufacturers/suppliers and/or the manufacture process. Notifications of such changes and assessment to the agency and the customer whose applications reference this DMF would be complementary to the quality control strategy.

There were cases where the DMF holders were asked to re-designate the starting material(s) from an earlier point in the manufacturing process, even though much of the information mentioned above was provided. This often occurred when the starting materials did not comply with one or more of the principles outlined in the ICH Q11 guidance. Because re-designation of starting material may require update to many other sections (e.g., synthetic scheme, description, raw material information, intermediate and in-process controls, specifications, stability studies), it typically resulted in a longer response time. If the re-designation of the starting material involves a separate site, the associated facility information should be provided to the referencing ANDA applicant(s) as well for compliance purposes. Amending a DMF with the re-designation of a starting material is quite involved, especially when another site/manufacturer becomes a factor for determining DMF adequacy. Appropriate selection of the starting material was observed to be a critical factor in achieving “available for reference status” in a timely way.

Item 36 , “ Contains a summary of Manufacturing Process Development ”, is often responded to with “not applicable”, a simple reiteration of the process description, or “completion of validation”. Such DMFs were cited for a lacking meaningful summary of development effort to support commercial process robustness and a sound control strategy. ICH Q11 dedicates section 3 on manufacturing process development and particularly discusses the submission of manufacturing development information. The overall process development summary is the focus of this item. It is helpful that a short summary is provided on how the information gained during development is linked to the control strategy, such as attributes controlled by upstream monitoring, spike/purge studies to support specification limits at various stages, and selection of process parameters and controls. This may include, but is not limited to, citing prior knowledge when appropriate, a discussion on process design, the risk assessment made to determine the probability and severity of a failure mode, strategies to mitigate the identified risks in the process, potential scale-up issues addressed for scale dependent operations, etc. While either a traditional or enhanced approach may be taken during manufacturing process development, the summary should highlight the effort in establishing a commercial manufacturing process capable of consistently producing drug substance of the intended quality.

Item 37 , “ Basic characterization information appropriate for the material (i.e,. NMR, IR, UV, MS, Elemental Analysis etc.) ”, were cited for DMFs which did not provide a complete characterization information. As mentioned in the CA guidance, the initial CA does not replace the full scientific review, which is performed to determine the adequacy or inadequacy of the information contained in the DMF to support an ANDA review decision. The CA review per item 37 does not evaluate how well the characterization data supports the API structure; rather, it examines the completeness of the characterization data set so that the scientific review can be based on a complete package. The package typically includes, but is not limited to, proton NMR, carbon NMR, FT-IR, UV, MS, elemental analysis, melting point, specific optical rotation, pXRD, TGA, DSC, DVS, etc. Most of the analyses are one-time tests for characterization purposes, and are therefore not burdensome. A summary of how these data support the structure and physical properties of the API would be helpful. Additionally, discussion of potential impurities, including related substances, degradants, inorganic impurities, residual solvents as well as genotoxic impurities, is needed to satisfy the other items in this section. Tabular forms with structures, names, origins, proposed acceptance criteria and analytical method with LOD/LOQ, etc. would be helpful for ease of review ( 26 ).

Section S.4 did not generate many citations. Item 43 , “ Method Validation and/or method verification reports are provided .” is the only one cited in over 10% of incomplete DMFs. This is mostly due to lack of method verification data for the methods adopted from the USP monograph. If a USP method is used with additional control of non-compendial impurities, the method should be validated for these in-house impurities. If in-house methods are used instead of compendial methods, method equivalency data should be provided to demonstrate that the in-house method is equivalent or superior to a compendial method.

On average, Section S.5 has been the most cited section for incomplete DMFs. The four items together, item 48 , “For a compendial drug substance, comparative data between the USP RS and the in-house WS is provided for the drug substance”, item 49, “The source, Lot#, CoA for RS and WS are provided for each identified impurity”, item 50, “Physical/chemical characterization data for non-USP reference standards are provided”, and item 51, “For impurities with compendial RS available, comparative data between the USP RS and the in-house WS is provided” , are aimed at examining the reference standard qualification program. Most of the quality control methods are used in comparative modes which require the use of reference standards for quantitation or identification. The quality of reference standards is critical and these materials are highly purified and well-characterized. Reference standards from the USP/NF and other official sources do not require further characterization ( 28 ). If a compendial reference standard is used as the primary RS, the lot number and certificate are sufficient. When non-compendial material is used as the primary RS, the material should be of high purity and well-characterized to assure the identity (e.g., by spectroscopic characterization), and the strength/assay (e.g., by mass balance). Working reference standards are cost-effective for routine analysis, and are usually materials qualified against primary reference standards with both identification tests and assays. If the primary reference standard is non-compendial, the Compliance Program Guidance Manual ( 29 ) highly recommends establishing the equivalency of in-house reference standards to current official reference standards when they become available.

Similar to items 23, 24 and 27 in section S.2, item 54 , “ Source, specifications and Representative COA for each material are provided ”, is about the material control, particularly the primary contact material and functional secondary packaging components. The specifications typically include description and identification (and critical dimensions, with drawings where appropriate). For non-functional secondary packaging components (e.g., those that neither provide additional protection nor serve to deliver the product), a brief description is sufficient. Item 53 , “ Certification statements for contact materials for use in food and drugs are provided ” is also referred to as the food safety statement. Reference documentation from each vendor showing compliance for each primary packaging material with 21 CFR (174–186) is the satisfactory response to this item ( 30 ). Though these two items were cited for 30 and 10% of incomplete DMFs, respectively, they are also easily corrected.

The stability section S.7 was not cited often for being incomplete. As mentioned in the CA guidance, the initial CA does not replace the full scientific review, so does not specify how much stability data needs to be provided in the initial submission of a Type II API DMF. The standard applied for the CA is whether or not an appropriate stability program is in place. Information including the stability protocol, summary, conclusion, proposed retest date, appropriate commitments, and any available data (at least one-time point beyond the initial will suffice for the CA) would demonstrate the existing stability program. It is assumed that the DMF will be amended to include the additional stability data required to meet the standard for scientific review consistent with the Guidance for Industry. ANDAs: Stability Testing of Drug Substances and Products ( 31 ). The adequacy of the stability information will be evaluated during the scientific review when the DMF is referenced by a submission.

Item 59 , “ Firm includes representative Executed Batch Records with translation, where appropriate ”, and item 60 , “ Yields, results of in-process controls, and analytical results for intermediates are provided ” were cited together for one third of the incomplete DMFs. Either no batch record or batch records in foreign languages without translation were observed. Submission of a representative executed batch record (EBR) is not only required for type II API DMFs, but also for ANDAs if the drug substance information is included in ANDAs instead of referencing separate DMFs, and ANDAs are also required to submit executed batch records for drug products ( 32 ). During the CA, the DMF will be checked for English translations of non-English originals, including, but not limited to, the executed batch record. DMF guidance states that English translations of any documents in the DMF must be accurate, but a separate certification statement that any translated document is accurate is not required ( 23 ). When a DMF holder submits a translated document, it is assumed that the holder is certifying to its accuracy by including it in the submission. An EBR in a foreign language with an accompanying English translation of the master batch record (MBR) would be an alternative if the critical analytical data and operational notes in the EBR are translated into English.

The large overall number of DMF fee payments received during the first year of GDUFA was two and a half times the projected number and the large bolus of paid DMFs received in the first 2 months immediately after the fee schedule was published created substantial challenges to the timely execution of Completeness Assessments. The challenge was exacerbated by the limited review resources that were available to perform the CA over the first year. The stratified priority scheme employed for CA assignments worked to effectively concentrate the limited resources on DMFs that were at higher risk of causing a potential RTR for an ANDA submission. As a result, RTRs caused by failure to pass the CA were largely avoided over the first year of the program. Later, as the number of DMF fee payments started to decrease, the initial bolus was cleared, and additional review resources became available through GDUFA hiring, the DMFs with low priority were gradually cleared out of queue with a manageable backlog remaining by the end of the first year. The average review time, especially for non-expedited DMFs, was longer than originally expected, mostly due to the high workload. Although the average review time for CAs is expected to continue decreasing with additional review resources, DMF holders should consider paying the DMF fee as early as possible in order to avoid the potential risk of causing an RTR of the referencing ANDA. When GDUFA goal dates are implemented at the start of fiscal year 2015, the DMFs must be “available for reference” at the time of ANDA submission (allowing for the 20 day grace period), making it imperative that DMF fees are paid with sufficient lead time to allow for the CA. Given that the majority of DMFs require at least two cycles of CA before being deemed complete, and an average response time to the initial Incomplete letter of 45 days, it is strongly recommended that DMF fees are paid at least 6 months in advance of the ANDA submission ( 11 , 13 ). This will require an increased level of communication and coordination between ANDA applicants and their API suppliers in the near future.

DMF holders can positively impact the efficiency of the CA process by improving the quality of their initial DMF submissions. The CA metrics analysis indicates that half of the paid DMFs need a full CA review, but only 20% of those DMFs were deemed complete after one CA cycle. It appears that previously submitted DMFs were not proactively amended or that new DMFs were not prepared using CA checklist as a guide. While it is acknowledged that the CA is a new GDUFA initiative and the CA guidance was not publicly available until just prior to GDUFA implementation, the CA elements have been used previously by FDA to evaluate DMFs during full scientific review and are thus not completely new. A few recently submitted DMFs included a self-evaluated version of the checklist with remarks in the note sections when the locations of the information are not obvious. Not only did these DMFs pass the initial CA in the first cycle, they also made the CA process efficient for the reviewer. This may be a useful practice for both electronic and paper submissions going forward.

The CA metrics analysis also revealed that electronic DMFs appear to improve the completeness of submission and shorten both the review and response times. In particular, the requirement for a complete update does not apply to the electronic DMF if the entire DMF is in eCTD format because eCTD format can always present the DMF in its current state. This advantage alone can save the holders much effort maintaining DMFs throughout the DMF lifecycle. Though currently there is no requirement to file DMFs in electronic format, and paper DMFs will continue to be accepted, the newly published Guidance, Providing Regulatory Submissions in Electronic Format—Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications, strongly encourages DMF submissions in electronic format.

This analysis of CA reviews performed during the first 6 months of GDUFA identifies the checklist items most often leading to incomplete DMFs. By focusing extra attention on these items when preparing a DMF submission, it is hoped that both the quality of the submissions and first cycle “complete” rate will increase. With increased awareness and familiarity with the procedure and criteria for CAs by DMF holders, it is expected that the CA process will improve in efficiency over the subsequent years of GDUFA.

This article reflects the views of the authors and should not be construed to represent the FDA’s views or policies.

Home » Knowledge Center » GDUFA II Key changes and implications for API manufacturer and drug master file (DMF) holders

GDUFA II Key changes and implications for API manufacturer and drug master file (DMF) holders

Sr Dir Regulatory Affairs

• Regulatory Affairs

The Teva api regulatory team has taken a good long look at the new GDUFA II commitment letter issued by the US FDA and has come up with the following highlights to help understand the implications and benefits of the updated regulation for DMF holders.

The original GDUFA (Generic Drug User Fee Amendments) was designed to increase the FDA review efficiency and reduce the gap in generic application approvals. GDUFA II is intended to further streamline and quicken the application processes. It was reauthorized in August 2017 and came into effect on October 1 st  2017 and will remain in effect until the end of September 2022.

This article will give you an overview of the changes from API manufacturer and DMF holder perspective.

What’s new?

• New Performance Goals

DMF Completeness Assessment (CA) initial review: 90% of Type II API DMFs complete within 60 days of the later of the date of the DMF submission or DMF fee payment.

• Communication of DMF Review Comments

DMF review comments to be issued in parallel with the review comments relating to the DMF for the ANDA.

• Teleconferences to Clarify DMF First Cycle Review Deficiencies

DMF holders have 20 business days from issuance of the first cycle deficiency letter to submit a teleconference request.

DMF holders may request an email exchange with the FDA in lieu of the teleconference. The request must list the specific issues to be addressed. The DMF holder can submit one follow up email to obtain additional clarification from the FDA, if needed.

• DMF First Adequate Letter

Once a DMF has undergone a full scientific review and has no open issues related to the review of the referencing ANDA, the FDA will issue a First Adequate Letter.

• DMF No Further Comments Letter

Once a DMF has undergone a complete review and the ANDA referencing the DMF has been approved or tentatively approved, FDA will issue a no further comments letter.

• Guidance on Post-Approval Changes to Drug Substances

By October 1, 2018 the FDA will issue a guidance regarding post-approval changes to a Type II API DMF and submission mechanisms for ANDA applicants who reference the Type II API DMF.

Implications

GDUFA II puts the DMF filings and review processes into scope: faster review upon submission, timely scientific review, more options for communication in cases of unclear questions, and more clarity on the status of DMF reviews.

The FDA’s commitment to improving their review procedures is dependent on the API manufacturers cooperation. In order for the procedures to work we must:

• Improve the quality and content of our files.
• Respond faster to scientific review comments to stay in line with the ANDA review round.
• Make full and efficient use of the communication channels on offer.

Additionally API manufacturers should take careful note of all updated guidelines given to ANDA holders as many have a direct impact on drug substance submissions that include:

“ANDA Submissions – Refuse to Receive” (RtR) guidance, lists specific requirements for drug substances regarding the definition of the regulatory starting materials and limits of impurities.”

“ANDA Submissions – Amendments to Abbreviated New Drug Applications Under GDUFA”  draft guidance  that lists items from a DMF review that can become a major amendment to the ANDA.”

“Good ANDA Submission Practices” draft guidance that addresses requirements from Drug Substance manufacturers.”

Manufacturer data presented in Type II API DMF must include all  manufacturing  facilities involved in the manufacturing and testing of the drug substance in order to correctly identify them in the corresponding ANDA.

The FDA’s goal of approving ANDAs in the first review cycle depends upon improving the DMF review process. It is therefore vital to reduce the total number of review cycles and the time for response from the DMF holders, to increase the chances of first cycle ANDA approval. Teva api’s global team is closely monitoring the newly published regulations and working on constant improvements of the submissions in order to provide best support for our customers.

Disclaimer: Information in this article represents Author’s interpretation of the GDUFA II commitment letter and is provided to outline Teva api‘s commitment to support our customers. Author or Teva api are not responsible for readers’ use of the information for any other purpose.

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Guidance on procedures and administrative requirements for master files: Overview

• Implementing, processing, assessing and updating master files
• Definitions and abbreviations
• Sample letter templates

Document change log:

Date adopted: 2008/08/08 Effective date: 2024/01/02

Download in PDF format (655 KB, 46 pages)

Organization: Health Canada

Date published: January 2024

Cat.: H164-267/2024E-PDF

ISBN: 978-0-660-68736-0

Pub.: 230567

On this page

Introduction, policy objective, policy statements, scope and application, note about guidance documents in general.

A master file (MF) is a reference that provides information about specific processes or components used to manufacture, process or package a drug. The MF is a useful vehicle for providing information to Health Canada, where that information is confidential business information (CBI) and is not available to the:

• manufacturer of the dosage form
• sponsors of a drug submission
• applicants of a drug identification number (DIN) application or clinical trial application (CTA)

Health Canada must protect CBI in accordance with the law.

This guidance document provides MF-related definitions, information on filing requirements, processing and assessment procedures for Type I to V MFs. It also outlines the registration requirements for new MFs, as well as other MF transactions including administrative changes, updates, withdrawals and closures.

The policy objective is to provide direction on the procedures that allow MF holders, authorized MF agents and authorized third parties filing on behalf of MF holders to file CBI directly with Health Canada. The CBI referenced is in support of an applicant’s drug submission (including DIN applications) or CTA with respect to quality information.

Note: ‘MF holder’ includes authorized MF agents and authorized third parties filing on behalf of the MF holder. This term is used throughout this guidance document.

MFs are categorized as regulatory transactions.

For more information, consult:

• Guidance document: Preparation of regulatory activities in non-eCTD format
• Guidance document: Preparation of regulatory activities in the electronic common technical document (eCTD) format

MFs are voluntary registrations filed with Health Canada. They can be referenced by applicants seeking drug marketing authorizations or clinical trial authorizations involving pharmaceuticals and biologics for human and/or veterinary use.

Applicants are responsible for submitting non-CBI provided by the MF holder. This information is public and/or developed by the applicant in the drug submission, DIN application or CTA.

The information included in the MF should be up-to-date. Applicants should also contact the MF holder to confirm that Health Canada has received this information before filing their submission, DIN application or CTA with us.

The restricted part of the MF will be held in strict confidence. Health Canada will use it in support of the drug submission or CTA only when we have received a written letter of access (LoA) from the MF holder.

The LoA is signed by the MF holder. It indicates to Health Canada that the applicant and MF holder have agreed that the MF can be referred to during Health Canada’s assessment of the drug submission or CTA.

This guidance document applies to all MF holders intending to file MFs that support drug submissions and DIN applications for products for human and/or veterinary use or CTAs. In addition, this guidance document applies to applicants that use an MF to support their drug submissions and DIN applications for products for human and/or veterinary use or CTAs. Finally, this guidance document also applies to Health Canada employees involved in MF processes.

Submissions and applications that can be supported by MFs include the following:

• extraordinary use new drug submission (EUNDS)
• new drug submission (NDS)
• new drug submission with flexibilities for designated COVID-19 drug (NDS CV)
• abbreviated new drug submission (ANDS)
• abbreviated EUNDS (AEUNDS)
• supplements (SNDS, SANDS, EUSNDS, EUSANDS)
• applications for DINs (DINA and DINB)
• post-authorization Division 1 changes (PDC and PDC-B)
• notifiable changes (NC)
• yearly biologic product reports (YBPR)
• CTAs, CTA-notifications (CTA-N) and CTA-amendments (CTA-A)
• investigational new drug (IND) submission and IND amendments
• experimental studies certificate (ESC) application and ESC amendments

This guidance document does not apply to MFs used in support of natural health products (NHPs) subject to the Natural Health Products Regulations . For NHP MFs, contact the Natural and Non-prescription Health Products Directorate (NNHPD) at [email protected] .

MFs may be referenced by more than 1 applicant and are classified according to the types listed in Table 1.

The principles outlined in this guidance document are intended to create greater alignment with the procedures used internationally for the management of MFs. Extensive knowledge has been gained through international regulatory initiatives such as the International Generic Drug Regulators Programme (IGDRP).

This guidance document also incorporates procedures and terminology from the International Council for Harmonisation (ICH) guidelines and the use of certificates of suitability to the monographs of the European Pharmacopeia (CEPs).

In keeping with international best practices, the term ‘master file’ (MF) is used. This term was previously known as drug master file (DMF).

Guidance documents provide assistance to industry and health care professionals on how to comply with governing statutes and regulations. They also provide guidance to Health Canada staff on how mandates and objectives should be met fairly, consistently and effectively.

Guidance documents are administrative, not legal, instruments. This means that flexibility can be applied. However, to be acceptable, alternate approaches to the principles and practices described in this document must be supported by adequate justification. They should be discussed in advance with the relevant program area to avoid the possible finding that applicable statutory or regulatory requirements have not been met.

As always, Health Canada reserves the right to request information or material, or define conditions not specifically described in this document, in help us adequately assess the safety, efficacy or quality of a therapeutic product. We are committed to ensuring that such requests are justifiable and that decisions are clearly documented.

This document should be read along with the accompanying notice and the relevant sections of other applicable guidance documents.

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Cover, as a birthday present Crossword Clue

By: Sarah Perowne | Last edited: Sep 21, 2024

Uncover the answer to the Sep 21, 2024 New York Times Mini puzzle's Cover, as a birthday present clue right here! We cracked the code and found the 4-letter word, the exact solution to help you solve this clue and finish your daily challenge. Ready to reveal it?

Crossword Answer:

New York Times Mini, September / 21 / 2024

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cover or enclose in paper or soft material

4 letter anagram that can be created from “warp”

Similar to swathe, bundle up, swaddle

Shoulder shawl (4)

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Critical Writing Program - Craft of Prose - Fall 2024: Cover Letter Resources

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• Cover Letter Writing Guide - Penn Career Services  - A writing guide on cover letters prepared by Penn Career Services that covers the purpose of cover letters, cover letter etiquette,  
• Job Search Letters - Purdue Online Writing Lab (OWL)  - These OWL resources will help you write job application letters, thank you and follow up letters, as well as effective acceptance and rejection letters. Also included are links to other OWL resources geared for entry-level and skilled labor positions.
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Generic Drug User Fee Amendments

On September 30, 2022, the President signed into law the FDA User Fee Reauthorization Act of 2022, which includes the reauthorization of the Generic Drug User Fee Amendments (GDUFA) through September 2027 (GDUFA III). Congress first enacted GDUFA in 2012, following negotiations between the FDA and industry and with input from public stakeholders. Congress enacted GDUFA to ensure patients have access to safe, high-quality, and affordable generic drugs . GDUFA enables FDA to assess industry user fees to bring greater predictability and timeliness to the review of generic drug applications.

This page features news and information for industry and stakeholders about GDUFA, its fee structure, payment methods, and related information. Additional information can be found on the GDUFA III Reauthorization web page .

Latest News

• FY 2025 cover sheets are now available in the User Fee System .
• The fiscal year (FY) 2025 GDUFA fee rates were published in the  Federal Register  on July 31, 2024. For more information regarding the FY 2025 fee rates, please see the FR notice available  here .

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• FDA reports GDUFA III activities and metrics —including approvals, submissions, meetings, DMF fees, and other actions—on a monthly basis.
• Points of Contact for Questions Related to Generic Drugs provides information and assistance on topics related to the Generic Drugs Program and GDUFA.
• As FDA publishes and updates guidances, CDER’s Manual of Policies and Procedures, and other deliverables to fulfill GDUFA III commitments, these items are added to the appropriate pages linked on the left.

FY 2024 and FY 2025 User Fee Rates

Background and Legislation

On July 9, 2012, GDUFA was signed into law by the President as part of the Food and Drug Administration Safety and Innovation Act (FDASIA). GDUFA is designed to speed the delivery of safe and effective generic drugs to the public and improve upon the predictability of the review process. GDUFA is based on an agreement negotiated by FDA and representatives of the generic drug industry to address a growing number of regulatory challenges.

GDUFA must be reauthorized every five years. On September 30, 2022, the President signed the bill reauthorizing GDUFA III through September 30, 2027.

GDUFA reflects input received during an open process that included regular public meetings, posting of meeting minutes, and consideration of comments from a public docket. Agreed upon recommendations were sent to Congress, and Congress held hearings on GDUFA that included testimony from FDA, the generic drug industry, and other interested parties.

GDUFA aims to put FDA’s generic drug program on a firm financial footing and ensure timely access to safe, high-quality, affordable generic drugs. GDUFA enables FDA to assess user fees to fund critical and measurable enhancements to the performance of FDA’s generic drugs program, bringing greater predictability and timeliness to the review of generic drug applications.

Sources for Additional Background and Legislation:

• 21 USC CHAPTER 9, SUBCHAPTER VII, Part C, subpart 7: fees relating to generic drugs
• Generic Drug User Fee Amendments of 2022
• FDA Reauthorization Act of 2017 (FDARA)
• Generic Drug User Fee Amendments of 2012; Pub. L. 112-144, Title III
• FDA User Fee Corrections Act of 2012 signed into law Oct. 5, 2012 to enable collection of FY 2013 GDUFA user fees without enactment of an appropriations Act
• GDUFA III Commitment Letter: GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 2023-2027
• GDUFA II Commitment Letter: GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 2018-2022
• GDUFA Commitment Letter: Human Generic Drug Performance Goals and Procedures Fiscal Years 2013 through 2017  (PDF - 99 KB)

Federal Register Documents and Guidances

Federal Register Documents

• Generic Drug User Fee Rates for Fiscal Year 2025
• Generic Drug User Fee Rates for Fiscal Year 2024
• Generic Drug User Fee Rates for Fiscal Year 2023
• Generic Drug User Fee Rates for Fiscal Years 2013-Present

To find older GDUFA Federal Register documents, please check the Federal Register .

Guidance Documents

• Assessing User Fees Under the Generic Drug User Fee Amendments of 2022 Guidance for Industry
• Information Requests and Discipline Review Letters Under GDUFA
• ANDA Submissions - Amendments to Abbreviated New Drug Applications Under GDUFA Guidance for Industry
• Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA Guidance for Industry

To find older GDUFA guidances, please check the GDUFA Guidances and MAPPs page .

Program Fees

What is the generic drug applicant program fee? GDUFA III includes a generic drug applicant program fee, which is assessed annually. Each company and its affiliates will be assessed an annual program fee depending on the number of approved ANDAs in their portfolio. To determine the fee amount, there are three tiers of the program fee:

Large: 20 or more approved ANDAs; Medium:  between 6 and 19 approved ANDAs; Small: 5 or fewer approved ANDAs

The term “affiliate” is defined as a business entity that has a relationship with a second business entity if, directly or indirectly, one business entity controls, or has the power to control, the other business entity; or a third-party controls, or has the power to control, both of the business entities.

Effective October 1, 2018, generic drug applicants and their affiliates, or an authorized representative, can submit the list of all approved ANDAs via the CDER Direct NextGen Collaboration Portal. Submissions will be for the upcoming fiscal years 2023-2027. To register for an account with the CDER Direct NextGen Collaboration Portal, navigate to  https://edm.fda.gov . 

For more on logging in:  CDER Direct NextGen Collaboration Portal FAQs

Due to processing times, you might encounter data discrepancies that might have an impact on your portfolio. If you encounter any discrepancies in your portfolio, please update your portfolio in the portal and submit as appropriate. Please note that Withdrawal Requests and Transfers of Ownership must be sent to the official record of the ANDA via the Electronic Submissions Gateway (ESG) .

When is the program fee due? The program fee is due on October 1 of the fiscal year. If October 1 falls on a weekend, federal holiday, or day when the FDA is otherwise closed, then the fee is due on the following business day. Any ANDA approved after October 1 will be included in the parent company’s portfolio for the following fiscal year.

What is the penalty for not paying the program fee? There are three effects if an applicant fails to pay the program fee within 20 calendar days after the due date: (1) The parent company will be placed on a  publicly available arrears list . (2) Any ANDA submitted by the applicant or its affiliates will not be received. (3) All drugs marketed pursuant to any ANDA held by such applicant or an affiliate of such applicant shall be deemed misbranded.

Are discontinued ANDAs included in the calculation of program fees? Yes, discontinued ANDAs are still considered approved for user fee purposes unless the ANDAs are officially withdrawn.

If Company A that has 4 approved ANDAs is affiliated with Company B that has 16 approved ANDAs, can they pay a small and medium fee? Or, must they pay one large fee? Since Company A and B are affiliated, their portfolio includes 20 ANDAs and they, therefore, must pay one large fee. According to 21 U.S.C. § 379j-42(b)(2)(E), if a person has affiliates, a single program fee shall be assessed.

If two companies are affiliated, does the parent company have to pay the program fee or can the affiliate pay the fee? Either the parent company or any of the affiliated companies can pay the program fee on behalf of the parent company.

When is the deadline for making changes to the approved ANDA list? For FY 2023 through FY 2027, an ANDA shall be deemed not to be approved if the applicant has submitted a request for withdrawal of approval of such ANDA by April 1 of the previous fiscal year.

• For example, if a company has 6 approved ANDAs and a withdrawal request is submitted for one ANDA before or on April 1, 2022, then the company’s program fee tier would change from medium tier to small tier for FY 2023.
• For transfers of ownership, consolidations, and other changes to a company’s portfolio, FDA will use the information effective as of October 1 to determine program fee tier.
• For example, if a company has 6 approved ANDAs and requests a consolidation of 2 ANDAs into 1, but the Office of Generic Drugs does not grant the consolidation request until after October 1, 2022, then the company would remain medium tier for FY 2023. (Total remains 6 ANDAs).
• For example, if a company with 5 approved ANDAs is determined to be affiliated with another company with 1 approved ANDA, and the date of affiliation is on or prior to October 1, 2022, then the company would be assessed the medium tier fee for FY 2023. If the company had already paid the small tier, then they would need to pay the difference between the medium tier fee and the small tier fee.

For other scenarios not listed, please contact  [email protected]  for assistance. When should the industry inform the Agency about their affiliates? By April 1 of each year, each person that owns an ANDA, or a designated affiliate of such person, shall submit, on behalf of the person and the affiliates of such person, to the Agency a list of (1) all approved ANDAs owned by such person, and (2) if any affiliate of such person also owns an ANDA, all affiliates that own any such ANDA and all approved ANDAs owned by any such affiliate. 

Please submit your responses to the CDER Direct NextGen Collaboration Portal . Are there any drugs or applications excluded from the program fee? The following are excluded from the program fee: Positron emission tomography (PET) drugs, and applications submitted by a State or Federal Government entity for a drug that is not distributed commercially.

How does a company pay the program fee? A company can create a program fee cover sheet via the User Fee System and then pay via check, wire transfer, or pay.gov .

What if the wrong tier is displayed on the coversheet? Please report any discrepancies via the CDER Direct NextGen Collaboration Portal . Once corrected, the Generic Drug User Fee staff will reach out when the amended cover sheet is available.

Facility Fees

What are the facility fee types under GDUFA III? There are three types of facility fees: (1) an active pharmaceutical ingredient (API) facility fee; (2) finished dosage form (FDF) facility fee; and (3) Contract Manufacturing Organization (CMO) facility fee.  If considered an API/FDF manufacturer or a CMO, a facility owner is required to pay an annual facility fee. Please refer to the GDUFA Fees table above for the exact fee amounts of each facility fee type. Each person who owns a facility that is identified in (1) at least one approved generic drug submission in which the facility is approved to produce one or more APIs, or (2) a Type II API drug master file referenced in at least one approved generic drug submission incurs the API facility fee.  Each person who owns a facility that is identified in at least one generic drug submission that is approved to produce one or more FDFs incurs the FDF facility fee. Some FDF facilities may be qualified as CMOs. An annual CMO facility fee is owed by each person who owns an FDF facility that is identified in at least one approved ANDA, where the facility is not identified in an approved ANDA held by the owner of that facility or its affiliates. The CMO facility fee is 24 percent of the amount of the FDF facility fee. A facility owner who qualifies as a CMO will owe the CMO facility fee; no other facility fee amount will be assessed.

Is there a difference in fees between foreign and domestic generic drug facilities? Yes. GDUFA III specifies that the amount of the fee for a facility located outside the United States and its territories and possessions shall be $15,000 higher than the amount of the fee for a domestic facility. The basis for this differential is the extra cost incurred by conducting an inspection outside the United States and its territories and possessions.

When are facility fees due? Facility fees are incurred annually and due on the first business day on or after October 1 of each fiscal year, or the first business day after the enactment of an appropriations act providing for the collection of fees for such year.

Under what conditions is a facility fee incurred? Under GDUFA III, the owner of a facility incurs a fee when both of the following conditions are met on the facility fee due date:

• the facility is referenced in an approved generic drug submission; and
• the facility is engaged in manufacturing or processing an API or FDF

A facility does not incur a fee for being referenced only in pending or tentatively approved generic drug submissions under GDUFA III.

Do all facilities, sites, and organizations that have to self-identify also have to pay facility fees? No. Self-identification does not, in and of itself, trigger a liability to pay GDUFA facility fees. However, most facilities that self-identify tend to be required to pay an annual facility user fee. These include facilities manufacturing API and/or FDF contained in human generic drugs. Other sites and organizations must self-identify but are not required to pay the annual facility user fee. These include facilities that solely manufacture positron emission tomography (PET) drugs, facilities that are only referenced in applications submitted by State and/or Federal Government entities for drugs that are not distributed commercially, or sites and organizations that only perform testing, repackaging, or relabeling operations. Please note that while repackagers are not required to pay user fees, drug product packagers are, in most cases, subject to FDF or CMO facility fees. This is also the case for drug product labelers and relabelers.

Facilities manufacturing for only pending or tentatively approved generic drugs will also perform self-identification. However, these facilities will not incur a GDUFA facility fee if the generic drug is still pending or tentatively approved on the GDUFA facility fee due date.

If a facility is first identified in an approved generic drug submission after the due date for payment of the facility fee for a fiscal year, is it required to pay the fee for that fiscal year? No. If a facility is first identified in an approved generic drug submission after the due date for payment of the facility fee for a fiscal year, the facility is not required to pay the fee for that fiscal year. In most cases, the critical question is whether there is a generic drug submission approved on the due date in which the facility is referenced.

If the facility is first identified in an approved generic drug submission after the due date, its owner will owe a facility fee on the next due date. For example, if a facility is first identified in an approved abbreviated new drug application on October 15, 2022 (after the fiscal year 2022 due date and during fiscal year 2023), it will start incurring facility fees on the fiscal year 2024 due date (the first business day of October 2023). If a facility is identified in an approved generic drug submission on the due date, and that reference to the facility or the drug submission is later withdrawn, the fee will not be refunded.

Is a facility owner required to pay a GDUFA fee if the facility is manufacturing only non-generic APIs or FDFs but is referenced as a fee-incurring operation type in an approved generic drug submission? Yes.

Is a facility owner required to pay a GDUFA fee if the facility is referenced as a fee-incurring operation type in an approved generic drug submission but is only manufacturing drugs for the non-US market? Yes.

Is a facility that is not currently manufacturing an API or FDF required to pay the applicable facility fees? A facility listed in at least one approved generic drug submission incurs annual facility fees for as long as it is identified in a generic drug submission, even if the facility has not started commercial-scale production of the API or FDF covered by that submission, or if the facility has stopped, temporarily or permanently, the production of that API or FDF.

The facility will cease to incur additional fees if it is no longer identified in any generic drug submission or has stopped manufacturing all APIs and FDFs (including both generic and non-generic APIs and FDFs) by the date that the fee is due. Any outstanding fee obligations will, however, remain due.

See Section VII.F. of the guidance for industry Assessing User Fees Under the Generic Drug User Fee Amendments of 2022 (GDUFA III guidance) for a description of how a facility can ensure that it is no longer identified in an ANDA. See Section VIII.J. of the GDUFA III guidance for information and instructions on facilities that cease manufacturing.

If a facility manufactures both APIs and FDFs for generic drugs, does it incur more than one facility fee? No. Unlike GDUFA I, under GDUFA II and GDUFA III, if a facility is identified in one or more approved generic drug submissions to produce both APIs and FDFs, the facility will only incur the annual FDF fee.

Is a facility that manufactures an API excipient mixture or a mixture of two or more APIs used to produce FDFs required to pay an annual FDF facility fee? Generally, manufacturers of API-excipient mixtures are required to pay the annual FDF facility fee. However, GDUFA provides one exception, for fee-paying purposes only, to the definition of FDF as inclusive of in-process materials. GDUFA defines an API-excipient mixture as an API when the mixture is produced because the API is unstable or cannot be transported on its own. In such cases, mixing the API with one or more excipients may prevent the loss of one or more critical quality attributes that allow the API to be made into a finished dosage form. Examples include an API mixed with an antioxidant for chemical stability when the API is prone to oxidative degradation or a highly potent API mixed with a polymer to facilitate safe handling. Additional examples include an API-excipient mixture for physical stability to maintain the API’s amorphous form or an API mixed with a lubricant to prevent agglomeration or solidification of a powder. When claiming this exception, the rationale should be clearly stated and accompanied by supporting information in the DMF or application, as appropriate, for each excipient added for stability purposes. APIs mixed with one or more excipients for commercial convenience only are not considered to fall under this exception to characterization as FDF.

Whom does FDA consider as a packager for purposes of GDUFA? If a facility receives product prior to the point in the manufacturing process in which the drug is first packaged in a container/closure system specified in the “How Supplied” section of an approved ANDA and it packages that product into such a container/closure system for the first time, the facility is a packager for the purposes of GDUFA. Every ANDA specifies the forms in which the approved drug product may be distributed in the “How Supplied” section.

For example, if a facility receives bulk drugs and packages them into the containers in which they are marketed, that facility is a packager.

A facility is also a packager if it receives product in a container/closure specified in the “How Supplied” section of an approved ANDA and applies the FDA-approved prescription package labeling to that product for the first time.

Are facilities that manufacture atypical APIs required to pay API facility fees? Facilities that process raw materials used to manufacture human generic drugs are generally required to pay annual facility fees if they supply a product that qualifies as an API as defined in GDUFA.

Are packagers required to pay FDF facility fees? Packagers are considered to be manufacturers, regardless of whether that packaging is done pursuant to a contract or by the applicant itself. Such facilities are required to pay annual FDF or CMO facility fees.

Repackagers are not required to pay facility fees under GDUFA.

Are quality control (QC) testing sites required to pay annual facility fees? No. They are only required to self-identify.

Are two locations of the same company required to pay separate facility fees? The answer depends on geography. If the same company’s two locations manufacture a U.S. generic product and they are in different geographic locations, each has to pay an annual facility fee. However, separate buildings within close proximity are considered to be at one geographic location or address if:

1.      the activities in them are closely related to the same business enterprise;

2.      they are under the supervision of the same local management; and

3.      they are capable of being inspected by FDA during a single inspection

These are the same criteria used to evaluate whether separate FDA Facility Establishment Identifiers (FEIs) are necessary for multiple facilities (see final guidance for industry  Self-Identification of Generic Drug Facilities, Sites, and Organizations ).

If a firm believes that multiple FEIs have been assigned in error, the firm may request consolidation of the FEIs. Please note that consolidation of FEI numbers is not an appropriate mechanism to address a non-compliant facility. Domestic firms should submit the request to the appropriate FDA District office. Contact information is available at http://www.fda.gov/downloads/ICECI/Inspections/IOM/UCM123522.pdf . Foreign firms should contact  [email protected] .

What is the penalty for failure to pay a facility fee? There are several consequences for failure to pay a facility fee:

(1) No new ANDA or supplement submitted by the person responsible for paying the fee or that person’s affiliates will be received; (2) No new generic drug submission referencing the facility will be received until the fee is paid; (3) the facility will be placed on a publicly available arrears list if the fee is not fully paid within 20 days of the due date; and  (4) FDA will notify the ANDA applicant of the facility’s failure to satisfy its user fee obligations.

Furthermore, all FDFs or APIs manufactured in the non-paying facility and all FDFs containing APIs manufactured in such a 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. Such violations can result in prosecution of those responsible, injunctions, or seizures of misbranded products. Products misbranded because of failure to pay facility fees are subject to being denied entry into the United States.

Additionally, goal dates will not apply to applications that have already been received but list facilities for which facility fees are owed. Please note that the fee is an obligation to the U.S. government, and the failure to pay the fee may result in collection activities by the government pursuant to applicable laws.

Drug Master File Fees

Which DMFs incur fees? Only DMFs that cover the manufacture of an API (Type II API DMFs) for use in a generic drug application incur fees. Specifically, each person who owns a Type II API DMF (DMF holder) that is referenced on or after October 1, 2012, in a generic drug submission, by any initial letter of authorization, shall be subject to a DMF fee.

When is a DMF fee incurred? The owner of a DMF incurs the fee on whichever of the following dates occurs earlier: 1) the first time that a generic drug submission references that DMF by an initial letter of authorization on or after October 1, 2012, or 2) the date the DMF holder requests the initial completeness assessment.

Do holders of DMFs submitted and reviewed by FDA before October 1, 2012, have to pay a DMF fee? GDUFA does not make a distinction between DMFs submitted before or after October 1, 2012. Holders of DMFs reviewed prior to GDUFA implementation must pay the one-time DMF fee if their DMF is referenced in a new generic drug submission after October 1, 2012.

Do DMF holders incur a fee each time their DMF is referenced? No. The DMF fee is a one-time fee, incurred on first reference of the DMF on or after October 1, 2012, or when the DMF holder requests the initial completeness assessment, whichever occurs earlier. This fee is not incurred every time a DMF is referenced.

When are DMF fees due? A drug master file fee shall be due on the date on which the first generic drug submission is submitted that references the associated Type II active pharmaceutical ingredient drug master file or the date the drug master file holder requests the initial completeness assessment, whichever occurs earlier.

Do DMF holders need to wait for a new ANDA applicant to request a letter of authorization before the DMF is assessed to be available for reference? No. DMF holders can pay the fee before a letter of authorization is requested. The DMF will then undergo an initial completeness assessment, using factors articulated in the final guidance Completeness Assessments for Type II Active Pharmaceutical Ingredient Drug Master Files Under the Generic Drug User Fee Amendments . If the DMF passes the initial completeness assessment, FDA will identify the DMF on the Type II Drug Master Files – Available for Reference List .

Can an ANDA applicant pay the DMF fee for an API referenced in its submission? Yes.

What is the penalty for failure to pay the DMF fee? The DMF will be deemed not available for reference. Once the DMF fee becomes due, no generic drug submission submitted referencing the DMF will be received unless the fee is paid and the DMF is deemed available for reference.

ANDA applicants that reference a DMF for which a fee is due but has not been paid will be provided notification of the DMF holder’s failure to satisfy the user fee obligation. If the DMF fee is not paid within 20 calendar days after notification, the ANDA referencing the DMF will not be received.

Abbreviated New Drug Application (ANDA) Fees

When will the ANDA filing fee be due? ANDA filing fees will be due on the date the application is deemed submitted.

If FDA refuses to receive an ANDA, is there any provision for a partial refund of the application fee? FDA will refund 75% of the application fee for the fiscal year in which the application is deemed submitted.

How does the ANDA sponsor receive the 75% refund if FDA has refused to receive the ANDA pursuant to section 505(j)(4) of the FD&C Act? To request a refund, submit an online form at https://userfees.fda.gov/fdarefund/ . If you do not submit a refund request, FDA will initiate a refund during its periodic review of outstanding refunds.

If such a previously refused application is then resubmitted, will the applicant be required to pay another full fee at the time of resubmission? Yes.

When is a response to an RTR letter considered a resubmission? A resubmission of an ANDA is a formal response to a refuse-to-receive (RTR) determination and is submitted to the ANDA refused for receipt. Submission of a dispute of an RTR determination without attempting to remedy the deficiencies (i.e., without resubmitting the ANDA) is not considered a resubmission and is therefore not subject to a new ANDA filing fee.

What is the penalty for failure to pay the ANDA filing fee? The application or supplement to an application will be deemed incomplete on the date of submission and will not be received.

If an ANDA applicant pays its filing fee more than 20 calendar days after the due date, what will FDA consider as the application’s date of submission? So long as FDA finds that none of the disqualifications outlined in 21 CFR 314.101(d) and (e) apply, the application will be considered submitted as of the date all obligations are satisfied and the payments are received in full.

If an ANDA is withdrawn, will FDA issue a refund? Yes, companies are entitled to a 75% refund of the application fee if the application is withdrawn prior to being received. 

If an ANDA is withdrawn before the filing fee is paid, will the obligation to pay the fee remain? Yes. An ANDA filing fee is incurred upon submission. Once the ANDA is submitted, the applicant is liable for paying that fee.

What is a generic drug submission? The phrase generic drug submission refers to an ANDA, an amendment to an ANDA, or a Prior Approval Supplement (PAS) to an ANDA.

If a generic drug submission includes API information other than by reference to a DMF, is the applicant required to pay an additional fee? Yes. An applicant is required to pay an API information fee for a generic drug submission that contains information concerning the manufacture of an API at a facility by means other than reference by a letter of authorization to a Type II active pharmaceutical DMF, and for which a fee in the amount equal to the DMF fee has not been previously paid. Similar to the DMF fee, this fee is paid only once.

An additional API information fee must be paid for each description, contained in a particular application, of the manufacture of an API by one facility. Therefore, the total amount of the API information fees for a particular application is a function of the number of APIs referenced in the application and the number of facilities in which those APIs are manufactured. The API information fee must be paid for each description of the manufacture of an API by a particular API facility, provided a DMF or API information fee has not already been paid for the manufacture of the same API by the same facility.

Because the calculation is potentially confusing, we provide the following two examples.

Example One:

An applicant (XYZ Corp.) submits an ANDA that, rather than referencing a DMF, describes the manufacture of three APIs at one or more facilities. No previous API information or DMF fee has been paid for the manufacturing of the APIs by these facilities.

In this example, XYZ Corp. owes the following API information fee:

Fee = (APIs (Alpha + Beta + Gamma) + extra facilities (Alpha 2 + Alpha 3 + Beta 2)) x DMF Fee Amount

= (3 APIs + 3 Extra facilities) x DMF Fee Amount

= 6 x DMF Fee Amount

Example Two:

XYZ Corp. then submits a new application for a second product with the following information about API manufacture other than by reference to a DMF:

The one-time fee has already been paid for the description of the manufacture of API Alpha at Facility 1, 2, and 3; API Beta at Facility 1 and 2, and API Gamma at Facility 1, so no additional fee is due with respect to these facilities.

The applicant owes and API information fee for the following:

Fee = (additional API Delta + manufacture of API Gamma at Facility 2) x DMF fee Amount

= (1 API + 1 extra facility) x DMF Fee Amount

= 2 x DMF Fee Amount

Are the references to fees for each API facility in the above example different from the annual fee that each API facility must pay (discussed below)? Yes. The reference to fees for each API facility in the calculation above is meant to replicate the DMF fee required if the information is submitted in a DMF. Annual API facility fees are discussed below and are required for each facility that makes an API for a generic drug, regardless of whether the API is identified in an ANDA or a DMF.

When should the application filing fee for a serially submitted ANDA be paid? In some circumstances, ANDA applicants choose to serially submit complete ANDAs in anticipation of a patent being listed for a reference listed drug (RLD) that is protected by new chemical entity (NCE) exclusivity and has no other patents listed. This is done because the ANDA cannot be submitted until the final year of the five-year exclusivity period, and then only if the submitter is challenging the patent. A single payment for multiple submissions of the same ANDA is required.

Applicants who choose to serially submit complete ANDAs in anticipation of a patent being listed for a RLD that is protected by NCE exclusivity and has no other patents listed should refrain from remitting their application filing fee until such time as the applicant is instructed by Office of Generic Drugs (OGD) that it has a valid application. Once a patent has been listed and an application can therefore be received for review by OGD, an applicant will have 20 days in which to pay its user fee.

User Fee Lists

Annual GDUFA facility fees and generic drug applicant program fees are due on the later of (i) the first business day on or after October 1 of each fiscal year, or (ii) the first business day after the enactment of an appropriations Act providing for the collection and obligation of GDUFA fees for such year. Corresponding user fee lists are linked below:

• GDUFA Program Fee Parent Company Details List (XLS)
• Generic Drug Applicant Program Fee Arrears List (PDF)
• Generic Drug Applicant Program Fee Arrears List (XLS)
• GDUFA Facility Arrears List (PDF)
• GDUFA Facility Arrears List (XLS)
• GDUFA Facilities with Outstanding Fees Not on the Arrears List (PDF)
• GDUFA Facilities with Outstanding Fees Not on the Arrears List (XLS)
• Type II Drug Master Files - Available for Reference List
• GDUFA Backlog Arrears List
• GDUFA Paid Facilities List
• GDUFA Type II API DMF Payment Receipts Report

Payment Information and Cover Sheet

When is the GDUFA cover sheet required? The GDUFA cover sheet is required for each of the following human generic drug user fees:

• Generic drug applicant program fee;
• Abbreviated new drug application (ANDA);
• Type II active pharmaceutical ingredient (API) drug master file (DMF) that is referenced on or after October 1, 2012, in a generic drug submission to the FDA and for which the DMF fee has not already been paid;
• Generic drug facility which is identified or intended to be identified in at least one generic drug submission approved to produce a finished dosage form (FDF) of a human generic drug or an API contained in a human generic drug; and

Note: A cover sheet is not required for all ANDA amendments and PAS. It is only applicable to a PAS or an amendment that is adding API manufacturing information other than by reference to a Type II DMF which is subject to the Section 744B(a)(3)(F) fee under GDUFA.

How to fill out a GDUFA cover sheet? Read the instructions below and then go to Create GDUFA cover sheet to fill out the form. A GDUFA cover sheet will be completed online using FDA’s User Fee System which requires the use of Google Chrome, Mozilla Firefox or Microsoft Edge.

• Access the User Fee System at Create GDUFA cover sheet .
• Register your organization by providing information about your organization.
• Create a user account for your organization and provide contact information.
• Create a cover sheet by answering a series of questions and making appropriate selections.
• Submit the cover sheet to complete the process and determine the user fee amount owed. Upon submission, a User Fee Payment I.D. Number (PIN), which begins with the letters “GD”, is generated. The PIN must be referenced in your payment submission.

Additional instructions for the User Fee System and the process to create a GDUFA cover sheet can be located under the Frequently Asked Questions (FAQs) within the User Fee System. For detailed instructions to complete the GDUFA cover sheet, please access Form FDA 3794 - Instructions .

Note: A signed copy of a completed GDUFA cover sheet must be included in the following submissions to the FDA: ANDA (placed in the first volume with Form FDA 356h) and Type II API DMF submission.

What information is needed to complete a GDUFA cover sheet?

How are payments submitted? A payment may be submitted by Pay.gov (electronic payment), check, bank draft, U.S. postal money order, or wire transfer. For all payment options, the payment must be made in U.S. currency drawn on a U.S. financial institution. FDA recommends that user fee payments be made in a timely manner to meet the required payment due date or to be received prior to an application submission. For application submissions, it is recommended that you send manual payments to the bank 4-5 business days before the application submission arrives at FDA so that there is no delay in starting the review of your application submission. Please follow the instructions below for your selected payment option:

How to Request a Refund?

To qualify for the return of a fee claimed to have been paid in error, a person shall submit to the Secretary a written request justifying such return within 180 calendar days after such fee was paid.  See section 744(m) of the FD&C Act.

For all refund requests, please enter the request and all pertinent information on the User Fee Payment Refund Request website.

How to Request a Transfer?

FDA no longer permits the administrative action of applying a previously paid GDUFA fee (also referred to as a “transfer”) from a closed-out fiscal year cover sheet to a different fiscal year cover sheet.   Instead, payments from closed-out fiscal year cover sheets will only be processed as refunds to the original payors, provided that the request is made within 180 calendar days from when the original payment was made.

Requests for the “transfer” of payments within the same fiscal year or open fiscal year may be permitted for the same fee type and for a fee obligation of the same payor, provided that the request is made within 180 calendar days from the original payment date.

To request a “transfer,” applicants should complete Form FDA 3914 and email the form to [email protected] .

Reauthorization Activities

Related information.

• GDUFA Financial Reports
• GDUFA Performance Reports
• GDUFA 5 Year Financial Plans

Questions for the Generic Drug User Fee staff? Contact us at [email protected] or 301-796-7900.

For general inquiries, please contact FDA's Division of Drug Information at 855-543-3784, or:

• For general GDUFA inquiries, contact  [email protected]
• For questions about generic drugs, contact  [email protected]

In the rare instance where you are unable to submit an electronic request, you may mail your request, via the carrier of your choice, to FDA, Division of User Fee Management, 10001 New Hampshire Ave, Silver Spring, MD 20993.