Getting Familiar With Reg-Affairs 16-Jun-09 [Compatibility Mode]

7/31/2019 Getting Familiar With Reg-Affairs 16-Jun-09 [Compatibility Mode]

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June 16, 2009

Presented by: N. Sheetal Anand

Regulatory Affairs


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Flow of Presentation Role of Regulatory Affairs

What are Generic drugs? Drug Master File

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U ng ystem

Europe filing system

What is CMC [Chemistry Manufacturing andControls]


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Role of Regulatory Affairs Involve in product development.

Ensure faster approvals by filing quality DMFs .

Periodically updating the post DMF changes throughamendments and updates.

Ensure the deficiencies are responded with in the

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s u a e e a e o su o aunc es. Ensure Pharmacopoeial compliance as and when a

product is published.

Interact with customers and authorities to resolve

product issues.

Extend technical support to the stakeholders.


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What are Generic Drugs?

Generic drugs:

A generic drug is one which contains the same active

substance in the same dose and pharmaceutical form, and is

administered in the same way and with the same therapeuticdosage and strength as the reference drug. Generic drugs must

have the same quality, strength, purity and stability as brand-

.

The applicant should prove the bioequivalence between the

generic version and its reference drug .

Reference Drug:

These are usually innovatory drugs whose effectiveness, safetyand quality have been proven scientifically. They are drugs

that generally have been a long time on the market and which

carry a well known brand namewww.drreddys.com


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What is the bioavailability test?

Bioavailability is related to the quantity absorbed and the

speed of the absorption process of the liberated active

substance in the pharmaceutical form administered. When twodrugs present the same bioavailability in the organism, its

clinical effectiveness is considered to be comparable


a s e oequ va ence esThe bioequivalence test consists of demonstrating that the

generic drug and its respective reference drug present the same

bioavailability in the organism. Bioequivalence, in the great

majority of cases, ensures that the generic drug is thetherapeutic equivalent of the reference drug (ie: that which has

the same clinical effectiveness and the safety level as the

reference drug).

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What is the advantage of buying the generic drug?

Due to its lower cost as compared to the reference drug.

What is an Orange book?

Approved Drug Products with Therapeutic Equivalence

Evaluations. The Electronic Orange Book is updated daily as

new eneric a rovals occur. The roducts in this are

approved under section 505 of the Federal Food, Drug, andCosmetic Act .

What is the name given to the application filed by a Generic

formulator ?

US: ANDA, Canada: ANDS, EU/JP: MAA

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Drug Master File

What is the active substance?

What is a DMF?

Who must file a DMF?

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Drug Master File

DMF is a document which can be submitted by the

manufacturer of the API in confidence to the Authorities.

Submitted only on the request for a letter of access by any

customer to allow the health authority in that country to access

the DMF in su ort of the marketin authorization a lication

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of the customer.

Copy of the Applicants part is required to include in the

marketing authorization application of the applicant.


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Types of US DMFs

Originally 5 types at present only 4 types

Type I - Manufacturing Site, Facilities, Operating Procedures,and Personnel No longer accepted as per final rulepublished on January 12, 2000.

Type II - Drug Substance, Drug Substance Intermediate, andMaterial Used in their manufacture

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ype - ac ag ng ater a

Type IV - Excipient, Colorant, Flavor, Essence, or Material Usedin their preparation

Type V - The following types of DMfs may be filed as Type VDMFs without requesting prior clearance from FDA. 1.Manufacturing site, facilities, operating procedures &personnel for sterile manufacturing plants.

- Contract facilities for the manufacture of biotech

products.


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Common Technical Document

1.0 Regional Administrative Information1.1 ToC of Module 1 or overall ToC,

including Module 1 (M 1.4.1-Experts rsume)

2.1 ToC of the CTD (Mod 2,3,4,5)

2.2 Introduction

Module 1

2.1

1.0

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.

2.4 Nonclinical Overview

2.5 Clinical Overview

2.7 Clinical Summary

2.6 Nonclinical Written andTabulated Summaries

Module 3 Module 4 Module 5

2.2

2.32.4 2.5

2.6 2.7

Quality NonclinicalStudy Reports

ClinicalStudy Reports


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Applicants Part

3.2.S Drug Substance

3.2.S.1 General Information

3.2.S.2 Manufacture

3.2.S.3 Characterization

Restricted Part

3.2.S.2.1 Manufacturer(s)

3.2.S.2.2 Description ofManufacturing andProcess Controls

3.2.S.2.3 Control of Materials

Module -3 - Quality

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3.2.S.4 Control of the activesubstance

3.2.S.5 Reference standards

3.2.S.6 Container Closure system

3.2.S.7 Stability

3.2.S.2.4 Control of CriticalSteps and Intermediates

3.2.S.2.5 Process Validation and

/or Evaluation

3.2.S.2.6 Manufacturing Process

Development


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Applicants Part

3.2.S.3 Characterization

Elucidation of structure&

other characteristics

Impurities

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Proof of structure :

with various spectraltechniques Polymorphicdetails

Impurities description

Impurity profile

Impurities COA &Characterization


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Applicants Part

3.2.S.7 Stability

Test intervals

Stora e Specificity of

Stability Summary Stability Data Degradation Studies

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conditions Packaging

configuration

Retest period

Post approval

commitment

Specification Accelerated

data

Long term

data

Stress study of drug

substance

Acid, Base, Water,

Peroxide, Thermaland UV

Photodegradation


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Restricted Part

3.2.S 2.2 Description of Manufacturing Process and

Process Controls

Synthetic scheme Process description

& process flow

Final product batchnumbering system

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Flow diagram of

chemical structures

Starting materials

Intermediates Reagents &

Drug substance

Description of final

drug substance and

batch numberfollowed


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Restricted Part

3.2.S 2.2 Description of Manufacturing Process and

Process Controls

Process description & process flow

Narrative sequential procedure

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uan es o raw ma er a s, so ven s, ca a ys s an reagen s

Batch size and Yield, operating conditions temperature, vacuum, pH conditions

etc.. Identification of critical steps,

In-process controls and Intermediate specifications Equipments used Reprocess procedure Recovery procedures


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Restricted Part 3.2.S.2 Manufacture

3.2.S 2.3 Controls of Materials

Raw and

Starting materials

Source ofStarting Materials

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Specifications of

Raw Materials

Starting Materials

Vendor Details

Justification & Criteria

Synthetic route

COAs Impurity profile


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Restricted Part 3.2.S.2 Manufacture 3.2.S 2.4 Controls of Critical Steps and Intermediates

Tests erformed to Tests and acce tance on the

In-process samples Intermediates

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demonstrate adequatecontrol of the synthesisExample:

TLC

pH Water content

Impurity content

quality and control ofintermediates isolated duringthe process should be

provided

Identity, Purity & Potency[wherever applicable]


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Annexure to Restricted Part : USDMF Annexure-I: Facilities Description- Plant Layout

- Warehousing Facilities- Production Facilities

- Quality Control Laboratories

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nnexure- : aw ater a s an ng roce ures

- Incoming Procedures

- Batch Numbering System

- Sampling and Release

- Distribution

Annexure-III & IVBatch Production Records

- Blank and Executed Batch Production Records


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Annexure-V Raw Materials: Certificate of Analysis

Annexure-VI Specimen Label

Annexure-VII Reserve Samples

Annexure-VIII Complaints File

Annexure to Restricted Part : USDMF

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Who must file a DMF ?NOBODY

There is no legal or regulatory requirement to file a DMF A DMF is submitted only to support formulator/applicant

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Permit review of confidential information referenced bynumber of applicants


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DMF supports US:IND filing: done for Investigational New Drug under evaluation.

It is an application which provides FDA with info regarding Proposed Clinical Protocols

Animal Pharmacology & Toxicology Studies

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anu actur ng n ormat on

NDA filing: contains all necessary information like safety, efficacy

data. It also includes the clinical trial data in support of the

application to fulfill FDAs requirement.

It also contains CMC relating to both drug substance and drug

product


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ANDA filing: Once the patent life of a successful drug has

expired, other companies are allowed to manufacture and sell

generic versions of it. They still need FDAs specific approvalfor these generic products, for which they submit an

Abbreviated New Dru A lication ANDA .

DMF supports

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Canada: ANDS

EU/China/Japan:

Marketing Authorization Application


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DMF Review Mechanism

The DMF is reviewed when referenced

On review, deficiencies if any are communicated tothe DMF holder.

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pp cant s not e t at e c enc es ex st ut t enature of deficiencies is not communicated to theapplicant.

A DMF IS NEVER APPROVED OR DISAPPROVED


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PARA FILINGS

An ANDA applicant must include in the ANDA a

patent certification

The certification must make one of the following statements

I. No patent information onthe dru roduct that is the

III. The date on which such patent

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subject of ANDA has beensubmitted to FDA

II. That such patent has

expired

IV. That such patent is invalid or willnot be infringed by the manufacture,use, or sale of the drug product for

which the ANDA is submitted. Thislast certification is known as

paragraph IV certification


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Approval Process Flow

DMF Filing ANDA FilingDMF Review &Bulk facility

inspection

ANDA review &form. Facility

inspection

ANDA

approval LAUNCH of

Drug product

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Impurity Profile

Stability

Bio-batch

Validation

Scale-up

R&D DevelopmentProduct selection

Formulation

Product

Selection

EIR

Successful Insp.

483/No 483

Prep. For insp.

Def. Resp.

DMF deficiency

Formulation

Facility inspection


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Deficiency Letter

Two types

Telephonic

Facsimile

Both the responses are submitted as DMF

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amendment Why it is important to respond to deficiencies?

Approval of ANDA is at stake


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Changes Minor Changes

Major Changes

- Changes being effected (CBE)- Changes being effected 30 days (CBE 30)

- Prior Approval supplement

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A holder must notify each affected applicant or sponsor who hasreferenced its DMF of any pertinent change in the DMF (21

CFR 314. 420(c)). Notice should be provided well before making

the change in order to permit the sponsor/applicant to

supplement or amend any affected application (s) as needed


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Amendments / Updates The changes made to the existing DMF (ex: Scale up, additional

vendor, specification revision, Manufacturing Block change,updated stability, etc) can be filed as an Amendment.

The amendment should also identify all changes and additionalinformation incorporated into the DMF since the previous

Amendment on the subject matter of the DMF

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Minor changes as mentioned above can be implemented,provided equivalency is proved.

Any major changes Ex: Change in Process to better the yield/reduce an impurity, change in make of equipment, additional

milling operation, etc, that may impact the impurity profile ordissolution profile will need Authorities approval after which itcan be implemented. The customer should also be intimated sothat the customer may initiate the Amendment at his end.


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EUROPEAN REGULATORY AGENCIES

National authorities : MHRA (UK), MEB (The

Netherlands), Spanish authorities (Spain) and so on

EMEA : Since January 1995 the pharmaceutical market in the

European Union has been regulated by the European Agency for

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the Evaluation of Medicinal Products (EMEA), which has its headquarters in London.

EDQM : Applications for dossiers for the certificate of

suitability are handled by the European Directorate for the Quality

of Medicines (EDQM), which is situated in France.


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EDMF and MA Submission Procedure

Preparation of the DMF (Applicants and Restricted part)

Preparation of the QOS/ Expert Report

Applicants part shared with customers

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Letter of access for the DMF given to customer

Drug Master file submitted to the authorities in that EU country

on request of a letter of access from a customer

Marketing Authorization Application (MAA) submitted by the applicant

to the authority(ies).


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COS / CEP Certificate of Suitabilityis a certificate which is granted by

the certification secretariat of the EDQM.

COS/ CEP is filed only for substances listed in Ph Eur.

The manufacturer of a drug substance should provide

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by the monograph of the European Pharmacopoeia.

A copy of the certificate is enough to include in the

marketing authorization application of the applicant.

Notification of the decision on an assessment by EDQM

will be done once at the end of 9th month of assessment


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Marketing Authorizations:

A medicinal product may only be placed on the market in the

European Economic Area (EEA) when a marketing authorization

has been issued by the competent authority of a Member State

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or its own territory (nationa aut orization) or w en an

authorization has been granted for the entire Community (a

community authorization).


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Types of submissions by the MAA

National procedure

Centralized Procedure

Mutual Recognition Procedure

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De-centralized procedure


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Type I A - notification

Minor Type I

Variations Type I B - simplified

Variations in a MAA

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MajorType II


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Purpose of CMC

Support the safety and effectiveness of the drug product

by ensuring the quality of the product.

This is accomplished by: Evaluating the provided

information in the context of the current standards in

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chemical science and technology, and the currentregulations.


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Complex KSMs :

Definition of Key Starting Material:

ICH Q7A:An API Starting Material is a raw material, intermediate, or anAPI that is used in the production of an API and that is

CMC required for [Contd]

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of the API.An API Starting Material can be an article of commerce, a

material purchased from one or more suppliers under contract orcommercial agreement, or produced in-house.

API Starting Materials normally have defined chemicalproperties and structure.


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In addition, for material that is not commercially available, it may

be necessary to carry out more testing for impurities than would

be needed for a commercially available product. The starting

material may be the subject of a DMF (e.g., some starting

CMC required for [Contd]

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materials for semisynthetic antibiotics).

When the starting material is itself a drug substance, the

synthesis of this material should be provided either in full or by

authorized reference to an NDA or DMF.


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CMC for KSMs

Source of

Starting Materials

Vendor Details

ustification & Criteria

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Synthetic route COAs

Impurity profile

Genotoxicity evaluation


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CMC for KSMs [Contd]

Synthetic scheme Process description

& process flow

Starting materials

Intermediates

Narrative sequential

procedure

Process controls

Intermediate

In-process

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Reagents & catalysts

Solvents

Drug substance / Key

starting material

To mention critical

parameters. [Based on

regulatory body]

Batch Production

records


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CMC for KSMs [Contd]Others:

Raw Material Specifications and MOA

Impurity Profile

Validation of critical process steps which may

impact the quality of the API.

Batch Production records

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Container closure

TSE / BSE Declaration

Gluten free

Aflatoxins

Genetically modified Organisms


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Documents

Getting Familiar With Reg-Affairs 16-Jun-09 [Compatibility Mode]