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 , Karnataka, India Cell No: 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

Maharashtra 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 + GMP 04th Oct. 2011 Maharashtra 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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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

Quality relationships
QA GMP QC 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

Good Manufacturing Practice
GMP Covers all aspects of production including Raw or starting materials Finished products Premises and environment Equipment personnel Training Hygiene 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

GOOD MANUFACTURING PRACTICE
Quality System with Traceable Documentation Approved Materials Manufacturing Instructions Controlled Environment Controlled Materials Handling, Storage, Segregation, Packaging & Labelling Material, Intermediate & Finished Products Testing Internal Audits & Reviews Validated Test Method Validated Processes Equipment Facilities Trained Personnel GOOD MANUFACTURING PRACTICE 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

QA and QC QA is company based QC is lab based 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

Quality Assurance Activities
Technology Transfer Validation Documentation Control Assuring Quality of Products Quality Improvement Plans 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

3. Documentation Control
Controlled distribution and archiving of documents Control of changes made by proper change control procedure Approval of all documents 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

Equipment /Instrument Qualification

Why to qualify According to GLP, cGMP, GAMP, ISO 9000 etc.
If the instrument is not qualified prior to use & if a problem occurs, the source of problem will be difficult to identify. Qualification is the part of validation Begins at Vendor’s site Structural Validation Design/Development stage of equipment/instrument Produced in validated environment According to GLP, cGMP, GAMP, ISO 9000 etc. 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

Qualification Involves
User Requirement Specification (USR) Functional Design Specification (FDS) Design Qualification (DQ) Factory Acceptance Tests (FAT) Installation Qualification (IQ) Site Acceptance Test (SAT) Operational Qualification (OQ) Performance Qualification (PQ) 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

Details Recorded in Complaint Investigation Report
Impact of complaint on other batches/products Batches/Products Review CAPA Impact of CAPA Implementation of Preventive action Close out of complaint 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

RPN: Risk Priority Number
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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

ROOT CAUSE ANALYSIS 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

Regulatory Compliance Pharmaceutical Product
For Pharmaceutical Product 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

Composition of Quality
Product / Service Materials Methods Means Manpower Media 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…) 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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

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 Maharashtra College of Pharmacy, Nilanga

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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 Maharashtra College of Pharmacy, Nilanga

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

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

API API Drug Product Manufacturing Plant Drug Product Regulatory Approval Bioequivalence CRO Clinical Trials National Regulatory dossiers Regional Re-registration/Renewal Global Post Approval Changes 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

National Regional Global 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

National (India) Compliance to (Drugs & Cosmetics Act 1940 & Rules under) 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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

National (India) Drug Regulatory approval Schedule Y Compliance Form 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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

Regional (US) Parameters US API USP (US DMF Type II) Excipients USP
Packaging materials Complying to USP (Type III DMF) Finished Product 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 356h 04th Oct. 2011

Regional (Europe) Parameters Europe API Ph.Eur. [COS (CEP) / EDMF]
Excipients Ph.Eur. Packaging materials Finished Product As per Ph.Eur. General requirement Submission batch 2 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 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

Regional (Others) Parameters Other markets API
USP / Ph.Eur. (DMF requirement depends on the target market) Excipients USP / Ph.Eur. Packaging materials Finished Product 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

Global Parameters Global API Harmonization of specification Excipients
Packaging materials Finished Product Submission batch 3 Submission batch size 100,000 units or 1/10th of commercial batch 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

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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 Reference product Depends on the target market Indian (if not available, then US or Europe) Packaging materials Complying to USP Finished product As per Ph.Eur. General requirement Submission batch 1 2 2 or 3 - Submission batch size 100,000 units or 1/10th of commercial batch No such requirement 04th Oct. 2011

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 Depends on the target market Zone IV condition Comparative dissolution study 3 media 1 to 3 media Input materials TSE/BSE, OVI statements TSE/BSE No such requirement Packaging materials Food grade certificate Method validation data As per ICH ICH No such guideline Process validation data Not required 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 In USFDA approved CRO anywhere in the world MHRA/EU approved CRO anywhere Indian study required 04th Oct. 2011

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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

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

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

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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

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 Maharashtra College of Pharmacy, Nilanga

Mean Kinetic Temperature (ºC)
Stability Global climatic zones Zone Mean 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) 70 04th Oct. 2011

Stability Distribution of nations into different climatic zones:
Region Zones I & II Zone III & IV European All countries - American Chile, Canada, United States Brazil, Jamaica, Venezuela Asian China, Japan, Turkey India, Philippines, Sri Lanka African South Africa, Zambia, Zimbabwe Botswana, Ghana, Uganda Australian / Oceanic Australia, New Zealand Fiji, Papua - New Guinea 04th Oct. 2011

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

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

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) Renewal / Re-registration 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

04th Oct. 2011

Post Approval Changes (US SUPAC) Post approval changes Reporting Level 1 Annual Report Level 2 Changes Being Effected (CBE) Changes Being Effected in 30 days (CBE-30) Level 3 "Scale-Up and Post-Approval Changes" Prior Approval Supplement (PAS) 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

Post Approval Changes (Europe) Category Reporting Minor Type 1A Moderate Type 1B Major Type II standard Critical Type II complex 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

Post Approval Changes (Other markets) 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 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

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

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

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

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

Important sites Regulatory sites: 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

Important sites ( agmed.sante.gouv.fr/htm/5/repec/repec0.htm 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

Important sites Useful links: 04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga

Thank You E-mail: bknanjwade@yahoo.co.in Cell No: 00919742431000

Quality Assurance and Regulatory Compliance for Pharmaceutical Product

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