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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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Examples of Information Covered in a Chemistry
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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Examples of Information Covered in a Chemistry
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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Examples of Information Covered in a Chemistry
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