Getting Familiar with Reg - Affairs

June 16, 2009

Presented by: N. Sheetal Anand Regulatory Affairs

 Role of Regulatory Affairs What are Generic drugs? Drug Master File US filing System

Flow of Presentation

Europe filing system

What is CMC [Chemistry Manufacturing and Controls]

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 Involve in product development. Ensure faster approvals by filing quality DMFs . Periodically updating the post DMF changes through amendments and updates. Ensure the deficiencies are responded with in the stipulated timeframe to support launches. 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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Role of Regulatory Affairs

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 therapeutic dosage and strength as the reference drug. Generic drugs must have the same quality, strength, purity and stability as brandname drugs. The applicant should prove the bioequivalence between the generic version and its reference drug . Reference Drug: These are usually innovatory drugs whose effectiveness, safety and 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 name
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What are Generic Drugs?

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 two drugs present the same bioavailability in the organism, its clinical effectiveness is considered to be comparable What is the bioequivalence test? The 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 the therapeutic 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 are Generic Drugs?

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 generic approvals occur. The products in this are approved under section 505 of the Federal Food, Drug, and Cosmetic 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 support of the marketing authorization application 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 rule published on January 12, 2000. Type II Type III Type IV Type V - Drug Substance, Drug Substance Intermediate, and Material Used in their manufacture - Packaging Material - Excipient, Colorant, Flavor, Essence, or Material Used in their preparation - The following types of DMfs may be filed as Type V DMFs 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 Information 1.1 ToC of Module 1 or overall ToC, Module 1 including Module 1 (M 1.4.1-Experts rsume) 1.0 2.1 ToC of the CTD (Mod 2,3,4,5) 2.2 Introduction 2.1 Module 2 2.3 Quality Overall Summary 2.2 2.4 Nonclinical Overview 2.4 2.5 2.5 Clinical Overview 2.3 2.6 Nonclinical Written and 2.6 2.7 Tabulated Summaries Module 3 Module 4 Module 5 2.7 Clinical Summary Clinical Nonclinical Quality Study Reports Study Reports

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Module -3 - Quality
Applicants Part 3.2.S 3.2.S.1 3.2.S.2 3.2.S.3 3.2.S.4 Drug Substance General Information Manufacture Characterization Control of the active substance Reference standards Container Closure system Stability 3.2.S.2.1 Manufacturer(s) Restricted Part 3.2.S.2.2 Description of Manufacturing and Process Controls

3.2.S.2.3 Control of Materials

3.2.S.5 3.2.S.6 3.2.S.7

3.2.S.2.5 Process Validation and /or Evaluation

3.2.S.2.4 Control of Critical Steps and Intermediates

3.2.S.2.6 Manufacturing Process Development

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Applicants Part
3.2.S.3 Characterization
Impurities Elucidation of structure & other characteristics

Proof of structure : with various spectral techniques Polymorphic details

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Impurities description Impurity profile Impurities COA & Characterization

Stability Summary Test intervals Storage conditions Packaging configuration Retest period Post approval commitment

3.2.S.7

Stability

Applicants Part
Stability Data Degradation Studies Specificity of analytical methods Stress study of drug substance Acid, Base, Water, Peroxide, Thermal and UV Photodegradation

Specification Accelerated data Long term data

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Restricted Part
Synthetic scheme

3.2.S 2.2 Description of Manufacturing Process and Process Controls

Process description & process flow

Final product batch numbering system

Flow diagram of chemical structures Starting materials Intermediates Reagents & Drug substance
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Description of final drug substance and batch number followed

3.2.S 2.2 Description of Manufacturing Process and Process Controls

Process description & process flow
Narrative sequential procedure Quantities of raw materials, solvents, catalysts and reagents 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 Raw and Starting materials

Restricted Part
Source of Starting Materials Vendor Details Justification & Criteria Synthetic route COAs Impurity profile
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3.2.S 2.3 Controls of Materials

Specifications of Raw Materials Starting Materials

 3.2.S.2

3.2.S 2.4 Controls of Critical Steps and Intermediates In-process samples Intermediates

Manufacture

Restricted Part

Tests performed to demonstrate adequate control of the synthesis Example: TLC pH Water content Impurity content

Tests and acceptance on the quality and control of intermediates isolated during the process should be provided Identity, Purity & Potency [wherever applicable]
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 Annexure-I: Facilities Description - Plant Layout - Warehousing Facilities - Production Facilities - Quality Control Laboratories Annexure-II : Raw Materials Handling Procedures - Incoming Procedures - Batch Numbering System - Sampling and Release - Distribution Annexure-III & IV Batch Production Records - Blank and Executed Batch Production Records
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Annexure to Restricted Part : USDMF

Annexure to Restricted Part : USDMF

Annexure-V Annexure-VI Annexure-VII Annexure-VIII Raw Materials: Certificate of Analysis Specimen Label Reserve Samples Complaints File

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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

Permit review of confidential information referenced by number of applicants

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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 Manufacturing Information 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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DMF supports

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 approval for these generic products, for which they submit an Abbreviated New Drug Application (ANDA). Canada: ANDS EU/China/Japan: Marketing Authorization Application
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DMF supports

DMF Review Mechanism

The DMF is reviewed when referenced On review, deficiencies if any are communicated to the DMF holder. Applicant is notified that deficiencies exist but the nature of deficiencies is not communicated to the applicant. 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
III. The date on which such patent expires IV. That such patent is invalid or will not be infringed by the manufacture, use, or sale of the drug product for which the ANDA is submitted. This last certification is known as paragraph IV certification
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I. No patent information on the drug product that is the subject of ANDA has been submitted to FDA II. That such patent has expired

Approval Process Flow

DMF Filing ANDA Filing DMF Review & ANDA review & Bulk facility form. Facility ANDA approval inspection inspection

LAUNCH of Drug product

Impurity Profile Stability Bio-batch Validation Scale-up R&D Development Product selection

Formulation Product Selection

EIR Successful Insp. 483/No 483 Prep. For insp. Def. Resp. DMF deficiency

Formulation Facility inspection

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 Two types Telephonic Facsimile Both the responses are submitted as DMF amendment Why it is important to respond to deficiencies? Approval of ANDA is at stake

Deficiency Letter

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 Minor Changes Major Changes

Changes

- Changes being effected (CBE) - Prior Approval supplement

- Changes being effected 30 days (CBE 30) A holder must notify each affected applicant or sponsor who has referenced 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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 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 additional information incorporated into the DMF since the previous Amendment on the subject matter of the DMF 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 or dissolution profile will need Authorities approval after which it can be implemented. The customer should also be intimated so that the customer may initiate the Amendment at his end.
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Amendments / Updates

EUROPEAN REGULATORY AGENCIES

National authorities : MHRA (UK), MEB Netherlands), Spanish authorities (Spain) and so on (The

EMEA : Since January 1995 the pharmaceutical market in the European Union has been regulated by the European Agency for the Evaluation of Medicinal Products (EMEA), which has its head quarters 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 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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Certificate of Suitability is 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 proof that the quality of the substance is suitably controlled 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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COS / CEP

Marketing Authorizations:
A medicinal product may only be placed on the market in the has been issued by the competent authority of a Member State European Economic Area (EEA) when a marketing authorization for its own territory (national authorization) or when 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 De-centralized procedure

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Variations in a MAA
Minor Type I Type I A - notification Type I B - simplified

Variations

Major

Type II

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 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 chemical science and technology, and the current regulations.

Purpose of CMC

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Complex KSMs :

CMC required for [Contd]

Definition of Key Starting Material: ICH Q7A: An API Starting Material is a raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API Starting Material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API Starting Materials normally have defined chemical properties 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 materials for semisynthetic antibiotics).

CMC required for [Contd]

material may be the subject of a DMF (e.g., some starting 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 Justification & Criteria Synthetic route COAs Impurity profile Genotoxicity evaluation

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Synthetic scheme

CMC for KSMs [Contd]

Process description & process flow

Process controls

Narrative sequential Starting materials procedure Intermediates Reagents & catalysts To mention critical Solvents parameters. [Based on Drug substance / Key regulatory body] starting material Batch Production records

Intermediate In-process

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Others: Raw Material Specifications and MOA Impurity Profile Validation of critical process steps which may impact the quality of the API. Batch Production records Container closure TSE / BSE Declaration Gluten free Aflatoxins Genetically modified Organisms

CMC for KSMs [Contd]

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