The document outlines the role and functions of regulatory affairs in the pharmaceutical industry, focusing on the interface with drug regulatory authorities, such as the FDA and CDSCO, to ensure the safety, efficacy, and quality of drugs. It discusses essential components like the Master Formula Record and Drug Master File, as well as the processes for New Drug Applications (NDA) and Abbreviated New Drug Applications (ANDA). Additionally, it highlights the significance of bioequivalence studies, the Hatch-Waxman Act, and post-marketing surveillance in drug development and approval.

1. REGULATORY
AFFAIRS
I Silambarasan
M pharm(pharmaceutics)
MTPG &RIHS

2. WHAT IS REGULATORY AFFAIRS?
◦ A regulatory affairs is a profession which act as interface between
pharmaceutical industry and drug regulatory authority around the
world.
COMPANY
PRODUCT
REGULATORY
AFFAIRS
REGULATORY
AUTHORITY

3. GOAL’S OF RA
◦ Protection of Human health
◦ Ensuring safety ,efficacy and quality of drugs
◦ Ensuring accuracy of product information

4. MAJOR REGULATORY AUTHORITY
Country Regulatory Authority
India Central Drugs Standard Control Organization(CDSCO)
US Food and Drug Administration (US FDA)
UK
Medicines and Health care products regulatory
(MHRA)
Australia Therapeutic Goods Administration (TGA)
Japan
Japanese Ministry of health, Labour and Welfare
(MHLW)
Canada Health Canada
Europe European Directorate for Quality of Medicines

5. ROLE OF REGULATORY AFFAIRS
Registration
document to
regulatory Agency
To keep Track in
every change in
legislation
To give strategic &
technical advice to
R&D,QC,
PRODUCTION

6. MASTER FORMULA
RECORD

7. MASTER FORMULA RECORD
◦ Master Formula Record (MFR) is a master document for any
pharmaceutical product.
◦ MFR contains all information about the manufacturing process for the
product.
◦ MFR is prepared by the research and development team of the
company.
◦ MFR is used as reference standard for preparing batch manufacturing
record (BMR) by manufacturing units.
◦ MFR is also called Master Manufacturing Record, Master Production
Record.

8. DEFINITION
◦ “A document or set of documents specifying the starting materials
with their quantities and the packaging materials, together with a
description of the procedures and precautions required to produce a
specified quantity of a finished product as well as the processing
instructions, including the in-process controls”

9. MASTER FORMULA RECORD CONTAIN’S
Product Details
◦ Name, logo and address of the
manufacturing company
◦ Dosage form name
◦ Brand name
◦ Product code
◦ Product description
◦ Batch size
◦ Pack size and packing style
◦ Shelf life
◦ Storage conditions
◦ MFR number and date
◦ Authorization by the
production and quality
assurance head

10. MFR SAMPLE

14. DRUG MASTER FILE

15. DRUG MASTER FILE
◦ It is a submission to USFDA or to concerned regulatory authority, that
may be used to provide confidential and detailed information about
manufacturing ,processing ,packaging or storing of one or more
human drugs.
◦ DMF is not mandatory by law or FDA regulation.
◦ DMF is submitted by API manufacturers.
◦ The information in DMF is used to support NDA,ANDA,IND.
◦ It is a submission that indicates that product of one company is a
quality product and meet the required standards.

16. TYPES OF DRUG MASTER FILES

17. REVIEWER When reviewer receives an application
(IND/NDA/ANDA) that references DMF
Requests the DMF from
the CDR (central document room)
After getting DMF, the
Reviewer starts the review
procedure
If Reviewer found any
deficiency in the content of
DMF,
The APPLICANT is notified for
deficiencies
DETAILED DEFICIENCIES
are communicated to the holder.
HOLDER should submit the
REQUESTED INFORMATION to the
DMF
REVIEW
OF
DMF

18. DISTRIBUTION
RECORD

19. DISTRIBUTION RECORDS
◦ Distribution: The division and the movement of pharmaceuticals
products from the premises of the manufacturer to the end user or to
an intermediate point by means of various transport methods.
◦ Distribution records: Are written data related to distribution of drug
products from manufacturer to the distributor.

20. DISTRIBUTION PROCEDURE
◦ A procedure whereby the oldest approved stock of a drug product is
distributed first.
◦ It must be constructed and procedures established to facilitate recall
of defective product.
◦ The manufacturer must maintain records of all distribution
transactions involving in process or finished goods.
◦ Computerized tracking systems are most common.

21. DISTRIBUTION RECORDS SHOULD
CONTAIN
◦ Name
◦ Strength of the product
◦ Name and address of consignee
◦ Date and quantity shipped
◦ Control number of drug product

22. GENERIC DRUG
PRODUCT
DEVELOPMENT

23. GENERIC DRUG
◦ A generic drug is “ a drug product that is comparable to/
bioequivalent to brand/innovator drug in dosage form, strength, route
of administration, quality & performance characteristics”.
◦ After the expiry of the patent or marketing rights of the patent drug ,
generic drugs are marketed.

24. PRODUCT DEVELOPMENT
◦ PRODUCT : A product is something sold by an enterprise to its
customers.
◦ PRODUCT DEVELOPMENT : Product development is the set of
activities beginning with the perception of a market opportunity and
ending in the production , sale and delivery of a product.

25. GENERIC PRODUCT DEVELOPMENT PROCESS
◦ The input of the process is a mission statement and the output of the
process is the product launch.
◦ MISSION STATEMENT :
Identifies the target market for the product , provides a basic
functional description of the product , and specifies the business
goals of the effort ; results from well executed product planning
phase.
◦ PRODUCT LAUNCH :
Occurs when the product becomes available for purchase in the
market place.

26. HATCH WAXMAN ACT
◦ It is otherwise called as “Drug Price competition & Patent term
Restoration Act” .
◦ Established in 1984.
◦ The main objective is
- to reduce the cost
- to make available more low cost generic drugs
- Motivating the generic drug Manufacturer
◦ Generic drug manufacturers files ANDA that incorporates safety and
effectiveness data submitted by original pioneer drug manufacturer
and adds only bioequivalence study.

28. PROVISIONS OF THE ACT
◦ Paragraph I: that such patent information has not been filed
◦ Paragraph II: that such patent has expired
◦ Paragraph III: of the date on which such patent will expire
◦ Paragraph IV: that such patent is invalid or will not be infringed by the
manufacture, use, or sale of the new drug for which the application is
submitted

29. ORANGE BOOK
◦ Contains the list of all FDA approved Drug products
◦ It is updated monthly.

30. CODE OF FEDERAL
REGULATIONS (CFR)

31. CODE OF FEDERAL REGULATIONS (CFR)
◦ CFR is the codification of the general & permanent rules and regulations (also
called as Administrative law) published in the federal register by the executive
departments & agencies of the federal government of the united states.
◦ It is divided into 50 titles that represent broad areas.
◦ Each title is further divided into chapters, subchapters, parts, and sections.
◦ A regulation is cited by title, part, and section, e.g. 14 CFR 121.313 (Title 14, Part
121, Section 313).
◦ Title 21 of the CFR is reserved for rules of the Food and Drug Administration.
◦ In all, 21 CFR consists of 1499 parts.
◦ There are a number of electronic sources for accessing CFR.

32. NOTABLE SECTIONS
◦ 11 Electronic records and electronic signature related.
◦ 50 Protection of human subjects in clinical trials.
◦ 54 Financial Disclosure by Clinical Investigators.
◦ 56 Institutional Review Boards that oversee clinical trials.
◦ 58 Good Laboratory Practices (GLP) for nonclinical studies.

33. DRUG PRODUCT
PERFORMANCE
(DPP)

34. DRUG PRODUCT PERFORMANCE
(DPP)
◦ DPP is defined as the release of the drug substance leading to
bioavailability of the Drug substance.
◦ Assessment of DPP is important since bioavailability is related both to
the pharmacodynamics response and to adverse effects.
◦ DPP – determined by In-vivo Bioequivalence studies or in-vitro by
comparative drug dissolution studies.

35. DRUG PRODUCT PERFORMANCE
DRUG PRODUCT PERFORMANCE FOR
NEW DRUG FOR GENERIC DRUG

36. METHOD FOR ASSESSING
BIOAVAILABILITY & BIOEQUIVALENCE
In-vivo Measurement
of active moiety or
moieties in biological
fluids
• Plasma drug
concentration
• Time for Peak Plasma
concentration (Tmax)
• Peak plasma
concentration (Cmax)
• Area under the
plasma drug
concentration-time
curve(AUC)
Urinary Drug
Excretion
• Cumulative amount
of drug excreted in
the urine(Du)
• Rate of drug
excretion in the
urine(dDu/dt)
• Time for maximum
urinary excretion (t)
In-vivo
Pharmacodynamic
comparison
• Maximum
pharmacodynamic
effect (Cmax)
• Time for Maximum
pharmacodynamic
effect
• Area under the curve
(AUC)
• Onset time for
Pharmacodynamic
effect
In-vivo studies
• Comparative drug
dissolution
Clinical Endpoint
study

37. NDA REGULATORY
APPROVAL PROCESS

38. NDA (NEW DRUG APPLICATION)
• The vehicle through which drug sponsors formally propose that the
regulatory body approve a new pharmaceutical for sale and
marketing.
• The data gathered during the animal studies and human clinical
trials of an Investigational new product become part of the NDA.

40. FUNDAMENTALS OF NDA
SUBMISSION
◦ Index
◦ Summary
◦ Chemistry, Manufacturing, and
Control
◦ Samples, Method Validation Package,
and Labeling
◦ Nonclinical Pharmacology and
Toxicology
◦ Human Pharmacokinetics and
Bioavailability
◦ Microbiology (for anti-microbial
drugs only)
◦ Clinical Data
◦ Safety Update Report (typically
submitted 120 days after the NDA's
submission)
◦ Statistical
◦ Case Report Tabulations
◦ Case Report Forms
◦ Patent Information

41. ANDA REGULATORY
APPROVAL PROCESS

42. ANDA(ABBREVIATED NEW DRUG
APPLICATION )
◦ Abbreviated new drug application (ANDA) is an application for a U.S.
generic drug approval for an existing licensed medication or approved
drugs.
◦ A generic drug product is one that is comparable to an innovator drug
product in its dosage form , strength , quality etc.
42

44. CONTENT AND FORMAT OF AN ABBREVIATED
APPLICATION
1. Application form
2. Table of contents
3. Basis for abbreviated new drug application submission
4. Conditions of use
5. Active ingredients
6. Route of administration, dosage form and strength
7. Bioequivalence
8. Labeling
9. Chemistry, manufacturing and controls.
10. Samples
11. Patent certification.
44

45. BE AND DRUG
PRODUCT
ASSESSMENT

46. BIOEQUIVALENCE AND DRUG
PRODUCT ASSESSMENT
By World Health Organization (WHO):
Two pharmaceutical products are bioequivalent if they are
pharmaceutically equivalent , and their bioavailabilities, in terms of rate
(Cmax and tmax) and extent of absorption (area under the curve), after
administration of the same molar dose under the same conditions, are
similar to such a degree that their effects can be expected to be
essentially the same.

47. NEED OF BIOEQUIVALENCE
◦ The need of bioequivalence studies is increasing due to the
large growth of the production and consumption of generic
product
Bioequivalence studies are conducted if there is :
◦ A risk of bio inequivalence or
◦ A risk of pharmacotherapeutic failure
◦ No clinical studies have been performed in patient with the
generic product to support its efficacy and safety

48. TYPES OF EQUIVALENCE
1. Chemical equivalence
Two or more drug product contain same labelled chemical in a same amount.
2. Pharmaceutical equivalence
Two or more drug are identical in strength, quality, purity, content uniformity,
disintegration and dissolution.
3. Therapeutic equivalence
Indicate that two or more drug product that contain the same therapeutically active
ingredient elicit identical pharmacological effect and control the disease to the same
extent.
4. 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 relative
extent.

49. DESIGN AND EVALUATION OF
BIOEQUIVALENCE STUDIES
Fasting study
• Use for immediate release
and modified release oral
dosage form
• Overnight fast and 4 hour
after dosing
Food intervention
study
• Co-administration of
food with an oral drug
product may affect the
bioavailability of drug
Multiple dose
study
• Multiple dose,
randomized, crossover
study
• Three consecutive
Trough concentration on
three consecutive days

50. TYPE OF DESIGN
1.Complete randomized design
All treatment are randomly allocated among all experimental subject.
example: if there is 20 subjects, number them from 1 to20. Random select non
repeating number
2. Randomized block designs
Subjects are sorted into homogenous group called blocks.
Method
Subjects having similar background characteristics are formed as blocks

51. EVALUATION OF DATA
 Analytical data
-Analytical method for measurement of drug must be validated for
accuracy, precision, sensitivity and specificity.
-More then one method during bioequivalence study may not
be valid because different methods may yield different values.

52. Dosage
Form
Drug in
solution
Gut wall
Blood
Site of
activity
Therapeutic
effect
Pharmacokinetic measurements

53. BIOWAIVERS
o The term Biowaiver is applied to a drug regulatory approval process when a dossier
(application) is approved based on the evidence of Bioequivalence.
o The biowaiver means that the in vivo bioavailability and bioequivalence studies may be
waived (i.e not necessary for the product approval)
o In 1995 , US department of Health and Human Services , and US-FDA started the
Biopharmaceutical Classification System ,with the aim of granting so called Biowaivers for
SUPAC.
o Applicant can request biowaiver for immediate release product based on an approach
termed the biopharmaceutics classification system BCS (32).

54.  The BCS is a framework for classifying drug substances based on
solubility and intestinal permeability.
 The BCS classifes drug substances as:

55. SCALE-UP PROCESS APPROVAL
CHANGES
◦ The scale-up process approval changes made after approval in the
composition, Manufacturing process, mfg. equipment & change of site
have become known as Scale-up and Post Approval Changes.
◦ Abbreviated as SUPAC.
NDA → Larger Batch Size
ANDA → Larger Batch Size

56. SCALE-UP POST APPROVAL CHANGES
◦ The FDA has issued various guidance for SUPAC. They are
SUPAC – IR
(For Immediate-release solid oral dosage form)
SUPAC – MR
(For Modified-release Solid oral dosage form)
SUPAC – SS
(For Non-sterile semisolid dosage form such as creams, ointments, gels
& lotions)

57. POST MARKETING SURVEILLANCE
(PMS)
◦ PMS is the practice of monitoring the safety of a pharmaceutical drug
or medical device after it has been released on the market.
◦ It is an important part of the science of Pharmacovigilance.
Objective:
 To develop information about drug effects under customary
condition of drug use.
 To assess a known serious risk related to the use of drug
◦ Advantages:
Helps to detect rare ADR’s
 Drug interaction

58. METHODS OF SURVEILLANCE:
Four types of studies are generally are used to identify drug effects
1. Controlled clinical trials
2. Spontaneous & Voluntary recording
3. Cohort studies
4. Case Control studies

59. SOURCES OF PMS
1. Customer surveys
2. Literature reviews
3. Expert user groups
4. Customer complaints
5. The media

60. OUTSOURCING BA AND BE TO CRO
Definition
◦ Contract research organisation (CRO) is an entity that extends support to
pharmaceutical, biotechnology and medical devices industry in the form of
research services outsourced on a contract basis.
◦ A CRO may offer such services like:
Biopharmaceutical
development
Clinical &
preclinical research
Clinical trial
Biological assay
development
Pharmacovigilance

61. OUTSOURCING BA AND BE
TO CRO
◦ Outsourcing is the business practice & hiring a party outside a
company to perform services & create goods that traditionally were
performed in-house by the company’s own employee & staff.
◦ It is generally done to
i. To reduce the costs and
ii. Improving the efficient resources within a company
Eg:
Outsourcing is Bioavailability, Bioequivalence, Research &
Development Department etc.

62. THANK U