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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: bknanjwade@yahoo.co.in Cell No: 00919742431000. Quality Assurance.

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quality assurance and regulatory compliance for pharmaceutical product
Quality Assurance and Regulatory Compliance for Pharmaceutical Product

Prof. Dr. Basavaraj K. NanjwadeM. Pharm., Ph. D

Department of Pharmaceutics

KLE University College of Pharmacy

BELGAUM-590010, Karnataka, India

E-mail: bknanjwade@yahoo.co.in

Cell No: 00919742431000

Maharashtra College of Pharmacy, Nilanga

quality assurance
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 soulof quality control

QA = QC + GMP

Maharashtra College of Pharmacy, Nilanga

the system of quality assurance
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

Maharashtra College of Pharmacy, Nilanga

the system of quality assurance4
The System of Quality Assurance
  • 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.

Maharashtra College of Pharmacy, Nilanga

the system of quality assurance5
The System of Quality Assurance
  • 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

Maharashtra College of Pharmacy, Nilanga

the system of quality assurance6
The System of Quality Assurance
  • 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

Maharashtra College of Pharmacy, Nilanga

the system of quality assurance7
The System of Quality Assurance
  • 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.

Maharashtra College of Pharmacy, Nilanga

slide8

Quality relationships

QA

GMP

QC

Maharashtra College of Pharmacy, Nilanga

quality assurance9
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

Maharashtra College of Pharmacy, Nilanga

good manufacturing practice
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

Maharashtra College of Pharmacy, Nilanga

good manufacturing practice11
Good Manufacturing Practice

GMP Covers all aspects of production including

  • Raw or starting materials
  • Finished products
  • Premises and environment
  • Equipment
  • personnel
      • Training
      • Hygiene

Maharashtra College of Pharmacy, Nilanga

slide12

GOOD

MANUFACTURING

PRACTICE

Maharashtra College of Pharmacy, Nilanga

quality control
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

Maharashtra College of Pharmacy, Nilanga

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 and QC
  • 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.

Maharashtra College of Pharmacy, Nilanga

qa and qc15
Operational laboratory techniques and activities used to fulfill the requirement of QualityQA and QC
  • All those planned or systematic actions necessary to provide adequate confidence that a product will satisfy the requirements for quality

Maharashtra College of Pharmacy, Nilanga

qa and qc16
QC is lab basedQA and QC
  • QA is company based

Maharashtra College of Pharmacy, Nilanga

quality assurance highlights
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 studies

Maharashtra College of Pharmacy, Nilanga

quality assurance activities
Quality Assurance Activities
  • Technology Transfer
  • Validation
  • Documentation Control
  • Assuring Quality of Products
  • Quality Improvement Plans

Maharashtra College of Pharmacy, Nilanga

1 technology transfer
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

Maharashtra College of Pharmacy, Nilanga

2 validation
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

Maharashtra College of Pharmacy, Nilanga

3 documentation control
3. Documentation Control
  • Controlled distribution and archiving of documents
  • Control of changes made by proper change control procedure
  • Approval of all documents

Maharashtra College of Pharmacy, Nilanga

4 assuring quality of products
4. Assuring Quality of Products
  • cGMP training
  • SOP compliance
  • Audit of facility for compliance
  • Line clearance
  • In‐process counter checks
  • Critical sampling
  • Record verification
  • Release of batch for marketing
  • Investigation of market complaints

Maharashtra College of Pharmacy, Nilanga

5 quality improvement plans
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

Maharashtra College of Pharmacy, Nilanga

slide26

FACTORS IN DRUG QUALITY ASSURANCE

Import

& Export

Control

Legislative

Framework

-Regulations

Packaging

Human

Resources-

Professionals

Labeling &

Product

Information

DRUG

PRODUCT

QUALITY

Raw

Materials-

Active &

Inactive

QC &

Analysis

Transport

Distribution

Dispensing

& Use

Manufacturing

Processes

& Procedures

Storage

Maharashtra College of Pharmacy, Nilanga

slide28

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 studies

Maharashtra College of Pharmacy, Nilanga

equipment instrument qualification
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

Maharashtra College of Pharmacy, Nilanga

equipment instrument qualification31
Equipment /Instrument Qualification

Maharashtra College of Pharmacy, Nilanga

equipment instrument qualification32
Equipment /Instrument Qualification

Maharashtra College of Pharmacy, Nilanga

why to qualify
Why to qualify

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

Maharashtra College of Pharmacy, Nilanga

qualification involves
Qualification Involves

Maharashtra College of Pharmacy, Nilanga

details record in change control
Details Record in Change Control
  • Request for change
  • Change control No.
  • Date
  • Change related to product/document/system/facility
  • Concerned documents with number
  • Description of change
  • Reason for change
  • Impact of change

Maharashtra College of Pharmacy, Nilanga

details record in change control36
Details Record in Change Control
  • Proposed methodology for implementation
  • Category of change
  • Type of change
  • Comparison criteria for evaluation of the change
  • Assessment of impact of change
  • Approval of change
  • Implementation of change
  • Closure of change

Maharashtra College of Pharmacy, Nilanga

details recorded in deviation approval
Details Recorded in Deviation Approval
  • Deviation no.
  • Deviation related to
  • Concerned identity number (Batch No., Code No. etc)
  • Type of deviation (Planed/Unplaned)
  • Description of deviation
  • Reason/Investigation with document
  • Category of deviation
  • Root cause analysis

Maharashtra College of Pharmacy, Nilanga

details recorded in deviation approval38
Details Recorded in Deviation Approval
  • Impact of deviation (on batches, Products, Items, etc)
  • Immediate action
  • CAPA (Corrective and Preventive Action)
  • Impact of CAPA
  • Intimation to concerned
  • Comments from concerned
  • Periodic review
  • Final review
  • Deviation close-out
  • Evaluation of implemented CAPA

Maharashtra College of Pharmacy, Nilanga

details recorded in out of specification report
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 summary

Maharashtra College of Pharmacy, Nilanga

area of self inspection
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 program

Maharashtra College of Pharmacy, Nilanga

areas of self inspection
Areas of Self Inspection
  • Calibration of instruments or measurement system
  • Recall procedure
  • Complaints management
  • Labels control
  • Computerized system
  • Engineering
  • Documents related to regulatory affairs
  • Discarding of residues
  • Quality assurance
  • Control on contract analysis
  • Results of previous self inspection, quality audit and any corrective steps taken

Maharashtra College of Pharmacy, Nilanga

details recorded in complaint investigation report
Details Recorded in Complaint Investigation Report
  • Complaint No.
  • Product Name
  • Manufacturing and Expiry of product
  • Source of complaint
  • Date of receipt of complaint
  • Nature of complaint
  • Category of complaint

Maharashtra College of Pharmacy, Nilanga

details recorded in complaint investigation report43
Details Recorded in Complaint Investigation Report
  • Investigation
  • Impact of complaint on other batches/products
  • Batches/Products
  • Review
  • CAPA
  • Impact of CAPA
  • Implementation of Preventive action
  • Close out of complaint

Maharashtra College of Pharmacy, Nilanga

acceptance criteria
Acceptance Criteria

RPN: Risk Priority Number

Maharashtra College of Pharmacy, Nilanga

root cause analysis
ROOT CAUSE ANALYSIS

Maharashtra College of Pharmacy, Nilanga

slide47
Regulatory Compliance

For

Pharmaceutical Product

Maharashtra College of Pharmacy, Nilanga

regulatory requirements
Regulatory Requirements
  • Regulatory 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

Maharashtra College of Pharmacy, Nilanga

regulatory compliance
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.

Maharashtra College of Pharmacy, Nilanga

pharmaceutical product quality cannot be tested in it is built in
Pharmaceutical Product Quality Cannot Be Tested in - It Is Built in
  • Pharmaceutical product quality is assured by
    • Comprehensive development program
    • Extensive manufacturing and environmental controls
    • Rigorous validation procedures and requirements
    • Compliance 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

Maharashtra College of Pharmacy, Nilanga

slide51

Manpower

Means

Materials

Product / Service

Media

Methods

Composition of Quality

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…)

Maharashtra College of Pharmacy, Nilanga

functions of a quality unit
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)

Maharashtra College of Pharmacy, Nilanga

functions of a quality unit53
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)

Maharashtra College of Pharmacy, Nilanga

value addition in qa function
Value 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 actions

Maharashtra College of Pharmacy, Nilanga

value addition in qa function55
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

Maharashtra College of Pharmacy, Nilanga

value addition in qa function56
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.

Maharashtra College of Pharmacy, Nilanga

value addition of regulatory function to enhance quality assurance
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 countries

Maharashtra College of Pharmacy, Nilanga

regulatory compliance58
Regulatory Compliance

API

API

Regulatory

Approval

Drug Product

Drug Product

Manufacturing Plant

Bioequivalence

CRO

Clinical Trials

National

Regulatory dossiers

Regional

Re-registration/Renewal

Global

Post Approval Changes

Maharashtra College of Pharmacy, Nilanga

regulatory compliance59
Regulatory Compliance

Regulatory Compliance

National

Regional

Global

Maharashtra College of Pharmacy, Nilanga

national india
National (India)

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

Maharashtra College of Pharmacy, Nilanga

national india61
National (India)

Maharashtra College of Pharmacy, Nilanga

regulatory dossier
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 ON
    • M4: Organization of the CTD
    • M4E: The CTD — Efficacy
    • M4Q: The CTD — Quality
    • M4S: The CTD — Safety

Maharashtra College of Pharmacy, Nilanga

regulatory dossier68
Regulatory Dossier
  • Regulatory approach:
regulatory dossier69
Regulatory Dossier
  • Regulatory approach:
specific requirements of an us anda
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

Maharashtra College of Pharmacy, Nilanga

specific requirements of an eu dossier
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 testing

Maharashtra College of Pharmacy, Nilanga

regulatory approval
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

Maharashtra College of Pharmacy, Nilanga

quality assurance common regulatory compliance issues
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)
quality assurance common regulatory compliance issues74
Quality Assurance: Common Regulatory Compliance Issues
  • 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)

Maharashtra College of Pharmacy, Nilanga

quality assurance common regulatory compliance issues75
Quality Assurance: Common Regulatory Compliance Issues
  • 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

Maharashtra College of Pharmacy, Nilanga

quality assurance common regulatory compliance issues76
Quality Assurance: Common Regulatory Compliance Issues
  • 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)

Maharashtra College of Pharmacy, Nilanga

quality assurance common regulatory compliance issues77
Quality Assurance: Common Regulatory Compliance Issues
  • 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

Maharashtra College of Pharmacy, Nilanga

quality assurance common regulatory compliance issues78
Quality Assurance: Common Regulatory Compliance Issues
  • 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

Maharashtra College of Pharmacy, Nilanga

quality assurance common regulatory compliance issues79
Quality Assurance: Common Regulatory Compliance Issues
  • 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

Maharashtra College of Pharmacy, Nilanga

quality assurance common regulatory compliance issues80
Quality Assurance: Common Regulatory Compliance Issues
  • Manufacturing of submission batches
  • 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.)
  • 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

Maharashtra College of Pharmacy, Nilanga

quality assurance common regulatory compliance issues81
Quality Assurance: Common Regulatory Compliance Issues
  • 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)

Maharashtra College of Pharmacy, Nilanga

quality assurance common regulatory compliance issues82
Quality Assurance: Common Regulatory Compliance Issues
  • 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)

Maharashtra College of Pharmacy, Nilanga

quality assurance common regulatory compliance issues83
Quality Assurance: Common Regulatory Compliance Issues
  • 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

Maharashtra College of Pharmacy, Nilanga

stability
Stability
  • Global climatic zones
stability85
Stability

Distribution of nations into different climatic zones:

quality assurance common regulatory compliance issues86
Quality Assurance: Common Regulatory Compliance Issues
  • 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)

Maharashtra College of Pharmacy, Nilanga

quality assurance common regulatory compliance issues87
Quality Assurance: Common Regulatory Compliance Issues
  • 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

Maharashtra College of Pharmacy, Nilanga

quality assurance common regulatory compliance issues88
Quality Assurance: Common Regulatory Compliance Issues
  • 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
  • OOS

Maharashtra College of Pharmacy, Nilanga

quality assurance common regulatory compliance issues89
Quality Assurance: Common Regulatory Compliance Issues
  • 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

Maharashtra College of Pharmacy, Nilanga

quality assurance in life cycle management
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

Maharashtra College of Pharmacy, Nilanga

slide92

Quality Assurance in Life Cycle Management

Post Approval Changes (US SUPAC)

Maharashtra College of Pharmacy, Nilanga

quality assurance in life cycle management93
Quality Assurance in Life Cycle Management

Post Approval Changes (Europe)

Maharashtra College of Pharmacy, Nilanga

slide94

Quality Assurance in Life Cycle Management

Post Approval Changes (Other markets)

Maharashtra College of Pharmacy, Nilanga

quality assurance in life cycle management95
Quality Assurance in Life Cycle Management
  • 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
quality assurance the most important element of regulatory compliance
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

quality assurance the state of compliance
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”

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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 Technology
  • France: Agence Française de Sécurité Sanitaire des Produits de Santé
  • Germany: Federal Institute for Drugs and Medical Devices

Maharashtra College of Pharmacy, Nilanga

important sites
Important sites

Regulatory sites:

  • www.fda.gov
  • www.tga.gov.au
  • http://www.emea.europa.eu/
  • www.ministeriodesalud.go.cr
  • www.mspas.gob.gt
  • http://www.minsa.gob.pa/minsa2006/inicio.php
  • http://www.minsa.gob.ni
  • http://www.salud.gob.hn/
  • www.cssp.gob.sv
  • http://www.sns.gov.bo/
  • http://www.inh.gov.ec/
  • http://www.mspbs.gov.py/
  • http://www.msp.gub.uy/index_1.html
  • http://digemid.minsa.gob.pe
  • http://www.inhrr.gov.ve
  • http://pharmacos.eudra.org

Maharashtra College of Pharmacy, Nilanga

important sites100
Important sites
  • (http://pharmacos.eudra.org/F2/eudralex/index.htm)
  • www.bfarm.de/de/index.php
  • agmed.sante.gouv.fr/htm/5/repec/repec0.htm
  • www.nam.fi
  • http://heads.medagencies.org/mrfg/sops

Maharashtra College of Pharmacy, Nilanga

important sites101
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.org
  • www.ijpsonline.com
  • www.pharmj.com
  • www.scripnews.com

Maharashtra College of Pharmacy, Nilanga

thank you e mail bknanjwade@yahoo co in cell no 00919742431000
Thank YouE-mail: bknanjwade@yahoo.co.inCell No: 00919742431000

Maharashtra College of Pharmacy, Nilanga