REGULATORY AFFAIRS

1. Discuss about drug master file in detail.

 Definition: “A drug master file (DMF) is a submission to the FDA of
information, usually concerning the confidential detailed information about
chemistry, manufacturing and controls (CMC) of a drug product or a
component of a drug product.”

 Reasons for a DMF:

 Maintain confidentiality of proprietary information (e.g., manufacturing
procedure) for the holder
 Permit review of information by reviewers at FDA to support applications
submitted by one or more Aps.

 Types of drug master files:

 Type I – Manufacturing site, facilities, operating procedures, and personnel.
 Type II - Drug substance, drug substance intermediate, and material used
in their preparation, or drug product.
 Type III – Packaging material
 Type IV – Excipient, colorant, flavour, essence, or material used in their
preparation.
 Type V – FDA accepted reference information

 Content of DMF:
The CTD is organized into five modules. Those are as follows:
 Module 1: administrative information and prescribing information
(Region specific)
 Module 2: Quality Overall summary
 Module 3: Quality
Common for all region
 Module 4: Nonclinical study reports
 Module 5: Clinical study reports

 Submissions to drug master files:

 The DMF must be in the English language. Whenever a submission
contains information in another language, an accurate certified English
translation must also be included.
  DMF contains:
1 – Transmittal (cover) letter
2 – Administrative information
3 – Technical information (DMF types)
4 – Format, assembly, and delivery
 Original submissions
o Initial/first time submission is known as original submission.
 Amendments
o Charge in the content of original submission i.e., specifications,
validations, etc.

o For each submission covering letter should be prepared to facilitate

processing of documents, list the submission type in bold type in the
header on the cover letter.
 Authorization to refer a drug master file:
 Letter of authorization to FDA.
 Before FDA can review DMF information in support of an applications,
the DMF holder must submit in duplicate to the DMF a letter of
authorization permitting FDA to refer the DMF.
 If the holder cross refers its own DMF, the holder should supply in a letter
of authorization the information designated by items 3, 5, 6, 7, and 8 of
this section. The holder does not need to send a transmittal letter with its
letter of authorization.
 The letter of authorization should include the following:
 The date
 Name of DMF holder
 DMF number
 Name of persons authorized to incorporate information in the DMF by
reference.
 Specific products covered by the DMF
 Submission dates
 Section numbers and/or page numbers to be referenced
 Statement of commitment that the DMF is current and that the DMF holder
will comply with the statements made in it.
 Signature of authorizing official
 Typed name and title of official authorizing reference to the DMF.
2. Write short note on MHRA.
 Medicine and healthcare product regulatory agency (MHRA):

 Definition: “The medicines and healthcare products regulatory agency

(MHRA) is a government body which of the Department of Health of United
Kingdom was set up in 2003 to bring together the functions of the medicines
control Agency (MCA) and the Medical Devices Agency (MDA).”

 Function of MHRA:

MHRA Functions:
 Regulation of clinical trials
 Safety and efficacy monitoring
 Providing information to public and health professionals
 Licensing
 o Manufacturer and dealer licenses
o Clinical trial licenses
o Parallel import licenses
 Enforcement of law

 The MHRA licenses/ authorizes:

 Pharmaceutical manufacturers
 Medicines importers
 New biological or chemical compounds
 Different brands of existing medicines
 Generics (identical but cheaper versions of existing branded medicines)
 New forms of existing medicines, such as syrups, patches, or injections
 New uses for existing medicines, such as different patient groups or
different conditions
 Reclassification of medicines from
 Prescription only to over-the-counter use, such as the cholesterol lowering
medicines simvastatin (Zocor Heart-pro)
 Traditional herbal medicines sold over the counter that meet required safety
and quality standards
 Clinical trials of both medicines and devices, from toothpaste to gene
therapy
 Blood banks that meet required safety and quality standards
 Applications on humanitarian grounds to use certain medical devices in the
UK not carrying a CE marking.

 Renewal of license:
 Cancellation of license:
 If Mas holder does not file an application for renewal within specified time,
Mas expires automatically.
 If the Mas holder does not wish to renew the license, a letter should be sent
indicating the cancellation to:
o Administrative support team
o Medicines and healthcare products regulatory agency
(MHRA)
 MHRA has authority to cancel license of product if it affects public health.

 Export drugs and medicines:

Permission must need to export certain drugs and medicines.
These are:
o Controlled drugs
o Drugs that can be used for lethal injections
o Medicines
o Export certificates for medicines for animals

3. Explain regulatory requirements of TGA.

 The Therapeutic goods administration (TGA) is Australia’s regulatory

authority for therapeutic goods.
 TGA carry out a range of assessment and monitoring activities to ensure
therapeutic goods available in Australia are of an acceptable standard.

Mission of TGA:
 To ensure that medicines and medical devices in the market place are safe and
of high quality.
 To provide a national framework for the regulation of therapeutic goods in
Australia and ensure their quality, safety and efficacy.
 To ensure public health and safety and freeing industry from any unnecessary
regulatory burden.
 To ensure that the Australian community has access, within a reasonable time
to therapeutic advances.
 What are Therapeutic Goods-
 A therapeutic good is broadly defined as a good which is represented in any
way to be, or is likely to be taken to be, for therapeutic use, unless specifically
excluded or included under section 7 of the therapeutic goods act 1989.
 For the purpose of evolution and assessment, therapeutic good is a product use
in humans that is used in, or in connection with –

 Prevention, diagnosis, curing or alleviating a disease, aliment, defect or injury

 Influencing inhibiting or modifying a physiological process
 Testing the susceptibility of persons to a disease or aliment
 Influencing, controlling or preventing conception
 Testing for pregnancy
 Replacement or modification of parts of the anatomy
TGA regulates –
TGA controls supply of therapeutic goods and is exercised through three main
processes-

o Pre-market assessment
o Licensing of manufacturers
o Post market vigilance

 Pre-market assessment
 Product assessed as having a higher level of risk (prescription medicines,
some non-prescription medicines and medical devices) are evaluated for
quality, safety and efficacy.
 Products assessed as being lower risk (many non-prescription medicines)
are assessed for quality and safety.
 In assessing the level of risk, factors are to be considered such as-
 Strength of product
 Side effects
 Potential harm through prolonged use
 Toxicity
 Seriousness of medical condition for which the product is intended to
be used
 Licensing of manufacturers
 Australian manufacturers of therapeutic goods must be licensed.
 The manufacturing processes must comply with principles of good
manufacturing practice (GMP)
 The aim of licensing and maintain standards are to protect public health by
ensuring that medicines and medical devices meet definable standards of
quality assurance and are manufactured in conditions that are clean and free
of contaminants.

 Post market vigilance

 Post marketing activities include investigating reports of problems,
laboratory testing of products on the market and monitoring to ensure
compliance with the legislation.

4. Discuss outsourcing BA and BE to CRO.

 Bioavailability and Bioequivalence (BA and BE):
 Bioavailability: measurement of the amount and rate at which the drug
from administered dosage form, reaches the systemic circulation and
becomes available at the site of action.
 Bioavailability describes the concentration of drug in systemic blood in
relation to the amount of drug given.
 Bioequivalence: it is a relative term which denotes that the drug substance
in two or more identical dosage form, reaches the systemic circulation at
the same relative rate and to the same relative extent i.e.; their plasma
concentration-time profiles will be identical without significant statistical
differences

 Typical services outsourced for BA-BE studies:

 Bioanalytical studies
 Bioanalytical site selection and Qualification
 Clinical study design
 Clinical protocol development
 Clinical site selection and Qualification
 Clinical conduct
 Clinical monitoring
 Data management
  Pharmacokinetic analysis
 Statistical analysis
 Pharmacokinetic report writing
 Integrated ICH report writing
 Project management
 FDA/Regulatory consultation

 Advantages:
 Improved customer service
 Increase productivity and efficiency
 Better people management
 Focus on core competencies
 Access to world class solutions
 Skilled expertise
 Cost savings

 Problems with outsourcing-

 CRO (contract research organisation):

 A contract research organisation (CRO) is an organisation that provide
support to the pharmaceutical, biotechnology and medical devise industries
in the form of research services outsourced.
  It offers various pharmaceutical research that is essential for conducting
clinical trials, the ICH technical requirements for registration of
pharmaceuticals for human use.
 A CRO is an organisation contracted by another company to manage and
lead to the company’s trials, duties and functions.
 Organisations and businesses that contract with CROs do so to acquire
specific expertise without hiring permanent staff.
 CRO independent organisation that steps in to the development process
once a pharma company has identified a promising new molecule.
 Example of CROs include: Quintiles, Covance, icon, Zydus Cadila and
HMR.

5. Discuss regulatory requirements for investigational medicinal product

dossier (IMPD).
 Definition:
 “The IMPD is one of several pieces of investigational medicinal product
(IMP) related data required whenever the performance of a clinical trial is
intended in one or more European union member states.”

 The IMPD includes summaries of information related to the quality,

manufacture and control of any IMP (including reference product and
placebo), and data from non-clinical and clinical studies.

 Format of IMPD:
 IMPD follow the structure of CTD module (3).
 Exist guidance on sectional headings to be used in full IMPD.

 IMPD contents:
 IMPs are submitted as part of clinical trial application dossier, as the basis
for approval of clinical trials by competent regulatory authorities within
European union.
IND application are equivalent in U.S.
 Contents: subsequent trial documentation
1) Protocols
2) Informed consent forms
3) Investigator brochure
4) Study reports
 5) Subject narratives
6) Risk management plans
7) Periodic safety update reports
 The IMP dossier required will depend on many factors including:
o Risk
o Nature of the product nature of the product
o State of development
o Patient population patient population
o Nature and severity of the illness
o Type and duration of the clinical trial itself

 Objective:
 Clinical trial often to be designed as multicentre studies potentially involve
in different member states.
 Aim of these guidelines to defines harmonized requirement of
documentation to be submitted throughout the European community.

 Scope:
 Guidelines addressed to IMPs containing chemically defined active
substances, synthetic peptides, herbal substance, herbal preparation and
chemically defined radioactive/radio labeled substance.
 It includes requirements of IMPs to be tested in phase I, phase II and phase
III clinical studies.

 Guidance and legal basis:

 The guidance is based on Regulation (EU) No 536/2014 on clinical trials
on medicinal products for human use (repealing directive 2001/20/EC) on
the approximation of laws, regulations and administrative provisions of
the member states.
 The regulation comes into force in 2016, harmonizing the laws,
regulations and administrative provisions of the member states relating to
the implementation of good clinical practice (GCP) in the conduct of
clinical trials on medicinal products for human use.
 European member states have transformed the requirements outlined in
the directive into the respective national laws.
6. Describe contents of investigator brochure used in clinical trial.
 Content of IB:
 It should include:
 Title page:
 Sponsor name
 The identity of each investigational product (i.e., research number,
chemical or approved generic name and trade name)
 The release date, reference number, date of edition.
 Confidential statement
 Table of contents
 Summary- Not exceeding 2 pages, highlighting the physic, chemical,
pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic
and clinical information available as per IP.
 Introduction
 Chemical name
 Active ingredients
 Pharmacological class
 Anticipated- therapeutic/diagnostic indications
 Description of IP – storage and handling, structural similarity of any other
compound.
 Non-clinical studies – it may include following information
 Species tested
 Number of sex in each group
 Unit dose (mg/kg)
 Dose interval
 Route of administration
 Duration of dosing
 Effect in human
 Pharmacokinetic and product metabolism in human
 Safety and efficacy
 Marketing experience
 Summary of data and guidance for the investigator – it contains non-
clinical and clinical data of IP.
 Thus, IB provide the investigator a clear understanding of –
 The possible risks
 Adverse reactions
 Observation and precautions needed for clinical trials.
7. Write short on HIPAA.

 Health Insurance Portability and Accountability Act (HIPAA)

The Goal of HIPAA:
 The primary goal of HIPAA is –
I. To make law easier for people to keep health insurance
II. Protect the confidentiality and security of health care information.
III. Help healthcare industry to control administrative cost.
 What does HIPAA consist of?
1. Standardized electronic Data interchange transactions and codes for all
covered entities.
2. Standards for security of data systems.
3. Privacy protection for individual health information.
4. Standard national identifiers for health care.
About HIPAA:
 HIPAA is divided into two different sections. Those are: -
Portability
Administrative simplification
 Portability:
 This section allows individuals to carry their health insurance from one
job to another, so that they do not have a lapse in coverage.
 It also restricts health plans requiring pre-existing condition of an
individuals who switch from one health plan to another.

 Administrative simplification:
 This section is the establishment of a set of standard for receiving,
transmitting and maintaining the healthcare information.
 Ensuring the privacy and security of individuals identifiable information.

Who must comply?

 The individuals responsible for implementing HIPAA rules and regulations.
Some examples are:
 Health plans
 Health care clearing houses
 Health care providers who conduct certain financial and administrative
transactions electronically.
HIPAA patient rights:
 HIPAA guarantees several rights to patients:
1. Right to privacy
2. Right to confidential use of their health information for their treatment,
billing process, and other health care operations (such as quality
improvement)
3. Right to access and amend their health information upon request
4. Right to provide specific authorization for use of their health information
other than for treatment, billing and other health care operations.
5. Right to have their name withheld from our patient directories
6. Right to request that individuals are not told of their presence in our
facilities.
Importance HIPAA Terminology:
 Protected health information (PHI)
 Covered Entities (CE)
 Treatment, Payment and Health care Operations (TPO)
 Notice of privacy practice (NPP)
Compliance:
 If you feel there has been a privacy violation, inform your instructor who
will immediately assist you in contacting the privacy officer.
 Refer patient who have a privacy concern or complaint to the nurse in
charge of the unit.

8. Describe Hatch – Waxman act and its amendments in detail.

 Definition: Hatch-Waxman Act- Also known as “THE DRUG PRICE
COMPETITION AND PATENT TERM RESTORATION ACT OF 1984.”
 OBJECTIVE OF THE 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.
 Drug approval:
 The FDA requires every new drug, including generic drugs, to be safe and
effective.
  Before the adoption of the Hatch-Waxman Act, the FDA required branded
and generic drug companies a like to demonstrate the safety and efficacy
of their products in the same manner through a New Drug Application
(NDA).
 Hatch Waxman Trade-off:

 BENEFITS FOR GENERIC MANUFACTURERS

 180-day market exclusivity for first successful challenger to orange
book patent
 Allows generics to challenge orange book patents without risk of
damages

 Exclusivity:
 The patent holder may obtain exclusivity for a brand name product, which
essentially extend the time of protection under certain circumstances.
Exclusivity also prevents the effective approval of ANDAs.
 Type of Exclusivity:
 Loopholes of the Act:

I. Authorized generics:
 Authorized Generics is the brand company’s own product repackaged
and marketed as a generic drug either through a subsidiary or a third
party.
 Authorized generics provides consumers with brand quality at generic
price which would compensate the loss after the patent expiry.

II. Warehousing patents:

 An innovator may patent multiple attributes of a product and keeps on
adding patents in the orange book. Which brings along the risks of
litigation and associated costs and delays in obtaining ANDA approval.
 The provision of filing a patent infringement lawsuit gives the brand
name manufacturer at least an additional two and a half years of product
monopoly.

 Conclusion:
 The Hatch-Waxman act allows for a patent term extension of a
maximum of 5 years for the branded drug manufacturer to compensate
for the time lost during the NDA approval by the USFDA.
 Permitted generic manufacturers to use safety and effectiveness
research performed by the brand name pharmaceutical companies.
 Encouraged patent challenges by providing 180-day market exclusivity
for the first generic manufacturer who files ANDA.
9. Explain PARA I to IV filling in ANDA.

 PARA- I:
 Required patent information has not been filed.

 FDA may approve generics immediately; one or more applicants may

enter.
 PARA- II:
 Patent has expired

 FDA may approve generics immediately; one or more applicants may

enter.
 PARA- III:
 Patent not expired, will be expired on a specific date.

 FDA may approve ANDA effective on the date of expiration, one or

more applicant may enter.
 PARA- IV:
 Patent is invalid or non-infringed by generic applicant.

 Generic applicant file notice to patent holder.

10. Write a note on post marketing surveillance.
 Definition: “ Post marketing surveillance is the practice of monitoring the
safety of pharmaceutical drugs or medical devices after it has been released
into the market for public use.”
 Limitations of pre-marketing clinical trials:
 Narrow population-often not providing sufficient data on special groups
 Narrow indication studies
 Short duration
 Rare ADRs may not get detected
 Benefits of PMS:
 Study of:
(In context of drugs)
 Low frequency reactions (not identified in clinical trials)
 High risk groups
 Long term effects
 Drug-drug/food interactions
 Increased severity and/or reporting frequency of known reactions
(In context of medical devices)
 Manufacturing problems
 Improvement in quality
 Verification of risk analysis
 Long term performance
 Performance in different user population
 Sources of PMS information:
 Expert user groups
 Customer surveys
 Customer complaints and warranty claims
 Literature reviews
 The media
 Methods of PMS:
following four types of studies are generally carried out to identify drug
effects:
 Controlled clinical trials
 Spontaneous or voluntary recording
 Cohort studies
 Case control studies
 Controlled clinical trials:
 Retrospective study
 Directly monitor patients
 Often costly
 Evaluate rare suspected side-effects
 Spontaneous/voluntary reporting:
 Communication from an individual to a company or regulatory
authority
 Submitted voluntarily
 May be encouraged or stimulated by media reports or articles
 In many parts of the world adverse event reports are submitted
electronically using a defined message standard by physicians and other
health providers and hospitals which may act to alert FDA and
pharmaceutical firms.
 Cohort studies:
 Prospective study
 Planned in advance and carried out over a future period of time
 Non-random
 Investigate the cause of disease
 Establish links between risk factors and health out comes
 Case control study:
 Identify patients with the adverse effects to be studied (the cases)
 Compare them with a sample (the controls)
 Both ‘the cases’ and ‘the controls’ are drawn from the same cohort
 Economical

11. Write note on guidelines of ICH-M.

 Multidisciplinary Guidelines (M):
 Those are the cross-cutting topics which do not fit uniquely into one
of the quality, safety and efficacy categories.
 It includes the ICH medical terminology (MedDRA), the common
technical document (CTD) and the development of electronic standards
for the transfer of regulatory information (ESTRI).
 Multidisciplinary Guidelines (M):
 M1 (MedDRA Terminology)
 M2 (Electronic Standards)
  M3 (Nonclinical safety studies)
 M4 (Common Technical Document)
 M5 (Data Elements and Standards for Drug Dictionaries)
 M6 (Gene Therapy)
 M7 (Mutagenic impurities)
 M8 (Electronic common technical document i.e., eCTD)
 M9 (Biopharmaceutics classification system-based Biowaivers)
 M10 (Bioanalytical method validation)
 M11 (Clinical electronic structured Harmonised protocol i.e., CeSHarP)
 M12 (Drug interaction studies)

 M1 (MedDRA Terminology):
 MedDRA: medical dictionary for regulatory activities
 M2 (electronic standards)
 ESTRI: electronic standards for the transfer of regulatory information
 M3 (Nonclinical safety studies)
 M3(R2)- guidance on non-clinical safety studies for the conduct of
human clinical trials and marketing authorization for pharmaceuticals
 M4 (Common Technical Document)
 CTD: the common technical document
 M5 (Data Elements and Standards for Drug Dictionaries)
 M6 (Gene Therapy)
 M6- virus and gene therapy vector shedding and transmission
 M7 (Mutagenic Impurities)
 M7(R1) – Assessment and control of DNA Reactive (Mutagenic)
impurities in Pharmaceuticals to limit potential Carcinogenic Risk
 M7 (R2) – Assessment and control of DNA reactive (Mutagenic)
impurities in pharmaceuticals to limit potential carcinogenic Risk
 M8 (Electronic common technical document i.e., eCTD)
 Electronic common technical Document(eCTD)
 M9 (Biopharmaceutics classification system-based Biowaivers)
 M10 (Bioanalytical method validation)
 M11 (Clinical electronic structured Harmonised protocol i.e., CeSHarP)
 M12 (Drug interaction studies)
12. Give in details of pharmacovigilance safety monitoring in clinical trials.
 Pharmacovigilance:
 Pharmacovigilance concerned with the detection, assessment and
prevention of adverse reactions of drug.
 The science and activities relating to the detection, assessment,
understanding and prevention of adverse effects or any drug related
problems.
 Safety Monitoring in Clinical Trials:
 Monitoring patient’s safety during clinical trials is a critical component
throughout the drug development life cycle.
 Pharmaceutical sponsors must work proactively and collaboratively
with all stakeholders to ensure a ensure a systematic approach to safety
monitoring.
These standards include:
 The international conference on harmonization good clinical practice
(ICH-GCP) guidelines.
 International ethical guidelines for biomedical research involving
human subject issued by the council for international organization of
medical science (CIOMS).
 Common practice in safety monitoring:
1. Stakeholders in safety monitoring:
A. Sponsors:
 Protocol: The protocol describes every aspect of the research,
including the rationale for the experiment.
 ICF (informed consent form) : Used to disclose current information
about the investigational drug and about the procedure, risk and
benefits for subject who participate in clinical trials.
 CRF (case report form): designed by the sponsor as data collection
tools. This tool is based on electronic data capture module via internet
rather than the traditional based route.
B. Subject:
 Subjects are patients or healthy volunteer who agree to participate in a
clinical trial and have signed ICF.
C. Investigator:
 Investigators are qualified individuals who are trained and experience
to provide medical care to the subject enrolled in the trails.
 D. Institutional review Board/Ethics committee
 The institutional review board (IRB) also known as ethics committee,
is charged with protecting the rights and welfare of human subject
recruited to participate in research protocol.
E. Data and safety monitoring board
 The data and safety monitoring board (DSMB), also called as data
monitoring committee (DMC) is an expert committee, chartered for one
or more clinical trials.
F. Regulatory Authority
 Prior to the initiation of a first human in clinical trials, pharmaceutics
sponsors must submit as investigational new drug (IND) application to
the FDA has require by the law.
G. Medical community and patients
 Clinical trials generate data that contribute to the body of knowledge about
the treatment and the disease that benefit the broader medical community
and, ultimately, the patients.

13. Explain code of federal regulation (CFR) 21.

 Federal govt. system in USA:

 Relating to a system of government in which several states form a unity but
remain independent in internal affairs.
CFR:
 The code of federal regulations (CFR) is a codification of the general and
permanent rules published in the federal register by the executive dependents
and agencies of the federal government.
 CFR 21 is widely followed in pharmaceutical companies and has great
importance in digital documentation.
 CFR 21 part 11 is well known in pharmaceuticals.
Title 21 of the CFR is reserved for rules of the food and drug administration.
 The CFR is divided into 50 titles that represent broad areas subject to federal
regulation.
 Each title is further divided into parts, and sections.
 E.g., 21 CFR 11.502
 Title:21
 Part:11
 Section:502
 Since, A regulation is cited by title, part, and section
The annual update cycle of CFR
 Each title of the CFR is revised once each calendar year.
 A revised title 21 is issued on approximately April 1st of each year.
 The annual update cycle of CFR is as follows:
 Titles 1 – 16 are updated as of January 1
 Titles 17 – 27 are updated as of April 1
 Titles 29 – 41 are updated as of July 1
 Titles 42 – 50 are updated as of October 1
Governing bodies of 21 CFR
 Title 21 of the CFR or the code of federal regulations deals with governing
of food and drugs in the United States for three of its governing bodies:
 The FDA (food and drug administration),
 DEA (drug enforcement agency) and
 ONDCP (Office of national drug control policy).
 CFR 21 part 11 is generally known for electronic signature. (Data in digital
form)
 Electronic Record: maintaining digital form of data that is created,
modified, maintained, archived, retried or distributed by a computer.

 Electronic Signature: A compilation of any symbol executed to be the

legally binding equivalent of an individual’s handwritten signature.

 21 CFR part 11 is a section in the CFR that sets forth the united states food
and drug administrations (FDA) guidelines on using electronic records and
electronic signatures.
 Each title of the CFR addresses a different regulated area, 21 CFR related
to pharmaceuticals and medical devices and part 11 being applicable to
electronic records and electronic signatures.
Chapters in 21 CFR
 The first edition of the CFR was published in 1938.
 Title 21 of the CFR is reserved for rules of the food and drug
administration.
  It is divided into three chapters:
Chapter I – food and drug administration,
Chapter II – Drug Enforcement Administration
Chapter III – office of national drug control policy

14. Write note on ANVISA.

 ANVISA means “Agencia Nacional De Vigilancia Sanitaria.” This
abbreviation is in Portuguese language. In English, it means “National
Health Surveillance Agency” or sometimes it is written as “Brazilian Health
Surveillance Agency”.
 ANVISAs Mission:
 “To protect and promote health, ensuring the hygiene and safety of
products and services and taking part in developing access to it.”
 Values:
 Transparency
 Knowledge (as a springboard for action)
 cooperation
 Vision:
 To be an agent for transformation of the decentralized sanitary
surveillance system, within a network, holding a distinct position,
legitimized by the population, as regulator and promotor of social
well-being.
 ANVISA is responsible for
- Monitoring drug prices
- Prices of medical devices
- Control and inspection of smoking products
- Technical support in granting of patents by the national institute
of industrial property.
- Protection of the health of the population by exercising sanitary
control over production
- Marketing of products and services subject to sanitary
surveillance, controlling ports, airports and borders
 ANVISA is a part of NSSS:
o National System of Sanitary Surveillance (NSSS) is an organization
of Brazil whose responsibility is
- To keep a watch over certain professional activities
- To put a stop to charlatanism
 - To inspect ships, cemeteries and places where food was on sale
to the public.
 Regulations by ANVISA:
o Blood and blood products
o Cosmetics
o Drugs
o Genetic drugs
o Food
o Health services
o International affairs
o Market regulations
o Medical devices
o Pharmacovigilance
o Ports, airports and borders
o REBLAS -Brazilian network of analytical laboratory
o Sanitizing products
o Tobacco
o Toxicology
 ANVISA- Guidelines
 Registration procedure of new drug is divided in mainly 3 parts as
follows-
1) Pre-registration measures
o Protocol for clinical study
2) Registration
o Documents to be submitted
o Protocol for the new drug
o Protocol for import of new drug
3) Post-registration
o Alteration in registration, renewal of registration
 Thus, these three parts can be considered similar to IND, NDA and
supplementary NDA as per US FDA.

15. Write the importance of informed consent process.

 The process of consent:
 Choose the right environment and location to obtain consent.
 Involve multiple health care personnel as necessary.
 Include family members in the process as warranted.
  Ensure that the subject or legally authorized representative is
competent.
 Ensure the subject or LAR has sufficient understanding.
 Continue the process of consent throughout the study.
The plan of consent process:
 Identify obstacles to participation in study and ways to overcome
obstacles
 Identify words subject may not understand
 Compile “frequently asked question” list
 Decide who will do consent discussion
 Decide where consent discussion will be held
 Provide adequate time to explain study to subject.
 Provide adequate time for subject to read and consider and for questions
to be answered.

16. write short note on CMC.

 CMC (Chemistry, Manufacturing and Control):

 CMC regulatory affairs is a specific area with RA that has ultimate
responsibility for providing CMC regulatory leadership and strategy
required to achieve regulatory approvals.
 CMC RA provides knowledge, understanding, interpretation and
utilization of regulatory guidance and regulations, as well as industry and
government agency best practice and trends.
 CMC RA is a high value-added function within a company that is critical
to successful development, registration, approval and life cycle
management of pharmaceutical product.

 Example: CMC regulatory submission may contain information associated

with API and the finished dosage form, including:
 Names and location of manufacturing and testing sites
 Characterization of the API and composition of the dosage form
 Raw materials used to manufacture the API and finished dosage form
 Description of the product and process development
 Description of the manufacturing process
  Analytical methods and specifications used for testing and release of
raw materials, in-process controls, container and closure system, API
and dosage form.
 Quality testing, bio equivalence testing
 Release and stability testing data for both API and the dosage form.

17. Describe specific requirements and contents of an NDA.

 Requirement for NDA:
 NDA technical section (specific) requirement:
1. Chemistry, manufacturing, and control
A) Drug substance
B) Product
2. Non clinical pharmacology and toxicology
3. Human pharmacokinetics
4. Bioavailability section
5. Microbiology
A) Mechanism of action
B) Pharmacokinetics
C) Antimicrobial activity
D) Enzyme hydrolysis rate
E) Assessment of resistance
F) In vivo animal studies
G) In vitro studies during clinical trial
H) Published literature
I) Miscellaneous studies
 NDA Contents:
 The NDA have as many as 15 different sections in addition to the form
FDA 356h itself.
 The specific content of NDA will depend on the nature of the drug
product and the information available at the time of submission the
application.
18. Explain ANDA regulatory approval process in detail.
 ANDA (Abbreviated New Drug Application) regulatory approval
process:

 Steps:
 Filing review
 Coordination of generic drug review process
 Bioequivalence review process
 Chemistry review process
 Labelling review process
 Putting it all together
Filling review:
 The process begins when an applicant submits an ANDA to the OGD.
 The document room staff assigns it an ANDA number and stamps a
received date on the cover letter of ANDA.
 It is sent to a consumer safety technician who reviews the preliminary
sections of ANDA checklist.
 It is sent to a consumer safety technician who reviews the preliminary
sections of ANDA checklist.
Coordination of the generic drug review process:
 The application is assigned to a bioequivalence reviewer, a chemist and a
labelling reviewer.
 Each chemistry team consists of a team leader, a project manager and
several reviewers.
 The chemistry project manager serves as the “Applicant project manager
(APM)”, they plan, organize and coordinate all of the review activities for
the applications that they manage.
Bioequivalence review process:
 Bioequivalence project manager (BPM) access list of pending ANDA
assign to individual reviewers according to “first-in, first-reviewed”
policy.
 The DBEs responsibilities include BE section of ANDA, Bio-
investigational new drug applications (Bio-INDs), protocols and
controlled correspondence.
 This process establishes BE between a proposed generic drug and the
RLD.
Chemistry review process:
 The chemistry, manufacturing and controls (CMC) section of the
application is assigned to the app chemistry division and team based on
therapeutic category of the drug product.
 The team leader assigns the application to a reviewer on team according
to the “first-in, first-reviewed policy”.
 The chemistry division reviews CMC section of ANDA, drug master file,
annual reports and controlled correspondence.
Labelling review process:
 Labelling section of the application is assigned to the app labelling
reviewer based on the therapeutic category of the drug product.
 The labelling review branch is part of DLPS.
 A team leader oversees the work of 4-6 reviewers.
 The basis for the labelling review is to ensure that the generic drug
labelling is the “same as” the RLD labelling.
Putting it all together:
 After the final office level administrative review and individual disciplines
have resolved their deficiencies, the application will either receive a full
approval or a tentative letter.
 When the review of an ANDA is completed, the APMs draft the app
approval letter and circulate it with the reviews and application for
concurrence.
 The APMs communicate with the OGD management on a weekly basic to
update them on the progress of reviews.

19. Discuss CTD and eCTD in detail.

 CTD (Common Technical Document): Its a format set by ICH which was
agreed by the regulatory agencies of Europe, Japan and the US.
 The CTD Triangle:
 CTD Modules:
 Module 1 – administrative information (Region specific)
 Module 2 – CTD summaries (QOS)
 Module 3 – quality (CMC)
 Module 4 – non-clinical study reports
 Module 5 – clinical study reports
 eCTD (Electronic Common Technical Document): its electronic version of
CTD, so called as eCTD.
 eCTD composed of two types of specification
 content specification- As defined by ICH
 Technical specification- Electronic software’s

 CTD TOC (Pdf) (paper)

 eCTD XML Backbone
 eCTD is highly recommended by USFDA for NDAs, BLAs, DMFs
and INDs filing
 from year 2010 European Union also make compulsory for electronic
CTD submission to all procedures

 eCTD Characteristics:
Structure
 all modules 1 to 5 have granularity options.
 PDF documents linked via XML backbone
 Increased document granularity.
 Transparency of entire submission
 Ease of navigation and review
  Benefits of eCTD:

20.