Quality assuranceandregulatorycomplianceforpharmaceuticalproduct(4)

Quality Assurance and Regulatory
Compliance for Pharmaceutical Product

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

The System of Quality Assurance
 Pharmaceutical products are designed and developed
in a way that takes account of the requirements of
GMP and other associated codes such as those of
good laboratory practice (GLP) and good clinical
practice (GCP)
 Product and control operations are clearly specified in
a written form and GMP requirements are adopted

 Managerial responsibilities are clearly specified in
job description
 Arrangements are made for the manufacture, supply
and use of the correct starting and packaging
materials.
 All necessary controls on starting materials,
intermediate products, and bulk products and other
in-process controls, calibrations, and validations are
carried out.

 The finished products is correctly processed and
checked according to the defined procedures.
 Pharmaceutical products are not sold or supplied
before the authorized persons have certified that each
production batch has been produced and controlled in
accordance with the requirements of the marketing
authorization and any other regulations relevant to the
production, control and release of pharmaceutical
products

 Satisfactory arrangements exist to ensure, as far as
possible, that the pharmaceutical products are stored
by the manufacturer, distributed and subsequently
handled so that quality is maintained throughout their
shelf-life.
 There is a procedure for self-inspection and/or quality
audit that regularly appraises the effectiveness and
applicability of the quality assurance system

 Deviation are reported, investigated and recorded
 There is a system for approving changes that may
have an impact on product quality
 Regular evaluations of the quality of pharmaceutical
products should be conducted with the objective of
verifying the consistency of the process and ensuring
its continuous improvement.

Quality relationships
QA
GMP
QC

Quality Assurance
It is the sum total of the
organized arrangements with
the objective of ensuring that
products will be of the
quality required for their
intended use

Good Manufacturing Practice
Is that part of Quality
Assurance aimed at ensuring
that products are consistently
manufactured to a quality
appropriate to their intended
use

Good Manufacturing Practice
GMP Covers all aspects of production including
• Raw or starting materials
• Finished products
• Premises and environment
• Equipment
• personnel
• Training
• Hygiene

Quality System
with Traceable
Documentation
Approved
Materials
Approved
Manufacturing
Instructions
Controlled
Environment
Controlled Materials
Handling, Storage,
Segregation,
Packaging &
Labelling
Material,
Intermediate
& Finished
Products
Testing
Internal
Audits &
Reviews
Trained
Personnel
Approved
Manufacturing
Facilities
Validated
Equipment
Validated Test
Method
Validated
Manufacturing
Processes
GOOD
MANUFACTURING
PRACTICE

Quality Control
Is that part of GMP concerned
with sampling, specification
& testing, documentation &
release procedures which
ensure that the necessary &
relevant tests are performed
& the product is released for
use only after ascertaining
it’s quality

QA and QC
 QC is that part of GMP
which is concerned with
sampling,
specifications, testing and
with in the organization,
documentation,and
release procedures which
ensure that the necessary
and relevant tests are
carried out
• QA is the sum total of
organized
arrangements made
with the object of
ensuring that product
will be of the Quality
required by their
intended use.

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

QA and QC
• QA is company  QC is lab based
based

Quality Assurance-Highlights
 In process quality checking in manufacturing
 Validation of facilities, equipments, process,
products and cleaning
 Complaint handling
 Storage of quality records and control samples
 Stability studies

Quality Assurance Activities
1. Technology Transfer
2. Validation
3. Documentation Control
4. Assuring Quality of Products
5. Quality Improvement Plans

1. Technology Transfer
 Receipt of product design documents from R & D
Department
 Distribution of documents to different departments
 Checking and approval of documents generated based
on R & D documents i.e. batch manufacturing record
 Scale‐up and validation of product

2. Validation
• Preparation of validation plans for facility,
equipments/process including cleaning
• Approval of protocol for validation of facility
/equipment /product /process
• Team member for execution of validation of
facility/equipment/ product/process

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

4. Assuring Quality of Products
 cGMP 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

5. Quality Improvement Plans
 To take Feedback from different departments
 Proposals for corrective and preventive actions
 Annual Products review
 Trend analysis of various quality parameters for
products, environment and water

FACTORS IN DRUG QUALITY ASSURANCE
Legislative
Framework
-Regulations Packaging
DRUG
PRODUCT
QUALITY
Labeling &
Product
Information
Import
& Export
Control
Raw
Materials-
Active &
Inactive
Manufacturing
Processes
& Procedures Storage
Transport
Distribution
Dispensing
& Use
QC &
Analysis
Human
Resources-
Professionals

Quality Assurance Cycle
Research
Development
Raw Materials
Facilities
Documentation
Equipment
Personnel

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

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

Equipment /Instrument Qualification

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.
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.

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)

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

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

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

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

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

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

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

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

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

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

Regulatory Compliance
For
Pharmaceutical Product

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

In general, compliance means conforming to a
rule, such as a specification, policy, standard
or law.
Regulatory compliance describes the goal
that corporations or public agencies aspire to
in their efforts to ensure that personnel are
aware of and take steps to comply with
relevant laws and regulations.

Pharmaceutical Product Quality Cannot Be Tested in - It
Is Built in
Pharmaceutical product quality is assured by
Comprehensive development 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

Composition of Quality
Product / Service
Manpower Means
Materials
Methods
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…)

Functions of a Quality Unit
Quality Control
–Sampling and testing of components
(raw materials, Packing materials),
intermediates and finished products
–Compliance to Good Laboratory
Practices (GLPs)

Functions of a Quality Unit
Quality Assurance
–Designing robust quality
systems
–Ensure compliance to
relevant regulatory
requirements
–Ensure compliance to
requirements of Good
Manufacturing Practices
(GMP)

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

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

Quality Assurance:
– Training & Knowledge Management
– Perform literature survey of FDA /
ICH / ISO guidelines, revisions in
the Pharmacopoeial specifications
and the current regulatory
requirements and provide training to
the production personnel.

Value addition of Regulatory function to enhance Quality
Assurance
Regulatory Compliance:
–Knowledge of the current
international regulatory
requirements
–Comprehensive compilation of
the ‘Product Registration
Dossiers’ for the specific
customer countries

Regulatory
Approval
API
Drug Product
Manufacturing Plant
CRO
API
Drug Product
Bioequivalenc
Cleinical
Trials
Regulatory dossiers
Nationa
l
Regional
Global
Re-registration/Renewal
Post Approval Changes

Regulatory
Compliance
National Regional Global

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

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

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 356h

Regional (Europe)
Parameters Europe
API Ph.Eur. [COS (CEP) / EDMF]
Excipients Ph.Eur.
Packaging materials Ph.Eur.
Finished Product As per Ph.Eur. General requirement
Submission batch 2
Stability Zone II requirement
25º+2ºC/60+5%RH & 40º+2ºC/75+5%RH
Reference Product Europe
Bioequivalence study Generally fasting condition
Compliance to Orange guide, EDQM, CHMP, CPMP guidelines, ICH
Generic application AS per Article 10 and its sub sections

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

Global
Parameters Global
API Harmonization of specification
Excipients Harmonization of specification
Packaging materials Harmonization of specification
Finished Product Harmonization of specification
Submission batch 3
Stability Zone III & IV
Reference Product Multiple region
Bioequivalence study Fasting & Fed condition
Compliance to Global Standards
Generic application AS per respective country guidelines

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

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
100,000 units or
size
1/10th of commercial
batch
100,000 units or
1/10th of
commercial batch
Depends on the
target market
No such
requirement

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

Specific requirements of an US ANDA
 QOS: in QbR format (Quality overall summary:Question-based review)
 Exhibit batches (1 batch)
 Stability data at the time of submission (3 Months)
 TSE/BSE certificate (Transmissible spongiform encephalopatics/Bovine spongiform encephalopathy)
 Structured Product Labeling (SPL) & side by side labeling comparison
 OVI statement (Organic volatile impurities)
 Financial certification / disclosure statement (Bioequivalence study)
 Environmental assessment or claim for categorical exclusion
 Declaration under Generic Drug Enforcement Act (Debarment certification & conviction statement)
 Patent certification & exclusivity statement
 Appointment of US agent & letter of US agent authorization
 Copy of executed batch records

Specific requirements of an EU dossier
 Release testing in EU (QP)
 Exhibit batches (2 batches)
 Stability data (6 Months)
 Process validation study
 Release and shelf life specification
 Microbiological considerations
 TSE/BSE certificate
 SPC (Summary of product characteristics)
 Braille labeling (Just another way to read and write English)
 Readability testing

Regulatory Approval
 Product Approval / Authorization
Successful registration of the product in the target market involves:
 Successful review of API DMF / COS
 Successful audit of API plant (wherever applicable)
 Successful review of Drug Product Dossier (ANDA, MAA etc.)
• CMC data review
• Bioequivalence study data review
• Administrative data review
 Successful audit of the drug product manufacturing plant
 Successful audit of the bioequivalence study CRO

Quality Assurance: Common Regulatory Compliance Issues
 API
 Infringing route of synthesis
 Not consistent with respective Pharmacopoeial requirement
 Impurity profile out of limit
 Residual solvents not meeting the requirements
 Unapproved site of manufacture (by concerned regulatory body)
 Unacceptable physico-chemical properties (particle size, polymorphism, bulk
density, etc.)
 From manufacturer who does not assure uninterrupted supply of API
 Unapproved vendor (by drug product manufacturer)
 Use of non DMF / COS material (e.g.: US, Europe etc.)
 High cost (commercial viability)

 Excipient
 Use of rarely available / or commonly not used excipients
 Use of Non GRAS materials (Generally recognized as safe)
 Incompatible
 Not consistent with respective Pharmacopoeial requirement
 Residual solvents not meeting the requirements
 TSE / BSE / GMO (Genetically modified organisms)
 Unapproved vendor
 Unacceptable physico-chemical and functional properties (particle size,
bulk density, viscosity grade, surface area, degree of polymerization etc.)
 From manufacturers who do not assure uninterrupted supply
 High cost (commercial viability)

Formulation development
 Pre-formulation
 Improper API characterization
• Intrinsic solubility
• pH dependent solubility
• Saturation solubility
• Particle size
• Polymorph
• Bulk density
• Hygroscopicity study
• Impurity profile etc.,
 Wrong choice of reference product (e.g. Not selecting innovator product)
 Reference product not matching with the proposed market (e.g.: European
product selected for US market)
 Inadequate drug excipient compatibility studies

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

Formulation (Finished product)
 Dissolution profile not matching with the reference product
 Dissolution profile not matching with the bio strength in case of multi
strength products (for bio waiver purpose)
 Not meeting Pharmacopoeial requirement
 Dissolution – Lack of justification for selection of:
• Media
• Apparatus
• RPM
• Volume of media
• Sampling point
• Dissolution limit
• Justification for addition of surfactant (e.g.: SLS), enzymes (e.g.:
Pepsin, Pancreatin etc.) in the dissolution medium

 Formulation (Finished product specification)
 Not meeting Pharmacopoeial requirement / ICH Q6A
 Lack of second identification test (for non specific test)
 Inadequate impurities & residual solvent specification (ICH Q3A, B,
Q3C)
 Lack of testing for preservatives, anti-oxidants wherever used
 Lack of test for breakability / content uniformity for half tablets
(when functional score line exists)
 Lack of test for establishing polymorphic conversions
 Color identification test (e.g.: Europe)
 Test for water content in solid dosage form (e.g.: US)
 Missing of microbiological tests
 Lack of specification for testing after reconstitution

Packaging Materials
 Improper justification for the selection of packaging
materials
 Lack of data on release / sorption / leaching study
(specially for those used in liquid / parenteral
preparations)
 Lack of study to demonstrate integrity of container
closure system (where applicable)
 Primary packaging material not suitable for its intended
performance (e.g.: child resistant)
 Lack of identification test in the specification
 Lack of food grade certification for the materials
 Non use of virgin grade polymers

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

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)

Stability Study
 Inadequate batch size (e.g.: less than 100,000 units or 1/10th
of the commercial batch size whichever is higher)
 Inadequate number of batches (e.g.: minimum 1 batch for
US, 2 batches for Europe etc.)
 Chamber temperature and humidity condition not appropriate
to the target market (e.g.: Zone I & II and Zone III and Zone
IV conditions are different)
 Inadequate data at the time of submission (e.g.: 3 months
data for US, 6 months data for Europe)

Stability Study
 Photo stability study not considered
 Improper container orientation (specially for
liquid products)
 Inadequate stability study on bulk shipment
pack (if intended to ship it for repackaging)
 Inadequate parameters covered under stability
protocol (e.g.: microbial testing)
 Not charging samples under fall back condition

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) 30 70

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

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)

Bioequivalence study
 Use of non validated method for testing
 Stability of plasma samples not established
 Inadequate number of reserve samples (e.g.: 5 times of the sample
required for complete analysis)
 Use of unapproved CRO
 Inappropriate documentation [IEC / IRB approval of protocol, informed
consent, CRF, pharmacokinetic data, statistical data (SAS), etc]
 Bioequivalence study sample formula different from commercial batch
formula
 Bioequivalence study samples are not from GMP pivotal batch

Regulatory audits
 Training of personnel
 Facility upkeep
 Equipment upkeep and preventive maintenance program
 Area and environmental monitoring
 QA systems, documentation control and traceability
 Vendor approval procedure
 Inventory control and storage
 Change controls, deviations
 OOS

Regulatory audits
 Qualification / validation of system, facility, equipment etc.
 Water system
 HVAC system (Heating, ventilation and air conditioning)
 Stability program
 Process validation
 Laboratory control, testing and release of materials
 Documentation review (Batch records, analytical records, etc.)
 Batch release by QA

Quality Assurance in Life Cycle Management
Tasks to be performed
 Pharmacovigilance
Safety reports
 Post Approval Changes / Variations
To implement necessary up-dates and changes of the dossier
 Line extensions (major changes, requiring new MAA)
To implement necessary up-dates and changes of the dossier
 Renewal / Re-registration

Post Approval Changes
Formula
Batch size
Process
Site Change
Equipment Change
Source / Spec & test procedure
API / Excipients / Pkg Materials
Multiple Changes

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"
Changes Being Effected (CBE)
Changes Being Effected in 30 days (CBE-30)
Prior Approval Supplement (PAS)

Post Approval Changes (Europe)
Category Reporting
Minor Type 1A
Moderate Type 1B
Major Type II standard
Critical Type II complex

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

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
 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
 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”

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

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

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

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

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