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Transcript of Quality Assurance and Regulatory Compliance for Pharmaceutical Product Prof. Dr. Basavaraj K....
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
04th Oct. 2011 3Maharashtra College of Pharmacy, Nilanga
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.
04th Oct. 2011 4Maharashtra College of Pharmacy, Nilanga
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
04th Oct. 2011 5Maharashtra College of Pharmacy, Nilanga
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
04th Oct. 2011 6Maharashtra College of Pharmacy, Nilanga
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.
04th Oct. 2011 7Maharashtra College of Pharmacy, Nilanga
QC
GMP
QA
Quality relationships
04th Oct. 2011 8Maharashtra 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 9Maharashtra 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 10Maharashtra College of Pharmacy, Nilanga
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 MANUFACTURIN
G PRACTICE
04th Oct. 2011 12Maharashtra 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 13Maharashtra 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 14Maharashtra 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 15Maharashtra College of Pharmacy, Nilanga
QA and QC
QC is lab based • QA is company based
04th Oct. 2011 16Maharashtra College of Pharmacy, Nilanga
04th Oct. 2011 17Maharashtra College of Pharmacy, Nilanga
04th Oct. 2011 18Maharashtra 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 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
04th Oct. 2011 20Maharashtra 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 21Maharashtra 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 22Maharashtra 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 23Maharashtra College of Pharmacy, Nilanga
4. Assuring Quality of ProductscGMP trainingSOP complianceAudit of facility for complianceLine clearance In‐process counter checksCritical samplingRecord verificationRelease of batch for marketing Investigation of market complaints
04th Oct. 2011 24Maharashtra 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 25Maharashtra College of Pharmacy, Nilanga
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
04th Oct. 2011 26Maharashtra College of Pharmacy, Nilanga
Quality Assurance Cycle
Research
Development
Raw Materials
Facilities
Documentation
Equipment
Personnel
04th Oct. 2011 27Maharashtra College of Pharmacy, Nilanga
• 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
04th Oct. 2011 28Maharashtra College of Pharmacy, Nilanga
04th Oct. 2011 29Maharashtra 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 30Maharashtra College of Pharmacy, Nilanga
Equipment /Instrument Qualification
04th Oct. 2011 31Maharashtra College of Pharmacy, Nilanga
Equipment /Instrument Qualification
04th Oct. 2011 32Maharashtra College of Pharmacy, Nilanga
Why to qualifyIf the instrument is not qualified prior to use & if a problem occurs, the source of problem will be difficult to identify.
04th Oct. 2011 33Maharashtra College of Pharmacy, Nilanga
Qualification Involves
04th Oct. 2011 34Maharashtra College of Pharmacy, Nilanga
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
04th Oct. 2011 36Maharashtra College of Pharmacy, Nilanga
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
04th Oct. 2011 37Maharashtra College of Pharmacy, Nilanga
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
04th Oct. 2011 38Maharashtra 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 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
04th Oct. 2011 42Maharashtra College of Pharmacy, Nilanga
Details Recorded in Complaint Investigation Report
InvestigationImpact of complaint on other batches/productsBatches/ProductsReviewCAPAImpact of CAPAImplementation of Preventive actionClose out of complaint
04th Oct. 2011 43Maharashtra College of Pharmacy, Nilanga
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
04th Oct. 2011 44Maharashtra College of Pharmacy, Nilanga
RPN: Risk Priority Number
04th Oct. 2011 45Maharashtra College of Pharmacy, Nilanga
ROOT CAUSE ANALYSIS
04th Oct. 2011 46Maharashtra College of Pharmacy, Nilanga
Regulatory Compliance
For
Pharmaceutical Product
04th Oct. 2011 47Maharashtra College of Pharmacy, Nilanga
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
04th Oct. 2011 48Maharashtra 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 49Maharashtra College of Pharmacy, Nilanga
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
04th Oct. 2011 50Maharashtra College of Pharmacy, Nilanga
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
04th Oct. 2011 51Maharashtra College of Pharmacy, Nilanga
Functions of a Quality UnitFunctions 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 52Maharashtra College of Pharmacy, Nilanga
Functions of a Quality UnitFunctions 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.
04th Oct. 2011 56Maharashtra 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 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
Regulatory Compliance
04th Oct. 2011 58Maharashtra College of Pharmacy, Nilanga
Regulatory Compliance
National Regional Global
Regulatory Compliance
04th Oct. 2011 59Maharashtra College of Pharmacy, Nilanga
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)
04th Oct. 2011 60Maharashtra College of Pharmacy, Nilanga
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
04th Oct. 2011 61Maharashtra 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 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
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 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
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 65
Regulatory Dossier
CTD dossier componentModule 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
04th Oct. 2011 66Maharashtra College of Pharmacy, Nilanga
04th Oct. 2011 67Maharashtra 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 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
04th Oct. 2011 70Maharashtra 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 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
04th Oct. 2011 72Maharashtra 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 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)
Quality Assurance: Common Regulatory Compliance Issues
04th Oct. 2011 74Maharashtra 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
Quality Assurance: Common Regulatory Compliance Issues
04th Oct. 2011 75Maharashtra 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)
Quality Assurance: Common Regulatory Compliance Issues
04th Oct. 2011 76Maharashtra College of Pharmacy, Nilanga
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
04th Oct. 2011 77Maharashtra College of Pharmacy, Nilanga
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
04th Oct. 2011 78Maharashtra College of Pharmacy, Nilanga
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
04th Oct. 2011 79Maharashtra College of Pharmacy, Nilanga
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
04th Oct. 2011 80Maharashtra College of Pharmacy, Nilanga
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)04th Oct. 2011 81Maharashtra College of Pharmacy, Nilanga
Quality Assurance: Common Regulatory Compliance Issues
Stability Study 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.)
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 82Maharashtra College of Pharmacy, Nilanga
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 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
AfricanSouth Africa, Zambia,
ZimbabweBotswana, Ghana,
Uganda
Australian / Oceanic Australia, New Zealand Fiji, Papua - New Guinea
04th Oct. 2011 85
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)04th Oct. 2011 86Maharashtra College of Pharmacy, Nilanga
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
04th Oct. 2011 87Maharashtra College of Pharmacy, Nilanga
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
OOS04th Oct. 2011 88Maharashtra College of Pharmacy, Nilanga
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
04th Oct. 2011 89Maharashtra 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) To implement necessary up-dates and changes of the dossier
Renewal / Re-registration
04th Oct. 2011 90Maharashtra College of Pharmacy, Nilanga
Quality Assurance in Life Cycle Management
Post Approval Changes
Formula
Batch size
Process
Site Change
Equipment Change
Source / Spec & test procedure
Multiple Changes
API / Excipients / Pkg Materials
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Quality Assurance in Life Cycle Management
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
04th Oct. 2011 92Maharashtra College of Pharmacy, Nilanga
Quality Assurance in Life Cycle Management
Category Reporting
Minor Type 1A
Moderate Type 1B
Major Type II standard
Critical Type II complex
Post Approval Changes (Europe)
Variations
04th Oct. 2011 93Maharashtra College of Pharmacy, Nilanga
Quality Assurance in Life Cycle Management
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)
04th Oct. 2011 94Maharashtra College of Pharmacy, Nilanga
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
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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
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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
04th Oct. 2011 99Maharashtra College of Pharmacy, Nilanga
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
04th Oct. 2011 100Maharashtra College of Pharmacy, Nilanga
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
04th Oct. 2011 101Maharashtra College of Pharmacy, Nilanga
Thank YouE-mail: [email protected]
Cell No: 00919742431000
04th Oct. 2011 102Maharashtra College of Pharmacy, Nilanga