Qualityassuranceandregulatorycomplianceforpharmaceuticalproduct 150102060926-conversion-gate02

Quality Assurance and Regulatory
Compliance for Pharmaceutical Product
Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D
Department of Pharmaceutics
KLE University College of Pharmacy
BELGAUM-590010, Karnataka, India
E-mail: bknanjwade@yahoo.co.in
Cell No: 00919742431000
04th Oct. 2011 1
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 2

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 3

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 4

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 5

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 6

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 7

QC
GMP
QA
Quality relationships
04th Oct. 2011 8

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 9

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 10

Good Manufacturing Practice
• Raw or starting materials
• Finished products
• Premises and environment
• Equipment
• personnel
• Training
• Hygiene
04th Oct. 2011 Maharashtra College of Pharmacy, Nilanga 11
GMP Covers all aspects of production including

GOOD
MANUFACTURING
PRACTICE
04th Oct. 2011 12

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 13

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 14

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 15

QA and QC
QC is lab based
• QA is company
based
04th Oct. 2011 16

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04th Oct. 2011 18

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 19

Quality Assurance Activities
1. Technology Transfer
2. Validation
3. Documentation Control
4. Assuring Quality of Products
5. Quality Improvement Plans
04th Oct. 2011 20

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 21

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 22

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 23

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 24

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 25

FACTORS IN DRUG QUALITY ASSURANCE
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
Legislative
Framework
-Regulations Packaging
04th Oct. 2011 26

Quality Assurance Cycle
Research
Development
Raw Materials
Facilities
Documentation
Equipment
Personnel
04th Oct. 2011 27

• 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 28

04th Oct. 2011 29

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 30

04th Oct. 2011 31

04th Oct. 2011 32

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.
04th Oct. 2011 33

Qualification Involves
04th Oct. 2011 34

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 35

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 36

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 37

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 38

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 39

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 40

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 41

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 42

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
04th Oct. 2011 43

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 44
RPN: Risk Priority Number

04th Oct. 2011 45

ROOT CAUSE ANALYSIS
04th Oct. 2011 46

Regulatory Compliance
For
Pharmaceutical Product
04th Oct. 2011 47

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 48

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 49

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 50

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
Means
Manpower
Media
Composition of Quality
04th Oct. 2011 51

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 52

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 53

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 54

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 55

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 56

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 57

Regulatory
Approval
Regulatory
Approval
API
Drug Product
Manufacturing Plant
CRO
Bioequivalenc
e
Clinical
Trials
API
Drug Product
Regulatory dossiers
Nationa
l
Regional
Global
Re-registration/Renewal
Post Approval Changes
04th Oct. 2011 58

Regulatory
Compliance
National Regional Global
04th Oct. 2011 59

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 60

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 61

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
04th Oct. 2011 62

Regional (Europe)
Parameters Europe
API Ph.Eur. [COS (CEP) / EDMF]
Excipients Ph.Eur.
Packaging materials Ph.Eur.
Finished Product As per Ph.Eur. General requirement
Submission batch 2
Stability Zone II requirement
25º+2ºC/60+5%RH & 40º+2ºC/75+5%RH
Reference Product Europe
Bioequivalence study Generally fasting condition
Compliance to Orange guide, EDQM, CHMP, CPMP guidelines, ICH
Generic application AS per Article 10 and its sub sections
04th Oct. 2011 63

Regional (Others)
Parameters Other markets
API USP / Ph.Eur. (DMF requirement depends on the target
market)
Excipients USP / Ph.Eur.
Packaging materials USP / Ph.Eur.
Finished Product USP / Ph.Eur.
Submission batch 2 or 3
Submission batch size Depends on the target market
Stability Depends on the Target market (E.g.: ASEAN: Zone IVb)
Reference Product Depends on the Target market
Bioequivalence study Generally fasting condition
Compliance to Respective country guidelines
Generic application AS per respective country guidelines
04th Oct. 2011 64

Global
Parameters Global
API Harmonization of specification
Excipients Harmonization of specification
Packaging materials Harmonization of specification
Finished Product Harmonization of specification
Submission batch 3
Stability Zone III & IV
Reference Product Multiple region
Bioequivalence study Fasting & Fed condition
Compliance to Global Standards
Generic application AS per respective country guidelines
04th Oct. 2011 65

Regulatory Dossier
CTD dossier component
Module 1- Administrative & prescribing information (Region
specific)
Module 2: CTD summaries (Quality overall summary, the non-clinical
overview/summaries, clinical overviews/Summaries)
Module 3: Quality (CMC)
Module 4: Non clinical study reports (Documentation on
Toxicological and pharmacological tests)
Module 5: Clinical study reports (For Generics: Bioequivalence
study)
CTD ORGANIZATION IS BASED ON
M4: Organization of the CTD
M4E: The CTD — Efficacy
M4Q: The CTD — Quality
M4S: The CTD — Safety
04th Oct. 2011 66

04th Oct. 2011 67

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 70

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 71

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 72

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)
04th Oct. 2011 74

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 75

 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 76

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 77

 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 78

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 79

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 80

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 81

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 82

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 83

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
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 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 85

Bioequivalence study
 Use of wrong strength (in case of multiple strength products)
 Use of inappropriate reference product (e.g.: US reference product
for Europe study)
 Inadequate number of volunteers
 Inadequate sampling intervals to capture tmax / cmax (maximum time
points should be there around the expected tmax/cmax)
 Inadequate wash out period
 Design fault in deciding what to test (e.g. testing of parent
compound or active metabolite or both)
 Choice of study (Fast / Fed study or both)
04th Oct. 2011 86

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 87

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 88

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 89

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 90

Post Approval Changes
Formula
Batch size
Process
Site Change
Equipment Change
Source / Spec & test procedure
Multiple Changes
API / Excipients / Pkg Materials
04th Oct. 2011 91

Post approval changes Reporting
Level 1 Annual Report
Level 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 (US SUPAC)
SUPAC
04th Oct. 2011 92

Category Reporting
Minor Type 1A
Moderate Type 1B
Major Type II standard
Critical Type II complex
Post Approval Changes (Europe)
Variations
04th Oct. 2011 93

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 94

Registration validity
 US: Annual report every year
 Europe: Re-registration once in 5 years
 India: License renewal every 5 years
 Other countries: Generally 5 years
04th Oct. 2011 95

Quality Assurance: The most important element of regulatory
compliance
 The most important element for compliance is…..
Manpower … Manpower … Manpower
 It is the people who ensure Regulatory compliance at
every stage of product life cycle i.e. starting from
product development to life cycle management
 The best way to enhance their capability is through …….
Training…….Training ……. Training
04th Oct. 2011 96

Quality Assurance: The state of compliance
 Everything is likely to undergo change during the life
cycle of a product…….
Formula, Process, Equipment, Batch size, Suppliers,
Manufacturing site, Trade dress, Indications,
Regulatory requirements, Specifications & test
procedures, People and so on ………
 The only thing that can not be changed is the….
“State of Compliance”
04th Oct. 2011 97

Regulatory Authorities
 India: DCGI & State Drug Administration
 European Union: EMEA and national
 USA : Food and Drug Administration (FDA)
 Australia : Therapeutic Goods Administration
 Newzeland : Medsafe
 South Africa: Medicines council control
 Japan : Ministry of Health & Labour Welfare
 Switzerland : Swissmedic
 Brazil : ANVISA (The National Health Surveillance Agency)
 Mexico: COFEPRIS (The Federal Commission for the Protection against Sanitary Risk)
 Chile : ISP - Instituto de Salud Pública de Chile
 Columbia: INVIMA – Instituto Nacional de Vigilancia de Medicamentos
Alimentos Carrera 68 D No. 17 - 11 / 21
 Argentina: ANMAT - set in 1992 Argentine National Administration of
Drugs, Food & Medical Technology
France: Agence Française de Sécurité Sanitaire des Produits de Santé
Germany: Federal Institute for Drugs and Medical Devices
04th Oct. 2011 98

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
04th Oct. 2011 99

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
04th Oct. 2011 100

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
04th Oct. 2011 101

Thank You
E-mail: bknanjwade@yahoo.co.in
Cell No: 00919742431000
04th Oct. 2011 102

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