Quality assurance and regulatory compliance for pharmaceutical product

Quality Assurance and Regulatory Compliance for Pharmaceutical Product

Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D

Department of Pharmaceutics

KLE University College of Pharmacy

BELGAUM-590010, Karnataka, India

E-mail: [email protected]

Cell No: 00919742431000

04th Oct. 2011 1Maharashtra College of Pharmacy, Nilanga

Quality Assurance

Quality assurance is a wide ranging concept covering all matters that individually or collectively influence the quality of a product.

It is the totality of the arrangements made with the object of ensuring that pharmaceutical products are of the quality required for their intended use.

QA is the heart and soul of quality control

QA = QC + GMP04th Oct. 2011 2Maharashtra College of Pharmacy, Nilanga

The System of Quality Assurance

Pharmaceutical products are designed and developed in a way that takes account of the requirements of GMP and other associated codes such as those of good laboratory practice (GLP) and good clinical practice (GCP)

Product and control operations are clearly specified in a written form and GMP requirements are adopted



Managerial responsibilities are clearly specified in job description

Arrangements are made for the manufacture, supply and use of the correct starting and packaging materials.

All necessary controls on starting materials, intermediate products, and bulk products and other in-process controls, calibrations, and validations are carried out.



The finished products is correctly processed and checked according to the defined procedures.

Pharmaceutical products are not sold or supplied before the authorized persons have certified that each production batch has been produced and controlled in accordance with the requirements of the marketing authorization and any other regulations relevant to the production, control and release of pharmaceutical products



Satisfactory arrangements exist to ensure, as far as possible, that the pharmaceutical products are stored by the manufacturer, distributed and subsequently handled so that quality is maintained throughout their shelf-life.

There is a procedure for self-inspection and/or quality audit that regularly appraises the effectiveness and applicability of the quality assurance system



Deviation are reported, investigated and recorded

There is a system for approving changes that may have an impact on product quality

Regular evaluations of the quality of pharmaceutical products should be conducted with the objective of verifying the consistency of the process and ensuring its continuous improvement.


QC

GMP

QA

Quality relationships


Quality Assurance

It is the sum total of the organized arrangements with the objective of ensuring that

products will be of the quality required for their

intended use


Good Manufacturing Practice

Is that part of Quality Assurance aimed at ensuring

that products are consistently manufactured to a quality appropriate to their

intended use


Good Manufacturing Practice

• Raw or starting materials• Finished products

• Premises and environment

• Equipment

• personnel• Training • Hygiene

04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga 11

GMP Covers all aspects of production including

GOOD MANUFACTURING

PRACTICE


Quality Control

Is that part of GMP concerned with sampling, specification & testing, documentation & release procedures which

ensure that the necessary & relevant tests are performed & the product is released for use only after ascertaining

it’s quality


QA and QC

QC is that part of GMP which is concerned with sampling,

specifications, testing and with in the organization, documentation,and release procedures which ensure that the necessary and relevant tests are carried out

• QA is the sum total of organized arrangements made with the object of ensuring that product will be of the Quality required by their intended use.


QA and QC

Operational laboratory techniques and activities used to fulfill the requirement of Quality

• All those planned or systematic actions necessary to provide adequate confidence that a product will satisfy the requirements for quality


QA and QC

QC is lab based • QA is company based


Quality Assurance-Highlights

In process quality checking in manufacturing

Validation of facilities, equipments, process, products and cleaning

Complaint handling

Storage of quality records and control samples

Stability studies04th Oct. 2011 19Maharashtra College of Pharmacy, Nilanga

Quality Assurance Activities

1. Technology Transfer

2. Validation

3. Documentation Control

4. Assuring Quality of Products

5. Quality Improvement Plans


1. Technology Transfer

Receipt of product design documents from R & D Department

Distribution of documents to different departments

Checking and approval of documents generated based on R & D documents i.e. batch manufacturing record

Scale up and validation of product‐


2. Validation

• Preparation of validation plans for facility, equipments/process including cleaning

• Approval of protocol for validation of facility /equipment /product /process

• Team member for execution of validation of facility/equipment/ product/process


3. Documentation Control

Controlled distribution and archiving of documents

Control of changes made by proper change control procedure

Approval of all documents


4. Assuring Quality of Products

cGMP trainingSOP complianceAudit of facility for complianceLine clearance In process counter checks‐Critical samplingRecord verificationRelease of batch for marketing Investigation of market complaints


5. Quality Improvement Plans

To take Feedback from different departments

Proposals for corrective and preventive actions

Annual Products review

Trend analysis of various quality parameters for products, environment and water


FACTORS IN DRUG QUALITY ASSURANCE

DRUGPRODUCTQUALITY

Labeling &Product

Information

Import& ExportControl

Raw Materials-Active &Inactive

ManufacturingProcesses

& Procedures Storage

TransportDistributionDispensing

& Use

QC &Analysis

HumanResources-

Professionals

Legislative Framework-Regulations Packaging


Quality Assurance Cycle

Research

Development

Raw Materials

Facilities

Documentation

Equipment

Personnel


• In process quality checking in manufacturing

• Validation of facilities, equipments, process, products and cleaning • Complaint handling

• Storage of quality records and control samples

• Stability studies

Quality Assurance Highlights


Equipment /Instrument Qualification

Before a process can be validated the equipment, facilities & services used in that process must themselves be validated such an operation is referred to as qualification

Qualification therefore, an integral part of process validation which in turn is part of GMP


Why to qualifyIf the instrument is not qualified prior to use & if a problem occurs, the source of problem will be difficult to identify.


Qualification Involves


Details Record in Change ControlRequest for changeChange control No.DateChange related to

product/document/system/facilityConcerned documents with numberDescription of changeReason for changeImpact of change04th Oct. 2011 35Maharashtra College of Pharmacy, Nilanga

Details Record in Change ControlProposed methodology for implementationCategory of changeType of changeComparison criteria for evaluation of the

changeAssessment of impact of changeApproval of changeImplementation of changeClosure of change


Details Recorded in Deviation Approval

Deviation no.Deviation related toConcerned identity number (Batch No., Code No. etc)Type of deviation (Planed/Unplaned)Description of deviationReason/Investigation with documentCategory of deviationRoot cause analysis


Details Recorded in Deviation Approval

Impact of deviation (on batches, Products, Items, etc) Immediate actionCAPA (Corrective and Preventive Action)

Impact of CAPA Intimation to concernedComments from concernedPeriodic reviewFinal reviewDeviation close-outEvaluation of implemented CAPA


Details Recorded In Out of Specification Report

OOS No. (Out of Specification)

Reporting of OOS Information of OOS to immediate senior Assessment of analytical data by immediate senior Discussion between analyst and immediate senior Sampling and analysis Data compilation Assignable cause identification Full scale OOS investigation (Cause not identified) Evaluation Conclusion CAPA OOS results summary04th Oct. 2011 39Maharashtra College of Pharmacy, Nilanga

Area of Self Inspection Personal & Personal details Premises including personnel facilities Maintenance of building & equipment Storage of starting material & finished products (Stores) Equipment Production & In-process controls Cephalosporin Mfg & Packing Manufacturing Packing Quality control Documentation Sanitation & Hygiene Validation and revalidation program04th Oct. 2011 40Maharashtra College of Pharmacy, Nilanga

Areas of Self InspectionCalibration of instruments or measurement systemRecall procedureComplaints managementLabels controlComputerized systemEngineeringDocuments related to regulatory affairsDiscarding of residuesQuality assuranceControl on contract analysisResults of previous self inspection, quality audit and any

corrective steps taken04th Oct. 2011 41Maharashtra College of Pharmacy, Nilanga

Details Recorded in Complaint Investigation Report

Complaint No.Product NameManufacturing and Expiry of productSource of complaintDate of receipt of complaintNature of complaintCategory of complaint


Details Recorded in Complaint Investigation Report

InvestigationImpact of complaint on other batches/productsBatches/ProductsReviewCAPAImpact of CAPAImplementation of Preventive actionClose out of complaint


Acceptance Criteria

Sr. No. RPN Rating RPN Category

1. Up to 25 Minor

2. 26 to 50 Moderate

3. 51 to 75 Major

4. 76 to ≤125 Critical


RPN: Risk Priority Number

ROOT CAUSE ANALYSIS


Regulatory ComplianceFor

Pharmaceutical Product


Regulatory RequirementsRegulatory requirements are part of the process of drug

discovery and drug development. Regulatory requirements describe what is necessary for a new

drug to be approved for marketing in any particular country. In the US, it is the function of the Food and Drug

Administration (FDA) to establish these regulatory requirements.

The European Medicines Agency (EMA) and Japanese Pharmaceuticals and Medical Devices Agency

(PMDA) are also important regulatory authorities in drug development. These three agencies oversee the three largest markets for drug sales


Regulatory Compliance

In general, compliance means conforming to a rule, such as a specification, policy, standard or law.

Regulatory compliance describes the goal that corporations or public agencies aspire to in their efforts to ensure that personnel are aware of and take steps to comply with relevant laws and regulations.


Pharmaceutical Product Quality Cannot Be Tested in - It Is Built in

Pharmaceutical product quality is assured by Comprehensive development programExtensive manufacturing and environmental

controls Rigorous validation procedures and

requirementsCompliance to regulatory requirements

The high quality thus built into the final product is ensured through in-process controls and verified in a series of confirmatory tests before each manufactured batch is released to the market


Quality = Quality of Manpower (Qualification, Training…)

+ Quality of Materials (Specifications, Approved Suppliers...)

+ Quality of Means (Qualified equipments, maintenance…)

+ Quality of Media (GMP premises, Controlled environment…)

+ Quality of Methods (Calibration, Validation…)

Product / Service

Materials

Methods

MeansManpower

Media

Composition of Quality


Functions of a Quality Unit

Quality Control

–Sampling and testing of components

(raw materials, Packing materials),

intermediates and finished products

–Compliance to Good Laboratory

Practices (GLPs)


Functions of a Quality Unit

Quality Assurance–Designing robust quality

systems

–Ensure compliance to

relevant regulatory

requirements

–Ensure compliance to

requirements of Good

Manufacturing Practices

(GMP) 04th Oct. 2011 53Maharashtra College of Pharmacy, Nilanga

Value addition in QA functionValue addition in QA function

Quality Assurance:

–Perform structured self-

inspection audits at regular

intervals to prevent any

failure or non-conformance

–Critically analyze the quality

non-conformance issues and

suggest corrective and

preventive actions04th Oct. 2011 54Maharashtra College of Pharmacy, Nilanga

Value addition in QA function

Quality Assurance:

–Perform documentation

audit to ensure realistic

recording of all the relevant

process parameters

–Review the adequacy of in-

process control checks to

prevent any potential

failures 04th Oct. 2011 55Maharashtra College of Pharmacy, Nilanga

Value addition in QA function

Quality Assurance:– Training & Knowledge Management

– Perform literature survey of FDA /

ICH / ISO guidelines, revisions in

the Pharmacopoeial specifications

and the current regulatory

requirements and provide training to

the production personnel.


Value addition of Regulatory function to enhance Quality Assurance

Regulatory Compliance:

–Knowledge of the current

international regulatory

requirements

–Comprehensive compilation of

the ‘Product Registration

Dossiers’ for the specific

customer countries04th Oct. 2011 57Maharashtra College of Pharmacy, Nilanga

Regulatory Approval

Regulatory Approval

API

Drug Product

Manufacturing Plant

CROBioequivalenceClinical

Trials

API

Drug Product

Regulatory dossiersNationa

l

Regional

Global

Re-registration/Renewal

Post Approval Changes




National Regional Global



National (India)

License Application Receipt

Manufacturing license Form No. 24 Form No. 25

Test license Form No. 30 Form No. 29

Import license Form No. 12 Form No.11

Compliance to (Drugs & Cosmetics Act 1940 & Rules under)


National (India)

Drug Regulatory approval

Schedule Y ComplianceForm 44

Manufacturing Schedule M Compliance

Documentation Schedule U Compliance

Packaging Schedule P Compliance

API/Excipients/FP/PM IP Inputs if not BP/USP/ or IH


Regional (US)

Parameters US

API USP (US DMF Type II)

Excipients USP

Packaging materials Complying to USP (Type III DMF)

Finished Product USP

Submission batch 1

Submission batch size 100,000 units or 1/10th of commercial batch

Stability Zone II requirement 25º+2ºC/60+5%RH & 40º+2ºC/75+5%RH

Reference product US RLD (Orange book listed)

Bioequivalence study Generally both fast & fed condition

Compliance to 21 CFR and its sub parts such as part 210 – 211, part 11, part 314, part 350, ICH etc.,

Generic application FDA form 356h04th Oct. 2011 62

Regional (Europe)Parameters Europe

API Ph.Eur. [COS (CEP) / EDMF]

Excipients Ph.Eur.

Packaging materials Ph.Eur.

Finished Product As per Ph.Eur. General requirement

Submission batch 2


Stability Zone II requirement 25º+2ºC/60+5%RH & 40º+2ºC/75+5%RH

Reference Product Europe

Bioequivalence study Generally fasting condition

Compliance to Orange guide, EDQM, CHMP, CPMP guidelines, ICH

Generic application AS per Article 10 and its sub sections

04th Oct. 2011 63

Regional (Others)

Parameters Other markets

API USP / Ph.Eur. (DMF requirement depends on the target market)

Excipients USP / Ph.Eur.

Packaging materials USP / Ph.Eur.

Finished Product USP / Ph.Eur.

Submission batch 2 or 3

Submission batch size Depends on the target market

Stability Depends on the Target market (E.g.: ASEAN: Zone IVb)

Reference Product Depends on the Target market

Bioequivalence study Generally fasting condition

Compliance to Respective country guidelines

Generic application AS per respective country guidelines

04th Oct. 2011 64

Global Parameters Global

API Harmonization of specification

Excipients Harmonization of specification

Packaging materials Harmonization of specification

Finished Product Harmonization of specification

Submission batch 3


Stability Zone III & IV

Reference Product Multiple region

Bioequivalence study Fasting & Fed condition

Compliance to Global Standards

Generic application AS per respective country guidelines

04th Oct. 2011 65

Regulatory Dossier

CTD dossier component

Module 1- Administrative & prescribing information (Region specific)Module 2: CTD summaries (Quality overall summary, the non-clinical overview/summaries, clinical overviews/Summaries)Module 3: Quality (CMC)Module 4: Non clinical study reports (Documentation on Toxicological and pharmacological tests)Module 5: Clinical study reports (For Generics: Bioequivalence study)

CTD ORGANIZATION IS BASED ONM4: Organization of the CTDM4E: The CTD — EfficacyM4Q: The CTD — QualityM4S: The CTD — Safety


Regulatory Dossier Regulatory approach:

Parameters US Europe Other markets India

API USP Ph.Eur. USP / Ph.Eur. IP

USDMF COS (CEP) / EDMF DMF requirement depends on the target market

Excipients USP Ph.Eur. USP / Ph.Eur. IP

Reference product US Europe Depends on the target market

Indian (if not available, then US or Europe)

Packaging materials

Complying to USP Ph.Eur. USP / Ph.Eur. IP

Finished product USP As per Ph.Eur. General requirement

USP / Ph.Eur. IP

Submission batch 1 2 2 or 3 -

Submission batch size

100,000 units or 1/10th of commercial

batch

100,000 units or 1/10th of

commercial batch

Depends on the target market

No such requirement

04th Oct. 2011 68

Regulatory Dossier Regulatory approach:

Parameters US Europe Other markets India

Stability data 1 batch 2 batches 2 or 3 batches 3 batches

Stability condition Zone I & II condition Zone I & II condition Depends on the target market

Zone IV condition

Comparative dissolution study

3 media 3 media Depends on the target market

1 to 3 media

Input materials TSE/BSE, OVI statements

TSE/BSE Depends on the target market

No such requirement

Packaging materials Food grade certificate Food grade certificate Depends on the target market

No such requirement

Method validation data As per ICH ICH ICH No such guideline

Process validation data

Not required Not required Depends on the target market

Not required for submission

Bioequivalence study US reference product under fast and fed

condition

European reference product (generally

under fasting condition)

Generally fasting bio study

Fasting bio study

Bioequivalence study In USFDA approved CRO anywhere in the

world

MHRA/EU approved CRO anywhere

Depends on the target market

Indian study required

04th Oct. 2011 69

Specific requirements of an US ANDA QOS: in QbR format (Quality overall summary:Question-based review)

Exhibit batches (1 batch)

Stability data at the time of submission (3 Months)

TSE/BSE certificate (Transmissible spongiform encephalopatics/Bovine spongiform encephalopathy)

Structured Product Labeling (SPL) & side by side labeling comparison

OVI statement (Organic volatile impurities)

Financial certification / disclosure statement (Bioequivalence study)

Environmental assessment or claim for categorical exclusion

Declaration under Generic Drug Enforcement Act (Debarment certification & conviction statement)

Patent certification & exclusivity statement

Appointment of US agent & letter of US agent authorization

Copy of executed batch records


Specific requirements of an EU dossier

Release testing in EU (QP)

Exhibit batches (2 batches)

Stability data (6 Months)

Process validation study

Release and shelf life specification

Microbiological considerations

TSE/BSE certificate

SPC (Summary of product characteristics)

Braille labeling (Just another way to read and write English)

Readability testing04th Oct. 2011 71Maharashtra College of Pharmacy, Nilanga

Regulatory Approval Product Approval / Authorization

Successful registration of the product in the target market involves:

Successful review of API DMF / COS Successful audit of API plant (wherever applicable) Successful review of Drug Product Dossier (ANDA, MAA etc.)

• CMC data review

• Bioequivalence study data review

• Administrative data review Successful audit of the drug product manufacturing plant Successful audit of the bioequivalence study CRO


Quality Assurance: Common Regulatory Compliance Issues

API Infringing route of synthesis Not consistent with respective Pharmacopoeial requirement Impurity profile out of limit Residual solvents not meeting the requirements Unapproved site of manufacture (by concerned regulatory body) Unacceptable physico-chemical properties (particle size, polymorphism, bulk

density, etc.) From manufacturer who does not assure uninterrupted supply of API Unapproved vendor (by drug product manufacturer) Use of non DMF / COS material (e.g.: US, Europe etc.) High cost (commercial viability)

04th Oct. 2011 73

Excipient

Use of rarely available / or commonly not used excipients Use of Non GRAS materials (Generally recognized as safe)

Incompatible Not consistent with respective Pharmacopoeial requirement Residual solvents not meeting the requirements TSE / BSE / GMO (Genetically modified organisms)

Unapproved vendor Unacceptable physico-chemical and functional properties (particle size,

bulk density, viscosity grade, surface area, degree of polymerization etc.) From manufacturers who do not assure uninterrupted supply High cost (commercial viability)



Formulation development Pre-formulation Improper API characterization

• Intrinsic solubility

• pH dependent solubility• Saturation solubility• Particle size• Polymorph• Bulk density

• Hygroscopicity study• Impurity profile etc.,

Wrong choice of reference product (e.g. Not selecting innovator product) Reference product not matching with the proposed market (e.g.: European

product selected for US market) Inadequate drug excipient compatibility studies



Formulation development

Use of overages without proper justification Use of banned / unapproved colours (in target market) Use of excipients without proper justification (e.g.: surfactants etc.) Use of excipients not consistent with the proposed route of administration Use of Pharmacopoeial grade not consistent with the target market Infringing process Lack of proper development report Inadequate optimization study data on process controls Complex / costly process / lengthy operating cycle Use of non-aqueous solvents (to be avoided)




Formulation (Finished product) Dissolution profile not matching with the reference product Dissolution profile not matching with the bio strength in case of multi

strength products (for bio waiver purpose) Not meeting Pharmacopoeial requirement Dissolution – Lack of justification for selection of:

• Media• Apparatus• RPM• Volume of media• Sampling point• Dissolution limit• Justification for addition of surfactant (e.g.: SLS), enzymes (e.g.:

Pepsin, Pancreatin etc.) in the dissolution medium



Formulation (Finished product specification) Not meeting Pharmacopoeial requirement / ICH Q6A Lack of second identification test (for non specific test) Inadequate impurities & residual solvent specification (ICH Q3A, B,

Q3C) Lack of testing for preservatives, anti-oxidants wherever used Lack of test for breakability / content uniformity for half tablets

(when functional score line exists) Lack of test for establishing polymorphic conversions Color identification test (e.g.: Europe) Test for water content in solid dosage form (e.g.: US) Missing of microbiological tests Lack of specification for testing after reconstitution



Packaging Materials

Improper justification for the selection of packaging materials

Lack of data on release / sorption / leaching study (specially for those used in liquid / parenteral preparations)

Lack of study to demonstrate integrity of container closure system (where applicable)

Primary packaging material not suitable for its intended performance (e.g.: child resistant)

Lack of identification test in the specification Lack of food grade certification for the materials Non use of virgin grade polymers



Manufacturing of submission batches Inadequate batch size (e.g.: less than 100,000 units or 1/10 th

of the commercial batch size whichever is higher) Inadequate number of batches (e.g.: minimum 1 batch for

US, 2 batches for Europe etc.) Inadequate packaging quantity (e.g.: minimum 100,000

units packed quantity for US) Lack of process validation (applicable to many Asia Pacific

countries) Lack of stratified sampling during in-process test (e.g.: US) Hold time study



Analytical methods Analytical methods not validated Analytical methods not stability indicating (for stability

studies) Forced degradation studies not performed Inadequate justification for choice / selection of method

(UV vs HPLC) Inadequate justification for selection of conditions

(column, wavelength, run time, mobile phase, flow rate, temperature etc.)

Non availability of method development report In adequate method validation parameters (e.g.: LOD,

LOQ in RS method)04th Oct. 2011 81Maharashtra College of Pharmacy, Nilanga


Stability Study Inadequate batch size (e.g.: less than 100,000 units or 1/10th

of the commercial batch size whichever is higher)

Inadequate number of batches (e.g.: minimum 1 batch for

US, 2 batches for Europe etc.)

Chamber temperature and humidity condition not appropriate

to the target market (e.g.: Zone I & II and Zone III and Zone

IV conditions are different)

Inadequate data at the time of submission (e.g.: 3 months

data for US, 6 months data for Europe)



Stability Study

Photo stability study not considered Improper container orientation (specially for

liquid products) Inadequate stability study on bulk shipment

pack (if intended to ship it for repackaging) Inadequate parameters covered under stability

protocol (e.g.: microbial testing) Not charging samples under fall back condition 04th Oct. 2011 83Maharashtra College of Pharmacy, Nilanga

Stability

Global climatic zones

ZoneMean Kinetic

Temperature (ºC)Yearly average RH

(%)

Zone I (Moderate) 21 45

Zone II (Mediterranean) 25 60

Zone III (Hot & Dry) 30 35

Zone IV (Hot & humid) 30 70

04th Oct. 2011 84

Stability

Distribution of nations into different climatic zones: Region Zones I & II Zone III & IV

European All countries -

American Chile, Canada, United StatesBrazil, Jamaica,

Venezuela

Asian China, Japan, TurkeyIndia, Philippines, Sri

Lanka

African South Africa, Zambia, Zimbabwe

Botswana, Ghana, Uganda

Australian / Oceanic Australia, New Zealand Fiji, Papua - New Guinea

04th Oct. 2011 85


Bioequivalence study

Use of wrong strength (in case of multiple strength products)

Use of inappropriate reference product (e.g.: US reference product

for Europe study)

Inadequate number of volunteers

Inadequate sampling intervals to capture tmax / cmax (maximum time

points should be there around the expected tmax/cmax)

Inadequate wash out period

Design fault in deciding what to test (e.g. testing of parent

compound or active metabolite or both)

Choice of study (Fast / Fed study or both)04th Oct. 2011 86Maharashtra College of Pharmacy, Nilanga


Bioequivalence study

Use of non validated method for testing

Stability of plasma samples not established

Inadequate number of reserve samples (e.g.: 5 times of the sample

required for complete analysis)

Use of unapproved CRO

Inappropriate documentation [IEC / IRB approval of protocol, informed

consent, CRF, pharmacokinetic data, statistical data (SAS), etc]

Bioequivalence study sample formula different from commercial batch

formula

Bioequivalence study samples are not from GMP pivotal batch



Regulatory audits

Training of personnel

Facility upkeep

Equipment upkeep and preventive maintenance program

Area and environmental monitoring

QA systems, documentation control and traceability

Vendor approval procedure

Inventory control and storage

Change controls, deviations

OOS04th Oct. 2011 88Maharashtra College of Pharmacy, Nilanga


Regulatory audits

Qualification / validation of system, facility, equipment etc.

Water system

HVAC system (Heating, ventilation and air conditioning)

Stability program

Process validation

Laboratory control, testing and release of materials

Documentation review (Batch records, analytical records, etc.)

Batch release by QA


Quality Assurance in Life Cycle Management

Tasks to be performed

Pharmacovigilance Safety reports

Post Approval Changes / Variations To implement necessary up-dates and changes of the dossier

Line extensions (major changes, requiring new MAA) To implement necessary up-dates and changes of the dossier

Renewal / Re-registration



Post Approval Changes

Formula

Batch size

Process

Site Change

Equipment Change

Source / Spec & test procedure

Multiple Changes

API / Excipients / Pkg Materials

04th Oct. 2011 91


Post approval changes Reporting

Level 1

Annual Report

Level 2Changes Being Effected (CBE)

Changes Being Effected in 30 days (CBE-30)

Level 3

"Scale-Up and Post-Approval Changes"

Changes Being Effected (CBE)

Changes Being Effected in 30 days (CBE-30)

Prior Approval Supplement (PAS)

Post Approval Changes (US SUPAC)

SUPAC



Category Reporting

Minor Type 1A

Moderate Type 1B

Major Type II standard

Critical Type II complex

Post Approval Changes (Europe)

Variations



Other markets India

Notifications e.g. Australia

•Part A: Non-assessable changes

•Part B: Self-assessable changes

•Part C: Changes requiring approval

No such requirement

Post Approval Changes (Other markets)



Registration validity

US: Annual report every year

Europe: Re-registration once in 5 years

India: License renewal every 5 years

Other countries: Generally 5 years

04th Oct. 2011 95

Quality Assurance: The most important element of regulatory compliance

The most important element for compliance is…..

Manpower … Manpower … Manpower

It is the people who ensure Regulatory compliance at every stage of product life cycle i.e. starting from product development to life cycle management

The best way to enhance their capability is through …….

Training…….Training ……. Training

04th Oct. 2011 96

Quality Assurance: The state of compliance

Everything is likely to undergo change during the life cycle of a product…….

Formula, Process, Equipment, Batch size, Suppliers, Manufacturing site, Trade dress, Indications,

Regulatory requirements, Specifications & test procedures, People and so on ………

The only thing that can not be changed is the….

“State of Compliance”04th Oct. 2011 97

Regulatory Authorities

India: DCGI & State Drug Administration European Union: EMEA and national USA : Food and Drug Administration (FDA) Australia : Therapeutic Goods Administration Newzeland : Medsafe South Africa: Medicines council control Japan : Ministry of Health & Labour Welfare Switzerland : Swissmedic Brazil : ANVISA (The National Health Surveillance Agency)

Mexico: COFEPRIS (The Federal Commission for the Protection against Sanitary Risk)

Chile : ISP - Instituto de Salud Pública de Chile Columbia: INVIMA – Instituto Nacional de Vigilancia de Medicamentos Alimentos Carrera 68 D No. 17 - 11 / 21 Argentina: ANMAT - set in 1992 Argentine National Administration of Drugs, Food & Medical TechnologyFrance: Agence Française de Sécurité Sanitaire des Produits de SantéGermany: Federal Institute for Drugs and Medical Devices04th Oct. 2011 98Maharashtra College of Pharmacy, Nilanga

Important sites

Regulatory sites:

www.fda.govwww.tga.gov.au http://www.emea.europa.eu/ www.ministeriodesalud.go.cr www.mspas.gob.gthttp://www.minsa.gob.pa/minsa2006/inicio.phphttp://www.minsa.gob.nihttp://www.salud.gob.hn/www.cssp.gob.svhttp://www.sns.gov.bo/http://www.inh.gov.ec/http://www.mspbs.gov.py/http://www.msp.gub.uy/index_1.htmlhttp://digemid.minsa.gob.pehttp://www.inhrr.gov.vehttp://pharmacos.eudra.org


Important sites

(http://pharmacos.eudra.org/F2/eudralex/index.htm)www.bfarm.de/de/index.php agmed.sante.gouv.fr/htm/5/repec/repec0.htmwww.nam.fihttp://heads.medagencies.org/mrfg/sops


Important sites

Useful links:

www.usp.org www.pheur.org www.jpdb.nihs.go.jp www.picscheme.org www.pda.org www.phrma.org www.pharmacy.org www.elsevier.com www.ich.orgwww.ijpsonline.com www.pharmj.com www.scripnews.com


Thank YouE-mail: [email protected]

Cell No: 00919742431000


Quality assurance and regulatory compliance for pharmaceutical product

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Transcript of Quality assurance and regulatory compliance for pharmaceutical product