INTERNATIONAL REGULATORY ASPECTS OF FNPCMB (MRA 103 T) USA AND CANADA

1. USA and CANADA
 Organization structure & Functions of FDA .
 Federal register &CFR (Code of Federal Register).
 History & Evolution Of US Federal, Food , Drug &
Cosmetic Act (FFDCA).
Hatch Waxman act & Orange book , Purple book , Drug
Master File (DMF ) system in US .
Submitted by:
Ranjini D.M.
I st M Pharmacy DRA
ACHBRCP
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2. COUNTRY REGULATORY BODY
1. United States Of America (USA) - Food and Drug Administration (FDA)
2. Canada Health Canada
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3. • It is responsible for regulating and supervising the safety of foods , dietary
supplements, drugs , vaccines , biological medical products , blood products ,
medical devices , radiation – emitting devices , Veterinary products , and
Cosmetics. .
• The FDA has its Headquarters at White oak , Maryland.
• The agency also has 223 field officers .
• 13 Laboratories located throughout the 50 states .
• The united states Virgin Islands , and Puerto Rico .
•FDA Organization, FDA is an agency within the
“ Department of Health and Human Services.”
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4. FDA - ORGANIZATIONS
1. The Office of the Commissioner (OC)
2. The Center for Drug Evolution and Research ( CDER)
3. The Center for Biologics Evolution and research ( CBER )
4. The Center for Foods Safety and Applied Nutrition ( CFSAN)
5. The Center For Devices and Radiological Health ( CDRH )
6. The Center For Veterinary Medicine ( CVM )
7. The National Center For Toxicological Research ( NCTR )
8. The Office of Regulatory Affairs ( ORA )
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5. FDA Center Areas of Responsibility
1. Center for Drug Evaluation and
Research
Safety and effectiveness of Rx and over
the counter drugs
2.Center for Biologics Evolution and
research
Safety and effectiveness of Vaccines ,
nations blood supply , other biologics
3.Center For Devices and Radiological
Health
Safety and effectiveness of medical
devices , diagnostic tests , radiation
emitting device
4.Center for Foods Safety and Applied
Nutrition
Safety of domestic and imported food
supply . Cosmetic dietary supplement
5.Center For Veterinary Medicine Safety and effectiveness of Veterinary
drugs
6.Center For Tobacco products Implementation of the Family smoking
prevention and Tobacco Control act
7.National Center For Toxicological
Research
Research to support regulatory decisions
and reduce risks associated with FDA –
regulated products
8.Office of Regulatory Affairs Enforcement of laws and regulations
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6. ORGANISATION STRUCTURE OF FDA
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7. Responsibility of US – FDA
• FDA is responsible for protecting the public health by assuring the
Safety , efficacy and security of human and veterinary drugs,
Biological products , medical devices , Us nation food supply
Cosmetics and products that emit radiation .
• FDA is also responsible for advancing the public health :
1 . By helping to speed innovations that make medicines more effective
safer and more affordable .
2 . By helping the public get the accurate , science – based information
they need to use medicines & foods to maintain and improve their health
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8. FUNCTIONS OF US – FDA
• FDA has 4 Roles :
1 . To promote health by reviewing research and approving new products .
2. To ensure foods and drugs are safe and properly labeled .
3. To work other nations to “ reduce the burden of regulation’’ .
4. To cooperate with scientific experts and consumers to effectively carry out
these obligations .
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9. US – FDA REGULATES :
• Foods , expect for most meat and poultry products , which are regulated by the
U.S. Department of Agriculture .
• Food additives
• Infant formulas , Dietary supplements
• Human drugs
• Vaccines , blood products , and other biologics
• Medical devices , from simple items like tongue depressors ,
to complex technologies such as heart pacemakers .
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10. US – FDA REGULATES :
• Electronic products that give off radiation , such as microwave ovens and X – ray
equipment .
• Cosmetics
• Feed , drugs , and devices used in pets , farm animals , and other animals .
• Tobacco products .
US – FDA Doesn't’ regulates :
• Advertising (except for prescription drugs, medical devices , and tobacco products).
• Alcoholic beverages
• Some consumer products , such as heroin and marijuana.
• Health insurance .
• Meat and poultry ( Except for game meats , such as venison , ostrich , and snake ).
• Restaurants and grocery stores
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11. FEDERAL REGISTER :
• The federal register is the official journal of the federal government of the United
States that contains government agency rules , purposed rules , and public notices
• It is published daily , except on federal holidays . The final rules promulgated by a
federal agency and published in the
• Federal register are ultimately recognized by topic or subject matter and codified in
the Code of Federal Regulations ( CFR ) .
• It is updated annually .
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12. CODE OF FEDERAL REGULATIONS (CFR)
• Is the codification of the general and permanent rules and regulations
(administrative law ) published in the federal register by the executive departments
and agencies of the federal government of the united states .
• The CFR is divided into 50 titles that represents broad areas subject to federal
regulation .
• The CFR annual edition is the codification of the general and permanent rules
published by the office of the Federal register ( part of the National Archives and
records administration ) and the government publishing office .
• In addition to this annual edition , the CFR is published in an unofficial
format online on the electronic CFR website which is updated daily
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13. EX . CODE OF FEDERAL REGULATIONS
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14. THE CODE OF FEDERAL REGULATIONS Content s
Discipline : Administrative law
Language : English
Publication Details
Publisher : Office of the federal Register (United states )
Frequency : Annually
License : Public domain
Standard abbreviations
Blue Book : C.F.R.
ISO 4 :Code of federal Regulations
Indexing
ISSN : 1946 – 4975
Links
• Journal homepage , Online access.
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15. • The Introduction of this act was influenced by the death of more than 100
patients .
• Due to a sulfanilamide medication where di ethylene glycol was used to
dissolve the drug and make a liquid form ( see elixir sulfonamide disaster)
• It replaced the earlier Pure Food and Drug Act Of 1906 ] .
INTRODUCTION OF UNITED STATES FEDERAL ,
FOOD , DRUG AND COSEMETIC ACT (FFDCA)
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16. HISTORYAND EVOLUTION OF UNITED STATES FEDERAL ,
FOOD , DRUG AND COSEMETIC ACT (FFDCA)
• The United States Federal Food , Drug , Cosmetic Act 1938 .
(abbreviated as FFDCA , FDCA or FD&C ),
• Is a set of laws passed by congress in 1938 giving authority to the U.S.
• Food and Drug Administration (FDA) to oversee the safety of food , drugs , and
Cosmetics.
• A Principal author of FDA law was Royal S. Copeland , a three – term senator
from New york
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17. HISTORYAND EVOLUTION OF UNITED STATES FEDERAL ,
FOOD , DRUG AND COSEMETIC ACT (FFDCA)
• In 1968 , the electronic product Radiation Control provisions were added to the
FD&C .
• Also in the year 1968 the FDA formed the new program Drug Efficacy Study
Implementation ( DESI ) .
• DESI to incorporate into FD&C regulations the recommendations from a National
Academy Of Sciences.
• DESI mainly deals investigation of effectiveness of previously marketed drugs .
• The act has been amended many times , most recently to add requirements about
bioterrorism preparations .
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18. FEDERAL FOOD , DRUG AND COSMETIC ACT (FFDCA)
LONG TITLE: To prohibited the movement in interstate commerce of
adulterated and misbranded food , drugs, devices, and
cosmetics, and for other purpose .
Acronyms(Colloquial) FFDCA , “FD&C Act “
Enacted by the 75 th united state congress .
Citations
Public Law 75 – 717
Statutes at Large 52 stat . 1040
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19. Codification
Acts replaced Pure Food and Drug Act
Titles amended 21 U.S.C. : Food and Drugs
U.S.C sections created 21 U.S.C. : Food and Drugs
U.S.C sections created 21 U.S.C c h 9 ₪s s 301 et .seq.
Legislative History
• Introduced in the senate as S. 5 by Royal Copeland (D-NY) on
January 6, 1937
• Passed the Senates on March 9 , 1937 (Voice)
• Passed the house with amendment on June 1 , 1938 (Voice )
• Reported by the joint conference committee on June 10 , 1938 :
agreed to by the senate on June 10 1938 (voice) and by the House
on June 13, 1938 (voice )
• Signed into law by President Franklin D . Roosevelt on June 25 ,
1938 .
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20. Major amendments
• 1951 Food , Drug , and Cosmetics act amendments , PL 82 – 215 , 65 stat 648
• 1962 Food , Drug , and Cosmetic act amendments, PL 87 – 781 , 76 stat 780
• Fair Packaging and Labeling Act , PL 89 – 755 80 stat 1296 .
• Medical Device Regulation act , PL 94 – 295 , 90 stat 539 .
• Radiation control for safety and health act , PL 90 – 602 , 82 stat 1173 .
• Drug price Competition and Patent term Restoration Act of 1984 , PL 98 – 471, 98
stat 1585 .
• Nutrition Labeling and education act ( 1990) PL 101 – 535 , 104 stat 2353)
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21. Major amendments
• Safe medical device Amendment of 1990, Pl 101 – 629 , 104 Stat 4511.
• Food and Drug Administration Revitalization Act (1990) , PL 101 – 635 , 104
Stat 4583.
• Dietary Supplemental Health Education Act (1994) , PL 103 – 417 , 108 Stat
4332 .
• Food Quality Protection Act of 1996 .
• Food and Drug Administration Modernization Act of 1997 , PL 105 – 115 Stat
2296.
• Food and Drug Administration Amendments Act 2007 , PL 110 -85 , 121 Stat 823 1
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22. HATCH WAXMAN ACT
INTRODUCTION
• 1962 – Proof of efficacy made compulsory for marketing approval of a new drug.
By (Kefauver – Harries Amendments )
• Before 1962 – new drug approved based on safety alone .
• In 1984 HATCH WAXMAN ACT enacted
• HATCH WAXMAN ACT also Known as “ The Drug Price Competition and Patent
Term Restoration Act”
• Amended in the patent laws .
• Amended the Federal food , Drug , and Cosmetics Act .
• There was no provision for patent term extension prior to enactment.
• Hatch Waxman Act , to make up for time lost out of the total patent term during
the marketing approval process .
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23. • Generic companies required to submit their own comprehensive NDA
Costly
Time consuming
• If Drug was Covered by patent testing could not begin until patent expired .
• To Overcome the above problems on act was needed to promote generic companies.
OBJECIVES OF HATCH WAXMAN ACT
• Reducing the cost associated with the approval of a generic drug .
• Allowing early – experimental – use .
• Compensating the branded drugs manufacturers for the time lost from the
patent term because of the regulatory approval formality
• Motivating the generic drug manufacturers
• “HATCH WAXMAN ACT strike a balance between the interests of
branded drug manufacturers , generic drug manufacturers and the
consumers “
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24. PROVISIONS OF HATCH WAXMAN ACT
• Creation of section 505 (j).
• Section 505 (j) established the ANDA (Abbreviated new drug application)
approval for an existing licensed medication / approved drug process .
• The limiting of an ANDA approval depends in part on patent protections for the
innovator drug .
• NDA ( New Drug Application)must include any patent the claims the “drug” or a “
method of using ( the ) drug or a “ method of using (the ) drug “for which a claim
of patent infringement could reasonably be asserted.
• On approval of NDA , FDA publishes patent
information for drug in
Orange Book ( “ Approval drug products with Therapeutic Equivalence Evolutions)
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25. ORANGE BOOK
• FDA publishes patent information on approved drug products in the orange book
• An NDA( new drug application ) applicant must submit the following
information for each patent :
 Patent no and date on which the patent will expire
 Type of patent . i e . Drug , drug product , or method of use
 Name of the patent owner
 The name of an agent of the patent owner of applicant
• Brand Drugs Listed for generics to compare with their purposed products
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26. 26

27. ORANGE BOOK
• The publication Approved Drug Products with Therapeutic Equivalence Evolutions
• Commonly known as Orange book .
• Identifies the drug products approved on the basis of safety and effectiveness by
the Food and Drug Administration (FDA) under the Federal Food , Drug , and
Cosmetic Act ( the act ) and related patent and exclusively information .
• Formally called Approved Drug Products with Therapeutic Equivalence Evolutions.
• Orange book does not include drugs only approved as safe .
• Drugs whose safety or efficacy approval has been withdrawal are also is excluded
from the Orange book .
• A drug that is currently subject to regulatory action may still appear in the orange
book .
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28. THE ORANGE BOOK CONSISTS OF 4 PARTS
• The orange book is composed of the following 4 parts :
 Approved prescription drug products with therapeutic equivalence evolutions
 Approved OTC (over the counter ) drug products for those medications that may
not be marketed without new drug applications or ANDs (abbreviated new drug
application ).
 Because they are not covered under existing OTC monographs : drug products
administered by the center for biologics evolution and research and discontinued
products .
 Drug Products with a codes are considered to be therapeutically equivalent .
Those with B code drugs ( requires further FDA investigation and review ) are
not therapeutically equivalent .
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29. PURPLE BOOK
• Lists Of Licensed Biological Products With Reference Product Exclusivity and
Bio similarity or Interchangeability Evolutions .
• The Purple book Lists biological products , including any bio similar and
interchangeable biological products , licensed by FDA under the public health
Service Act ( the PHS Act ).
• The Purple book includes the data a biological products was licensed under 351 (a)
PHS (Public health service act ).
• Whether FDA evaluated the biological product for reference product exclusivity
under section 351 (k) (7) of the PHS (Public health service) act .
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30. • The purple book in addition to the date licensed , also includes whether a biological
product licensed under section 351 ( k) of the PHS (Public health service)act.
• PHS (Public health service) has been determined by FDA to be bio similar to or
interchangeable with a reference biological product ( an already licensed FDA
biological product ) .
• The Patent Protection Act and Affordable Care Act (Affordable care act ) , Signed
into law by President Obama on March 23, 2010 .
• Amends the PHS act to create an abbreviated licensue pathway for biological that
are demonstrated to be
• “Bio similar” to or “ inter changeable “ with an FDA licensed biological product.
PURPLE BOOK
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31. PURPLE BOOK
• This pathway is provided in the part of the affordable care act Known as the
BPCI Biological Price competition and Innovation Act at 2009.
• Bio similar and inter changeable biological products licensed under section
351 (k) of the PHS (Public health Service) act .
• PHS (Public health Service) act will be listed under the reference product
to which bio similarity or inter changeability was demonstrated .
• Healthcare provides can prescriber bio similar and interchangeable
biological product just as they would prescribe other medications .
• The BPCI act Describes an inter changeable product as a product that may
be substituted for the reference product .
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32. • In contrast , FDA experts that a bio similar product will be specifically
prescribed by the healthcare provider and cannot be substituted for a
reference product at the pharmacy level separate lists for those biological
products regulated by the
CENTER FOR DRUG EVALUTION AND RESEARCH
(CDER )
and
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
(CBER)
• will be updated periodically .
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33. DRUG MASTER FILES ( DMF ) in US
• A Drug Master file (DMF) is a confidential , detailed document submitted by
Active Pharmaceutical Ingredient ( API)
• API manufacturers to the U.S. Food and Drug Administration ( FDA)
• A Drug Master File contains the chemistry , manufacturing , and controls of a drug
component .
• A DMF required to supply bulk materials to the United States , but the
• FDA does not require all manufactures to submit a DMF 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 related documents .
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34. • The FDA says a DMF cannot be substituted for an IND , NDA , ANDA or
Export application .
“ It is not Approved or disapproved “ ,
according to the FDA .
“Technical Contents of a DMF are reviewed only in connection with the review of
an IND , NDA , ANDA or an Export Application .”
• API manufactures with a large number of DMF s are often considered more
reliable in terms of Quality , regulatory standing , and ability to meet
Current good manufacturing Process (c GMP ) requirements .
• Before DMFs Can be reviewed , a manufacturer must submit a dose form filling
that references the DMF .
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35. • Not all DMF s are reviewed by the FDA , and the possessions of a DMF for
a product does not ensure that a manufacturer is producing that product or
able to supply it to the United States .
• In the Past , Filling a DMF was a way for less established firms to claim a
degree of creditability when trying to sell into the U.S. markets.
• However , since DMF’s are only reviewed when an ANDA or NDA
references them , a DMF that has not been reference is of questionable
value even if the DMF holder thinks having a DMF makes them look
legitimate .
• Filling the DMF s without any Customers in the U.S. has become much
less common , so more recent DMF s are better indicator of intent to
manufacture than older DMF s.
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36. TYPES OF DMFs
The Five Types Of DMF s
 TYPE I DMFs :
 Manufacturing site , facilities, operating procedures and personal not specific to a
drug substance .
 Type I DMFs are no longer accepted by the FDA , but old ones remain same .
 TYPE II DMF s :
 Drug Substances , substance intermediates , and materials used in their preparation
or a drug product .
 A type II DMF s , the most common form , can also cover dosage form drugs
manufactured under contract for another company which would file an ANDA .
 TYPE III DMF s :
 Packing materials , form bottles and caps to PVC resin used in their manufacture
must be covered in a DMF or other FDA document such as an NDA .
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37.  TYPE VI DMF s :
s
• Excipient , flavor , essence or material DMF .
• Excipients are chemically inactive substances such as starches or cellulose used to
bind drug powder together so that it can be pressured into a tablet .
• Other examples include flavorings in children's drugs , alcohol in liquids , etc .
 TYPE V DMF s :
• FDA accepted reference information not included in the other types .
• The FDA requires that DMF ‘s be current at the time they re reviewed .
• The FDA regulations regarding DMFs states :
“ 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 be describe by name , reference number, Volume ,
and page number the information affected in the drug master file .”
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38. • The FDA ensure that DMFs are current . If a company has not submitted an annual
report in for three years , the agency sends an
“ Overdue Notification Letters “ to DMF holders .
• The Holder has 90 days in which to respond and submit its annual report .
• If they fail to respond , their DMF may be Closed .
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39. DRUG MASTER FILE (TYPE II ) SPECIFICATIONS
• For drug substance (API) and intermediate DMF will falls under type II DMF
submission .
• DMFs for drug substances hall be submitted in the format
“ Guidance for industry M4Q : The CTD – Quality “ .
• U.S. standard paper size ( Letter : 8 ½ X 11 “ ) is performed .
The left margin should be at least 0.75 “ ( 2 cm )
The right margin should be at least 0.5 “ ( 1.25 cm )
• All submissions should be paginated within the submission .
• All submissions should be made in English only .
• 21 CFR .1(a) States : “ If any part of the application is an a foreign language , an
accurate and complete English translation shall be appended to such part “ .
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40. CONTENT OF DMF
 CTD is organized into Five modules , those are :
 MODULE I : References regional information such as forms , cover letter ,
labeling , and investigational brochures (region specific ).
 MODULE II : Quality Overall summary .
 MODULE III : Quality .
 MODULE IV : Non – Clinical information .
 MODULE V : Clinical information .
Common for all regions
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41. CONTENT OF DMF :
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42. MODULES -1 CONTENTS
 MODULES 1 : Administrative & Prescribed Information
Contain the following information :
 Cover letter .
 Administrative information .
• Addresses of DMF holder and manufacturing and testing facilities .
• Responsible & Contact persons .
 Statement of Commitment .
 US agent appointment letter .
 Declaration on Debarment [ Section 306 (k)(1)] .
 Environmental certification .
 Specimen product label 42

43. MODULES – 2 CONTENTS
 Module 2 Quality Overall Summary (QOS)
 The Quality Overall Summary (QOS) is a summary that follows the scope and
outline of the Body of Data in Module 3.
 The QOS should include sufficient information from each section to provide the
Quality reviewer with an overview of Module 3.
 The QOS normally should not exceed 40 pages of text , excluding tables and
figures . ss
 US DMF QOS should be submit in Question Based Review (Q bR) format
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44. MODULE – 2 CONTENTS
 ABOUT QUESTION BASED REVIEW (Q b R)
 The Office Of Generic Drug (OGD) is developing a question -based review
( Q b s R) for it its Chemistry , Manufacturing , and controls (CMC)
evolution that is focused on critical quality attributes.
 Q b R – QOS is designed with the expectation that the drug substance
application (DMF, NDA , ANDA ) is organized in the CTD format .
 The Q b Rs , a general framework for the CMC assessment of ANDAs ,
incorporates the most important scientific and regulatory review questions
that focus on critical attributes essential for ensuring generic drug product
quality .
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45. MODULE – 2 CONTENTS
Benefits of Q b R s
 Improves submission quality of Drug Master Files .
 Decrease number of review cycles .
 Encourage process understanding and control strategies
and proposed API specifications .
 Shift from data / regulation driven to knowledge driven review .
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46. MODULE - 3 CONTENTS
• MODULE 3 : QUALITY
• TABLE OF CONTENTS OF MODULE 3
• BODY OF DATA
• DRUG SUBSTANCE (NAME , MANUFACTRER)
• General information : Nomenclature , Structure , General Properties .
• Manufacture : Manufacturer (s) , Description of Manufacturing process and
controls , Control of materials , Control of critical steps and intermediates , Process
validation /evolution . Manufacturing process development .
• Characterization : Elucidation of structure and other characteristics , Impurities .
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47. • Control of Drug Substance : specification , analytical procedures ,
Validation of analytical procedures , batch analysis, justification of
specification .
 Reference Standards or Materials .
 Container Closure System
 Stability
• Stability summary and conclusions .
• Post – approval stability protocol and stability commitment .
• Stability Data .
• Relevant information shall be presented In relevant sections as prescribed
in ICH M4Q CTD guideline and should comply with GDUFA ( Generic
Drug User Fee Amendment Initial Complete assessment Checklist .
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48. • The FDA ensure that DMF s are Current .
• If a company not submitted annual reported in for three years , the agency sends an
“ Overdue Notification Letters “ to DMF holders .
The Holder has 90 days in which to respond and submit its annual report . If they fail
to respond , their DMF may be Closed .
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49. REFERENCES :
• www.slideshare.com
• www.ngsmips.nitee.edu.in .
• www.thebalance.com
• WIKIPEDIA Federal Register .
• WIKIPEDIA FFDCA .
• www.authourstream,com
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50. Submitted To :
Dr. SHANTA KUMAR G.S.
H.O.D
OF
DRUG REGULATORY AFFAIRS BRANCH
ACHRYA & B M REDDY COLLEGE OF PHARMACY .
BANGLORE .
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