13th nov 2011 reg comp for product approval

8/3/2019 13th Nov 2011 Reg Comp for Product Approval

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Regulatory Compliance Process

(Generic Drug Development )

13th Nov 2011


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Generic Drug Development

Science

Scientific evidence to demonstrate that generic product is

therapeutic equivalent to innovator product

Regulatory Policy

Regulatory Policy is based on Drugs and Cosmetic Act and

its amendments as applicable


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Regulatory Strategy and Its significance in drug

development

Regulatory strategy is an end product of regulatoryintelligence

High quality regulatory intelligence serves as a useful internal

resource in the drug development process

The goal of regulatory intelligence is to proactively understandthe regulatory environment, current trends, availableresources, applicable and adoptable factors, and the company

culture and philosophy that govern a successful DDP


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Brand Name Drug Generic Drug

NDA Requirements ANDA Requirements

1. Chemistry 1. Chemistry

2. Manufacturing 2. Manufacturing

3. Controls 3. Controls

4. Labeling 4. Labeling

5. Testing 5. Testing6. Animal Studies

7. Clinical Studies 6. Bioequivalence

8. Bioavailability

NDA vs. ANDA Review ProcessNDA vs. ANDA Review Process


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How do we assure the quality of

generic drugs?

First 5 steps of review process are identical to NDA process

Bioequivalence for complicated products is discussed with the

same staff that reviewed the brand product

FDA has experience with the product

Scientific literature published

Product is known to be safe


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What are the requirements for a

generic drug?

Labeling

Chemistry/Microbiology

Bioequivalence

Legal


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What are the requirements for a generic drug? :

Interms of Generic Equivalence

Same active ingredient(s)

Same route of administration

Same dosage form

Same strength

Same conditions of use

Compared to reference listed drug (RLD) - (brand name product)


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Labeling

Same as brand name labeling

May delete portions of labeling protected by patent

or exclusivity

May differ in excipients, PK data (?) and how

supplied


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Chemistry

Components and composition

Manufacturing and controls

Batch formulation and records

Description of facilities

Specs and tests

Packaging

Stability


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Examples of Information Covered in a Chemistry Review

Qualitative and quantitative listing of all active and

inactive ingredients; including grade of each component


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Examples of Information Covered in a Chemistry Review

Manufacturing and Controls Review includes evaluation of:

Process for manufacturing

Controls (Inspections, sample points, test, methods,

acceptance criteria) in place from the receipt of the raw

material to the labeling and storage of the finished product;

includes the Certificate of Authorization (COA) from the raw

material manufacturer and the firms own testing and

specifications in a COA

Synthesis of the active pharmaceutical ingredient(s) (API)(raw material, drug substance) or authorization to reference

a Drug Master File (DMF)


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Examples of Information Covered in a Chemistry

Review

Impurity profile of the API

Stability of the API

Characterization of degradation products with drug substance and

drug product

Microbiological testing when appropriate (Reviewed by

Microbiologists)


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Review

Batch formulation and batch records

Manufacturing record provides a representation of the formula,

manufacturing instructions, description and size of manufacturing

equipment


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Review

Description of the manufacturing facilities in general;

identification of all firms and facilities involved

Stability profile (with information on such things as

container/closure system); adequacy of protocol and

methods

Evaluation of methods validation information prior to

laboratory evaluation


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Review

Container/Closure Systems

Environmental Assessment compliance


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Manufacturing Compliance Programs

Purpose - To assure quality of marketed drug products

Mechanisms - Product Testing

Surveillance

Manufacturing/Testing plant inspections

Assess firms compliance with good manufacturing

processes


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Purpose of BE

Therapeutic equivalence (TE)

Bioequivalent products can be substituted for each other

without any adjustment in dose or other additional

therapeutic monitoring

The most efficient method of assuring TE is to assure

that the formulations perform in an equivalent manner


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6 12 18 24 30 36 42 48

0

1

2

3

4

5

6

7

8Test/Generic

Reference/Brand

Bioequivalence Example


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Model of Oral Dosage Form Performance

TherapeuticEffect

DosageForm

Gut WallDrug inSolution

BloodSite of

Activity

PharmacokineticMeasurement

Dosage FormPerformance

Clinical/PDMeasurement

ln DoseDose


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Clinical/PD Dose-Response

Clinical/PD

Resp

onse

Log Dose


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Waivers of In Vivo Study Requirements

Definition

Criteria (21 CFR 320.22)

In vivo bioequivalence is self-evident

Parenteral solutions

Inhalational anesthetics

Topical (skin) solution

Oral solution

Different proportional strength of product with

demonstrated BE


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In Vivo Bioequivalence Inspections

Covers clinical and analytical components

Objectives

Verify quality and integrity of the scientific data Ensure rights and welfare of human subjects are protected

Ensure compliance with the regulations and promptly

follow-up on significant problems (research misconduct;

fraud)


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GenericGenericDrugDrug

ReviewReviewProcess inProcess inUSUS

Bioequivalence

ReviewLabeling

Review

Chemistry & Micro

Review

Request for Plant

Inspection

APPLICANT

ANDA

Acceptable&

Complete

Application Review

NChem/Micro

OK?

Labeling

OK?

Bioequivalence

OK?

PreApproval

Inspection Results

OK?

NotApprovable

Letter

ApprovalWithheld until

ResultsSatisfactory

Bio DeficiencyLetter

APPROVEDANDA

NN N

N

Y Y Y

Y

Y

Refuse toReceive Letter


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Acceptable RiskAcceptable Risk--BenefitBenefit

Approval

General Access

Clinical Trial Data

Nonclinical animal data Foreign marketing data

Experience with other

drugs in classIn vitro studies

Post-marketing Surveillance

Context

Acceptable RiskAcceptable Risk--BenefitBenefit MaintainedMaintained


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NATIONAL PHARMACOVIGILANCE PROGRAM

To monitor the adverse drug reactions of medicines including the collation,review and evaluation of all spontaneous ADR reports received by the unit on anation-wide basis.

To review Periodic Safety Update Reports (PSURs) submitted by pharmaceuticalcompanies.

To maintain contacts with international regulatory bodies working inpharmacovigilance and exchange information on drug safety.

To assess the regulatory information relating to safety in order to determine whataction, if necessary, needs to be taken to improve safe use.

To make recommendations on product label amendments, product withdrawals

and suspension.

To provide information to end-users through adverse drug reaction news bulletins,drug alerts and seminars.


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Risk Minimization Tools Examples

Package insert (labeling)

Prescription only by specially certified physicians

Product dispensing only to patients with evidence of safety

Periodical monitoring laboratory tests

Medication guide for patients

Description of box warning and contraindication (including contraindicated

concomitant use of the drug) on the cover page of patient education pamphlet


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Key Points

Risk management is now an integral part of drugdevelopment

The Safety Specification should be defined early indevelopment

Risk management should be seen as formalization

and documentation of safety issues and theirmanagement during a products development and

post-authorisation


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Key Points

Regulators can request a Risk Management Plan at any timeduring product development or post-authorization

A robust Risk Management Plan can reduce the need for post-approval studies and restrictions in prescribing or supply

Consultation with Authorities is essential in developing riskmanagement plans

If there is any doubt whether a Risk Management Plan isrequired, consult the regulators


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Source:b

asic model adapted from FDA (1999). Managing theRisks from Medical Product Use.

Managing the risk of drug (medicinal) product use

Known Side Effects

Avoidable Unavoidable

Medication or DeviceError

Product Defects

PreventableAdverseEvents

Injury orDeath

UnexpectedConsequences

Public Health

ICH Q9

SafetyEfficacy Quality


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Hazards in Quality

Anythingthat has the potential to

harm patients,

product quality or

the business

(loss, interruption, image)

CONSIDERATI

Potential threat

- chemical reaction

- manufacturing issues

- facilities and equipment

System defect- not detected- insufficiently prevented

- emerges by degree

Failure- technical breakdown- human breakdown

- extrinsic effect

hazard


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Opportunities & Benefits

Encourages transparency

Create baseline for more science-based decisions

Facilitates communication

Matrix team approach

An aid to convince the stakeholders with trust

Encourages a preventive approach

Proactive control of risks and uncertainty

Benefit of knowledge transfer by team approach Changes behavior

Better understanding of risk-based decisions

Acceptance of residual risks


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Change in behaviour

From tick-boxapproach for compliance

towards

systematic

risk-based thinking


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Change in behaviour

Doing things,

that do not matterfor the patient

13th nov 2011 reg comp for product approval

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