Regulatory Affairs Regulatory

Prospective

Sachin GundechaRegulatory Affairs Department

Why Regulatory is needed?

What does Regulatory Affairs functions?

What do they regulate?

Why to give data to Regulatory Affairs ? ? ?

INTRODUCTION

Regulatory Affairs is bridge between Pharma Company and Govt. Agency in India as well as Abroad. It is centralized department for communication of Registrations, Queries associated with product in FDA as well as Ministry of Health of various countries

Regulatory affairs professionals usually have responsibility for the following general areas:

Role of RA To keep track of the ever-changing legislation Registration documents to regulatory agencies To give strategic and technical advice to R&D, Production, QC dept etc. right from the beginning of the development of a product, making an important contribution both commercially and scientifically to the success of a development programme and the company as a whole.They also advise on the legal and scientific restraints and requirements, and collect, collate and evaluate the scientific data their research and development colleagues are generating.

The regulatory professional

The regulatory function in healthcare industries is vital in making safety and effective healthcare products available worldwide.

Regulatory professionals are employed in industry, government and academia and are involved with a wide range of products, including:• pharmaceuticals• medical devices• in vitro diagnostics• biologics and biotechnology• nutritional products• cosmetics• veterinary products

The regulatory professional's roles and responsibilities often begin in the research and development phases, moving into clinical trials and extending through premarket approvals, manufacturing, labeling and advertising and post marketing surveillance.

Avoiding problems

It takes anything up to 15 years to develop and launch a new pharmaceutical product and many problems may arise in the process of scientific development and because of a changing regulatory environment.

Regulatory professionals help the company avoid problems caused by badly kept records, inappropriate scientific thinking or poor presentation of data.

Working internationally

Many companies operating in high-technology healthcare and related industries operate on a multinational basis and are significant exporters. Their regulatory affairs departments must be aware of the regulatory requirements in all the company’s export markets.

Despite recent international efforts towards harmonization of requirements, the regulations laid down by different governments and their interpretation by the regulatory agencies rarely match. The registration data prepared for one country frequently fail to meet the requirements for another.

Therefore great care has to be taken in drawing up efficient and economical research and development programmes whose results may be used as widely as possible.

Regulatory professionals, with their detailed knowledge of the regulations and guidelines, are frequently called in to advise on such matters.

• Pharmaceutical products are regulated in essentially every country of the world.

• These regulations are applicable to both the investigation and marketing of compounds.

A Broad Scope: Regulations and Agencies

Regulatory Affairs Defined • Regulatory Affairs is a specialized profession within the

pharmaceutical/biotechnology sector. • Regulatory Affairs oversees company compliance with

regulations and laws pertaining to the manufacture, marketing and development of regulated products.

• Regulatory Affairs acts as point of contact between the company, its products, regulatory authorities and Marketing

• Regulatory Affairs interacts with worldwide, federal, state, and local regulatory agencies (e.g., DCGI, Local FDA, FDA (US), EMEA (EU), BfARM- Federal Institute for Drugs and Medical Devices (Germany), TPD (Canada), TFDA Tanzania, BFAD Philippines etc) to assure…– licensing, – registration, – development, – manufacturing, – marketing and – labeling

…….of pharmaceutical, biopharmaceutical and medical products are conducted in compliance with all applicable rules

Regulatory Framework

• Development, approval for marketing, manufacturing, and ongoing compliance of pharmaceutical/biotech products is among the most regulated activities of any industry

• Regulations are complex systems of interrelated rules that govern a broad range of activities

• These rules are continuously undergoing amendment and supplementation

• Their main function is to assure that these products are safe (do no harm) and at the same time effective ( do some good)

Regulatory Framework

Why do we pay so much attention to regulation and process ??

• It takes 8 to 15 years to develop a new drug/biologic product.

• Costs up to millions of Dollar or Crores of Rupees.• Attention to early development, successfully execution

of significant clinical studies helps to reduce number of development failures.

• Regulatory affairs provides insight/guidance into this development through agency wisdom collected in guidance, previous experience, market precedence, etc.

Compliance with Regulator expectations therefore equates with development success. Patient Protection is of greatest importance .

Drug Discovery

You Should Know

What is Dossier ? What is DMF ? What is CTD / eCTD ? What is NDA / ANDA and MAA ?What is Biosimilar? Or What is generic biotech?

What is Dossier ?Dossier is a collection or file of documents that contains all the technical data of pharmaceutical product to be approved / registered / marketed in a country. It is most commonly called as Registration Dossier, In US : New Drug Application (NDA), In EU : Marketing Authorization Application (MAA)

What is DMF ? Drug Master File (DMF)US-USDMF: United States Drug Master FileEDMF/ASMF: European Drug Master File or Active Substance Master File[Applicant’s Part / Open Part and Restricted part / Closed part ]

Type I – Mfg. Site, Facilities, Operating Procedures, and Personnel (no longer applicable) Type II - DS, Intermediate & Material Used in Their Preparation or Drug Product Type III - Packaging Material Type IV - Excipient, Colorant, Flavor or Material Used in Their Preparation Type V - FDA Accepted Reference Information (FDA discourages its use)

Types of DossierEu-CTD or CTD ACTD National Format

Module 1: Administrative

Part I:Administrative Contains all the information but structure varies on country to country basis.

Module 2: QOS Part II: QOC and CMCDrug Substance Drug Product

Module 3: CMCDrug Substance Drug Product

Part III: Preclinical

Module 4: Preclinical Part IV: Clinical

Module 5: Clinical

Eu-CTD: European Common Technical Document

ACTD: Asean Common Technical Document

Module 1- Administrative Documents• Manufacturing Licence

• WHO-GMP Certificate• Free Sale Certificate• Site Master File• Engineering Layout• Equipment Drawing• Quality policy• Artwork• Patient Information Leaflet• Pack Insert

Module 1 does not only limited to above heading but it changes on

country to country basis

Module 2- QOS Quality Overall Summary

Module 2 contains Quality Overall Summary for following section

CMC information on Active Pharmaceutical Ingredient Section

CMC information on Finished Product Section Pre-clinical Section Clinical Section

Incase of ACTD QOS is presented section Part II and then Elaborated sections are followed.

Chemistry and Manufacturing

A major part of Module 3/ Part II

Drug Substance• Drug substance (Active pharmaceutical

ingredient)—– It is the material that is exerting the pharmacological

action. – Along with other ingredients (excipients, inactives) it

subsequently it is used to formulate, the drug product. • It can be composed of

– the desired active material, – product-related substances, – product—or process related impurities (subsequently

removed) • It also may contain other components, including

vehicles, or buffers.• Biologics and biotechnology industry.

– Alternatively referred to as bulk concentrate, bulk intermediate, or simply bulk

Drug Product

• Drug product (Dosage form; Finished product)—– one or more drug substances (active

pharmaceutical ingredients) – usually with excipients

• Excipients – components of a finished medicinal drug

product other than the active pharmaceutical ingredient (API).

– Included in the formulation to facilitate manufacture, enhance stability, control release of API from the product, assist in product identification, or enhance other product characteristics.

Impurity

• Impurity—An impurity is any component present in the excipient, drug substance, or drug product that is not: – the desired product, – a product-related substance, – or excipient, (including buffer components).

• It may be either process- or product-related.

• It may be the result of active principle degradation during holding/processing

Chemistry Manufacturing & Controls for API & FP

• Analytical Method• Degradation Products• Specifications• In-process controls• Methods Validation• Process Validation• (DP/DS) Characterization• Container / Closure System • Characterization• Stability

TABLE OF CONTENTS for

DRUG SUBSTANCE

3.2.S

Drug Substance3.2.S.1 General Information

3.2.S.1.1 Nomenclature3.2.S.1.2 Molecular Structure3.2.S.1.3 General Properties

3.2.S.2 Manufacture3.2.S.2.13.2.S.2.23.2.S.2.33.2.S.2.43.2.S.2.53.2.S.2.6

Manufacturer Description of Manufacturing Process and Process ControlsControl of MaterialsControl of Critical StepsProcess ValidationManufacturing Process Development

3.2.S.3 Characterization3.2.S.3.1 Elucidation of Structure and other characteristics3.2.S.3.2 Impurities

3.2.S.4 Control of Drug Substance3.2.S.4.1 Specifications3.2.S.4.2 Analytical Procedures3.2.S.4.3 Validation of Analytical Procedures3.2.S.4.4 Batch Analysis3.2.S.4.5 Justification of Specification

3.2.S.5 Reference Standards or Materials3.2.S.6 Container Closure Systems3.2.S.7 Stability

Some Important aspects to know 3.2.S DRUG SUBSTANCE1 (NAME, MANUFACTURER) 3.2.S.1 General Information (name, manufacturer) 3.2.S.1.1 Nomenclature (name, manufacturer) Information on the nomenclature of the drug substance should be provided. For

example: Recommended International Nonproprietary Name (INN); Compendial name if relevant; Chemical name(s); Company or laboratory code; Other non-proprietary name(s), e.g., national name, United States Adopted

Name (USAN), Japanese Accepted Name (JAN); British Approved Name (BAN), and

Chemical Abstracts Service (CAS) registry number.

3.2.S.1.2 Structure (name, manufacturer) Biotech: The schematic amino acid sequence indicating glycosylation sites or other post-

translational modifications and relative molecular mass should be provided, as appropriate.

3.2.S.1.3 General Properties (name, manufacturer) A list should be provided of physicochemical and other relevant properties of

the drug substance, including biological activity for Biotech 3.2.S.2 Manufacture (name, manufacturer) 3.2.S.2.1 Manufacturer(s) (name, manufacturer) The name, address, and responsibility of each manufacturer, including

contractors, and each proposed production site or facility involved in manufacturing and testing should be provided.

3.2.S.2.2 Description of Manufacturing Process and Process Controls (name, manufacturer)

The description of the drug substance manufacturing process represents the applicant’s commitment for the manufacture of the drug substance. Information should be provided to adequately describe the manufacturing process and process controls.

Biotech: Information should be provided on the manufacturing process, which typically

starts with a vial(s) of the cell bank, and includes cell culture, harvest(s), purification and modification reactions, filling, storage and shipping conditions

Some Important aspects to know

3.2.S.2.3 Control of Materials (name, manufacturer) materials, solvents, reagents, catalysts) should be listed identifying where each

material is used in the process. Information on the quality and control of these materials should be provided. Information demonstrating that materials (including biologically-sourced materials, e.g., media components, monoclonal antibodies, enzymes) meet standards appropriate for their intended use (including the clearance or control of adventitious agents) should be provided, as appropriate. For biologically-sourced materials, this can include information regarding the source, manufacture, and characterization. (Details in 3.2.A. 2 Appendices for both NCE and Biotech)

Biotech: Control of Source and Starting Materials of Biological Origin Summaries of viral safety information for biologically-sourced materials should be

provided. (Details in 3.2.A.2.) Source, history, and generation of the cell substrate Information on the source of the cell substrate and analysis of the expression

construct used to genetically modify cells and incorporated in the initial cell clone used to develop the Master Cell Bank should be provided as described in Q5B and Q5D.

Cell banking system, characterization, and testing Information on the cell banking system, quality control activities, and cell line

stability during production and storage (including procedures used to generate the Master and Working Cell Bank(s)) should be provided as described in Q5B and Q5D.

Reference (ICH M4Q Guideline)

Some Important aspects to know

3.2.S.2.6 Manufacturing Process Development (name, manufacturer) The developmental history of the manufacturing process, as described in 3.2.S.2.2,

should be provided. The description of change(s) made to the manufacture of drug substance batches used in support of the marketing application (e.g., nonclinical or clinical studies) should include, for example, changes to the process or to critical equipment. The reason for the change should be explained. Relevant information on drug substance batches manufactured during development, such as the batch number, manufacturing scale, and use (e.g., stability, nonclinical, reference material) in relation to the change, should be provided.

The significance of the change should be assessed by evaluating its potential to impact the quality of the drug substance (and/or intermediate, if appropriate). For manufacturing changes that are considered significant, data from comparative analytical testing on relevant drug substance batches should be provided to determine the impact on quality of the drug substance (see Q6B for additional guidance). A discussion of the data, including a justification for selection of the tests and assessment of results, should be included.

Testing used to assess the impact of manufacturing changes on the drug substance(s) and the corresponding drug product(s) can also include nonclinical and clinical studies. Cross-reference to the location of these studies in other modules of the submission should be included.

Some Important aspects to know

TABLE OF CONTENTS for

DRUG PRODUCT

3.2.P Drug Product

3.2.P.1 Description and Composition of the Drug Product

3.2.P.2 Pharmaceutical Development

3.2.P.2.1

Components of the Drug Product

3.2.P.2.1.1 Drug Substance

3.2.P.2.1.2 Excipients

3.2.P.2.2

Drug Product

3.2.P.2.2.1 Formulation Development

3.2.P.2.2.2 Overages

3.2.P.2.2.3 Physicochemical and Biological Properties

3.2.P.2.3

Manufacturing Process Development

3.2.P.2.4

Container Closure System

3.2.P.2.5

Microbiological Attributes

3.2.P.2.6

CompatibilityContinue…….

3.2.P.3 Manufacture3.2.P.3.1

Manufacturer(s)

3.2.P.3.2

Batch Formula

3.2.P.3.3

Description of Manufacturing process and Process Controls

3.2.P.3.4

Controls of Critical Steps and Intermediates

3.2.P.3.5

Process Validation and/ or Evaluation

3.2.P.4 Control of Excipients3.2.P.4.1

Specifications

3.2.P.4.2

Analytical procedures

3.2.P.4.3

Validation of Analytical Procedures

3.2.P.4.4

Justification of Specifications

3.2.P.5 Controls of Drug Product3.2.P.5.1

Specifications

3.2.P.5.2

Analytical Procedures

3.2.P.5.3

Validation of Analytical Procedures

3.2.P.5.4

Batch Analyses

3.2.P.5.5

Characterization of Impurities

3.2.P.5.6

Justification of Specifications

3.2.P.6 Reference Standards and Materials3.2.P.7 Container Closure System3.2.P.8 Stability

3.2.P.8.1 Stability Summary and Conclusion3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment3.2.P.8.3 Stability Data

Part III/Module 4 Preclinical Data

Part IV/Module 5 Clinical Data

This is also a part of CTD/EuCTD/ACTD or National Format

Contents and Applicability varies according to country.

Pre-requisite for Biotech product is

1. Viral clearance

2. Comparative clinical and preclinical study

3. PMS and or PSUR

Regulatory Affairs a never ending path

…………………..

? Questions please…..

Knowledge is already build in guideline it is up to us

How we implicate

How we replicate

How we inflate!

Thank You !!!!!!!