Formulation Regulatory Affairs and Intellectual Property Rights

1. REGULATORY AFFAIRS &
INTELLECTUAL PROPERTY RIGHTS
Dr. Santosh Kumar Narla,
M.Pharm., Ph.D,
NAG Manager - Regulatory Affairs,
Dr. Reddys Laboratories, Hyd.
 santoshmph@yahoo.com

2.  My Brief :
 Academics:
Awarded Ph.D (Pharmaceutical Sciences) from JNTUH (2008-2014),
M. Pharm (Pharmaceutics) from Roland, BPUT, Orissa,
B. Pharm from G.Pullareddy, OU, Hyderabad,
D. Pharm from SBTET, Tirupati.
 Holding 15+ years of professional experience with Hands on experience for Formulation
Development and Regulatory Affairs.
 Currently Working as NAG Manager - Formulation Regulatory Affairs, Dr. Reddys
Laboratories, Hyderabad.
 Previously associated with Laurus Labs, Novartis, Medreich and Aurobindo Pharma.
 Presented many oral presentations as INVITED SPEAKER in national and international
conferences.
 Published 3 Research and 4 Review articles in International Journals.
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Disclaimer:
The view and opinions expressed are those of presenter and do not necessarily
represent the view of Dr. Reddy’s Laboratories.

3. Types of Healthcare industries:
Drug Industry
• Pharmaceutical Industry
• Biotech Industry/Biologics
• Medical Device/Diagnostics Industry
• Functional food and natural health products
/ Nutraceuticals
Stages in New Drug Development:
1. Drug Discovery/Basic Research
2. Pre-Clinical Testing
3. Investigational New Drug Application (IND)
4. Clinical Trials
4.1) Phase I Clinical Trials
4.2) Phase II Clinical Trials
4.3) Phase III Clinical Trials
5. New Drug Application (NDA) / Biologics License Application (BLA)
6. Clinical Trials Phase IV and Beyond
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4. Life Cycle for new drug :
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5. dr.santoshkn@gmail.com
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6. 1) Drug Discovery/Basic Research:
It is the first phase of the drug development process
Researchers try to understand the mechanism of a certain disease.
Researchers look for new molecule with promising activity against disease.
Also studied: safety, toxicity and metabolic effects.
➢ Determine the target disease
➢ Determine each component of disease :
▪ Symptoms
▪ Target organ
▪ Biochemical pathways
➢ Search for the target drug : -
• Naturally screened compound (extracts)
• Chemically synthesized compound
• Biologically synthesized compound
• Computer simulated compound
➢ Isolate the compound
➢ Proceed to next Stage
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7. 2) Pre CLINICAL TRIALS:
✓ Conducted in ANIMALS and in vitro.
✓ To establish, drug is safe for use in clinical studies (HUMANS).
✓ To assess primary safety & activity.
Studied for:
➢ Synthesis and purification of the new drug
➢ Pharmacology of the new drug in ANIMALS:
Pharmacokinetics and Pharmacodynamics
Toxicology (carcinogenicity, teratogenicity …)
Evaluation of acute and short term toxicity. It Involves :
To assess primary safety & activity
Lethal dose determination
Effect of dose at normal level for short/Long term
FDA expectations:
(1) Pharmacological profile of the drug;
(2) Acute toxicity of the drug in at least two species of animals,
(3) Short-term toxicity studies 2weeks to 3months.
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8. 3) Investigational New Drug application (IND):
Application for conducting the Clinical Trials.
Apply to FDA with all of your lab and animal study data.
Along with a proposed clinical trial design
FDA reviews the IND application mainly for HUMAN safety.
4) Clinical Trials:
Clinical Trials are performed on humans.
The purpose of a clinical trial is to prove or disprove a hypothesis.
Active Clinical Trials are listed at ClinicalTrials.gov.
Overview of Clinical Study Phases:
Phase 1: Safety and tolerability studies on healthy volunteers
Phase 2: Clinical studies to demonstrate proof of concept and dose findings
Phase 3: Efficacy and safety studies on large number of subjects
NDA regulatory review
Phase 4: Post-marketing safety studies
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9. 4.1: Phase I Clinical Trials:
➢ Conducted in 20-100 healthy volunteers.
➢ Mainly focus on drug safety
➢ Effects of the drug as a function of dosage
➢ Establish limits of safe clinical dosage range.
➢ Following is studied here :
Initial safety & tolerability studies
Drug absorption/Metabolism in human.
Effect on organs and tissues.
Side effect of different dosages.
Thus early evidences on effectiveness are achieved.
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10. 4.2: Phase II Clinical Trials:
➢ Drug given to 100 - 500 patients.
➢ Mainly focus on effectiveness.
➢ Drug is tested for the first time in patients with the target
disease.
➢ To determine efficacy, safety, optimum dose.
➢ Evaluate short-term side-effects and risks.
➢ Compared to placebo or standard drug.
4.3: Phase III Clinical Trials:
➢ Drug given to 1000-5000 patients
➢ Following is studied here:
Confirm efficacy
Safety of Drug [Benefits v/s risk analysis]
Long term side effects in patients
Investigates different populations combination with other drugs
Compare to commonly used treatments
Designed to minimize errors by placebo effects
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11. 5) New Drug Application (NDA):
Application to market a new drug for sale in the U.S.
Safety and efficacy study in large population.
Preclinical and Clinical data will be part of the NDA.
Also included: Chemistry, Manufacturing and Control (CMC)
Inspection of production facilities.
Proposed labeling is appropriate??
6) Phase 4 / Market Launch:
launched to the Market (Post-market optimization).
Long term safety, efficacy under actual conditions of use.
Studied in very large numbers of patients: ADR.
Additional post marketing testing of patients to:
✓ Support the use of the approved indication.
✓ Finding new therapeutic opportunities.
✓ Extending use of the drug to children.
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API
Synthesis R&D
Analytical R&D
Technology Transfer
Developmental QA
Production
Quality Control
Quality Assurance
Packaging
Regulatory Affairs
Project Management
Business Development
Marketing
Intellectual Property Rights
Formulations
Formulations R&D
Analytical R&D
Technology Transfer
Developmental QA
Production
Quality Control
Quality Assurance
Packaging
Regulatory Affairs
Project Management
Business Development
Marketing
Intellectual Property Rights
Clinical Services
Pre-clinical research
Clinical research
Bio-Analytical R&D
Quality Assurance
SAS programmer
Statistician
Project Management
Business Development
Medical Research
Scope of Pharmacy – Indian Pharma Industry

14. dr.santoshkn@gmail.com
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Types of Applications @ USFDA:
❖ Investigational New Drug (IND) Application
❖ New Drug Application (NDA)
❖ Abbreviated New Drug Application (ANDA): Generics
❖ Therapeutic Biologic Applications (BLA)
❖ Drug Applications for Over-the-Counter (OTC) Drugs

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dr.santoshkn@gmail.com
CTD documentation (also called Dossier)
Application format for NDA/ANDA/BLA
Common Technical Document:
Harmonised format for applications for preparing marketing
authorisation in the three ICH* regions (Europe, Japan, USA)
Structure of the CTD
*ICH: International conference
on harmonisation of technical
requirements for registration of
pharmaceuticals for human use.
The CTD is organized into 5 modules.
Module 1 is region specific and
modules 2 - 5 are intended to be
common for all regions (ICH format).
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Content of CTD:
Module NDA Content ANDA Content
Module 1 Administrative (forms/labeling etc)
Module 2
Summaries of
Module 3, 4 and 5
Summaries of
Module 3 and 5
Module 3 Chemistry, Manufacturing and controls (CMC)
Module 4*
Non clinical study reports
(Preclinical data/Animal data)
Not applicable
Module 5
Clinical study reports
(Phase I, II, III and IV)
Bioequivalence data
* For ANDA, Module 4 is not required in USA. In Europe, we need to keep the Literature data.

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World wide Drug Regulatory Authorities

20. PHARMACEUTICAL MARKETS
 Regulated Markets
 USA – USFDA
 Europe – EMA/MHRA…
 Canada – Health Canada
 Japan – PMDA
 Australia – TGA
 Semi-Regulated Markets
 India, China, Brazil, Africa, Russia…
 Non-regulated Markets
 African countries – need minor documentation
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21. KEY COMPONENTS OF REGISTRATION
 Active substance info / DMF
 Drug product development data
 QbD data / DOE data
 Analytical method development data
 USP /EP method verifcations
 Drug product batches executed data
 Batch size / number of batches
 Specification/ validations data
 Comply to USP / EP / IP / BP
 Process validation data of API, DP
 Stability data of API, DP
 Climatic zones data – Long term/ accelarated / Intermediate
 Bioequivalency data / Clinical Data
 Biowaiver / fast / fed / study state
 Packaging information
 In USA – DMF needed
 Working standard data (USP/EP/IP)
 Genotoxic / Elemental impurities data
 Plant inspections / GMP status
 Use of Right Reference product
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Stability Conditions based on Climatic Zones

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24. Generic drug approval process:
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Marketing Applications: Post-1984
New Drug Applications
(NDAs)
Abbreviated New Drug
Applications (ANDAs)
• “Full Reports” of Safety
and Efficacy Investigations
• Applicant has right of
reference to essential
investigations?
• Duplicate of an already
approved product
• No safety/efficacy data
permitted (only
bioequivalence)
YES NO
505(b)(1) 505(b)(2) 505(j)

25. Types of ANDA filing:
ANDA is for a generic duplicate of an approved NDA product. Abbreviated New Drug Application contains data
that, when submitted to FDA, provides for the review and ultimate approval of a generic drug product:
•Gets safety and efficacy studies from NDA
•Must have identical active ingredient, route of administration, dosage form, strength, labeling and intended use
•Must demonstrate bioequivalence
www.fitzpatrickcella.com
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Patent Information/Certification
• Generic applicant (either ANDA or 505(b)(2)) must
make one of the following certifications:
– (I) patent information on the listed drug not filed
– (II) patent has expired
– (III) the date on which such patent will expire
– (IV) patent is invalid, unenforceable or not
infringed
– (viii) method of use patent does not claim a use
for which applicant is seeking approval.

26. Para IV ANDA filling process:

28. Exclusivities (NCE, NS, NP, NDF, PED, ODE, PC):
Exclusivity is exclusive marketing rights granted by the FDA upon approval of a drug and can run
concurrently with a patent or not.
NCE – New chemical entity – 5 years
NS – New salt – 3 years
NP – New product – 3 years
PED - Pediatric Exclusivity - 6 months added to existing Patents/Exclusivity
ODE - Orphan Drug Exclusivity - 7 years
PC - Patent Challenge – 180 days (this exclusivity is for ANDAs only

29. •New Chemical Entity (NCE) Exclusivity
◼Prohibits the filing of an ANDA (or 505(b)(2) NDA) for a product that contains the NCE for 5 years after
approval of the first NDA.
◼(4 years if ANDA includes a Paragraph IV challenge to listed patent)
◼NCE: "a drug that contains no active moiety that has been approved by FDA in any other [NDA].“
•3-Year Exclusivity
◼Available for NDAs which contain:
◼Reports of "new" "clinical trials"
◼That were "essential to approval" of the NDA
◼Conducted or sponsored by the applicant
◼FDA may not approve an ANDA or 505(b)(2) NDA for 3 years after approval
◼Applies for new indications, Rx → OTC switch, new dosing regimen, and some other labeling changes.
•Orphan Drug Exclusivity
◼7 year exclusivity
◼Drugs for rare conditions (<200,000 people in U.S.)
•Pediatric Exclusivity
◼6-month extension of existing patent or Waxman-Hatch exclusivity
•180-day generic (ANDA) exclusivity

30. EU REGULATORY PROCESSES
EU types of filling process (CP, NP, DCP, MRP)
The European system for the authorisation of medicinal products for human and animal use was
introduced in January 1995 with the objective of ensuring that safe, effective and high quality medicines
could quickly be made available to citizens across the European Union.
Marketing Authorisation Procedures
Procedures for application for a marketing authorisation
•Centralised procedure
•National procedure
•Mutual recognition procedure
•Decentralised procedure

31. www.diahome.org
Marketing Authorisation EU - Licensing of Medicines in the EU
Centralised
Procedure
Mutual Recognition
Procedure/DCP
One Pan- European
Marketing
Authorisation (MA)
MA in more than one
EU- Member State
MA in just one EU-
Member State
National
procedure

32. www.diahome.org
Protection Periods
➢ Regulatory Data protection
(= Data Exclusivity)
➢Protection of the registration documentation
➢6/10 years Old provision
➢8+2+1 years New provision
➢ Patent protection
International patent protection = 20 years
TRIPs: Agreement on
Trade-Related Aspects of Intellectual Property
Rights (1995)

33. www.diahome.org
Regulatory Data Protection - Generics
• 8+2+1 for all products – independent of
the approval procedure
➢ 10 (8+2) years market exclusivity
➢8 years data protection
➢2 years for generic companies to prepare, apply
for and receive a MA. The generic MAH is not
allowed to place his product on the market until 10
years have expired

34. www.diahome.org
Regulatory Data Protection - Generics
• +1 year
The ten-year period referred to in the second
subparagraph shall be extended to a maximum of
eleven years if, during the first eight years of those
ten years, the MAH obtains an authorisation for
one or more new therapeutic indications which,
during the scientific evaluation prior to their
authorisation, are held to bring a significant clinical
benefit in comparison with existing therapies

35. www.diahome.org
Protection
Extension if new therapeutic
indications
Ref. : Reg. 726/2004, Art. 14 and Dir. 2004/27/EC, Art. 10
Market Exclusivity
Years
Reference MP
initial
authorisation
5
1
0
0
Pre-clinical / clinical
data required*
*Bolar Clause
Data Protection

36. Launched in 1990, ICH is a unique undertaking that brings together the drug regulatory authorities and the
pharmaceutical industry of Europe, Japan and the United States. WHO, Canada, and EFTA are observers.
ICH stands for "International Conference on Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use".
Six parties: Europe (EU & EFPIA), Japan (MHLW & JPMA) & USA (FDA & PhRMA).

37. ICH Products
• ICH guidelines: ICH guidelines classified majorly into 4 types:
•Quality guidelines
•Safety Guidelines
•Efficacy guidelines
•Multidisciplinary guidelines
• Electronic Standards for the Transfer of Regulatory Information (ESTRI, E2B)
• Common Technical Document (CTD & eCTD)
• Medical dictionary for adverse event reporting and coding of clinical trial data (MedDRA)
• Consideration documents

38. Quality Guidelines:
Q1A - Q1F Stability
Q2 Analystical validation
Q3A – Q3D Impurities
Q4 – Q4B Pharmacopoeias
Q5A – Q5E Quality of Biotechnological Products
Q6A – Q6B Specifications
Q7 Good manufacturing practice
Q8 Pharmaceutical development
Q9 Quality risk management
Q10 Pharmaceutical quality system
Q11 Development and Manufacture of Drug Substances

39. JOB SOURCES
 LinkedIn / WhatsApp groups
 Job sites: Naukri, Times job
 Consultancies: Beware of high money demanding.
 Googling for jobs for Pharma
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dr.santoshkn@gmail.com
Visiting pharma news updates
Useful websites of Pharma from Global Research Online
(www.globalresearchonline.net)
Pharma Updates: RAPS Regulatory Focus, ECA Academy
GMP News, Pharmacompass.com.

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THANK YOU FOR YOUR ATTENTION, I HOPE THIS MESMERISES YOU ENOUGH
TO PREVENT YOU FROM ASKING DIFFICULT QUESTIONS!