Transcript 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
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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
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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
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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.
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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
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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
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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.
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Quality relationships
QA
GMP
QC
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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
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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
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Good Manufacturing Practice
GMP Covers all aspects of production including
• Raw or starting materials
• Finished products
• Premises and environment
• Equipment
• personnel
• Training
• Hygiene
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Quality System
with Traceable
Documentation
Approved
Materials
Trained
Personnel
Approved
Manufacturing
Facilities
Validated
Equipment
Approved
Manufacturing
Instructions
GOOD
MANUFACTURING
PRACTICE
Validated
Manufacturing
Processes
Validated Test
Method
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Controlled
Environment
Controlled Materials
Handling, Storage,
Segregation,
Packaging &
Labelling
Internal
Audits &
Reviews
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Material,
Intermediate
& Finished
Products
Testing
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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
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QA and QC
• QA is the sum total of
organized
arrangements made
with the object of
ensuring that product
will be of the Quality
required by their
intended use.
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 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
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QA and QC
• All those planned or
systematic actions
necessary to
provide adequate
confidence that a
product will satisfy
the requirements for
quality
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 Operational
laboratory techniques
and activities used to
fulfill the requirement
of Quality
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QA and QC
• QA is company
based
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 QC is lab based
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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
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Quality Assurance Activities
1. Technology Transfer
2. Validation
3. Documentation Control
4. Assuring Quality of Products
5. Quality Improvement Plans
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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
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2. Validation
• Preparation of validation plans for
equipments/process including cleaning
facility,
• Approval of protocol for validation of facility
/equipment /product /process
• Team member for execution of validation of
facility/equipment/ product/process
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3. Documentation Control
 Controlled distribution and archiving of documents
 Control of changes made by proper change control
procedure
 Approval of all documents
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4. Assuring Quality of Products
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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
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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
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FACTORS IN DRUG QUALITY ASSURANCE
Legislative
Framework
-Regulations
Import
& Export
Control
Human
ResourcesProfessionals
Raw
MaterialsActive &
Inactive
Manufacturing
Processes
& Procedures
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Packaging
Labeling &
Product
Information
DRUG
PRODUCT
QUALITY
Storage
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QC &
Analysis
Transport
Distribution
Dispensing
& Use
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Quality Assurance Cycle
Research
Development
Raw Materials
Facilities
Documentation
Equipment
Personnel
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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
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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
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Equipment /Instrument Qualification
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Equipment /Instrument Qualification
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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.
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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)
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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
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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
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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
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Details Recorded in Deviation Approval
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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
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Details Recorded In Out of Specification Report
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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
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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
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Validation and revalidation
program
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Areas of Self Inspection
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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
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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
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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
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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
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ROOT CAUSE ANALYSIS
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Regulatory Compliance
For
Pharmaceutical Product
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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
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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.
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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
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Composition of Quality
Manpower
Materials
Means
Product / Service
Media
Methods
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…)
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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)
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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)
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Value addition in QA function
Quality Assurance:
– Perform structured selfinspection audits at regular
intervals to prevent any
failure or non-conformance
– Critically analyze the quality
non-conformance issues and
suggest corrective and
preventive actions
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Value addition in QA function
Quality Assurance:
– Perform documentation
audit to ensure realistic
recording of all the relevant
process parameters
– Review the adequacy of inprocess control checks to
prevent any potential
failures
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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.
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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
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Regulatory Compliance
API
API
Drug Product
Regulatory
Approval
Manufacturing Plant
CRO
Regulatory dossiers
Drug Product
Bioequivalenc
e
Clinical
Trials
Nationa
l
Regional
Re-registration/Renewal
Global
Post Approval Changes
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Regulatory Compliance
Regulatory
Compliance
National
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Regional
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Global
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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
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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
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Regional (US)
Parameters
API
Excipients
Packaging materials
US
USP (US DMF Type II)
USP
Complying to USP (Type III DMF)
Finished Product
USP
Submission batch
1
Submission batch size
Stability
100,000 units or 1/10th of commercial batch
Zone II requirement
25º+2ºC/60+5%RH & 40º+2ºC/75+5%RH
Reference product
Bioequivalence study
Compliance to
Generic application
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US RLD (Orange book listed)
Generally both fast & fed condition
21 CFR and its sub parts such as part 210 – 211, part 11,
part 314, part 350, ICH etc.,
FDA form 356h
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Regional (Europe)
Parameters
API
Europe
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
Stability
100,000 units or 1/10th of commercial batch
Zone II requirement
25º+2ºC/60+5%RH & 40º+2ºC/75+5%RH
Reference Product
Bioequivalence study
Compliance to
Generic application
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Europe
Generally fasting condition
Orange guide, EDQM, CHMP, CPMP guidelines, ICH
AS per Article 10 and its sub sections
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Regional (Others)
Parameters
API
Other markets
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
Stability
Reference Product
Bioequivalence study
Compliance to
Generic application
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Depends on the target market
Depends on the Target market (E.g.: ASEAN: Zone IVb)
Depends on the Target market
Generally fasting condition
Respective country guidelines
AS per respective country guidelines
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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
Stability
Reference Product
Bioequivalence study
Compliance to
Generic application
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100,000 units or 1/10th of commercial batch
Zone III & IV
Multiple region
Fasting & Fed condition
Global Standards
AS per respective country guidelines
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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
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Regulatory Dossier
 Regulatory approach:
Parameters
US
Europe
Other markets
India
USP
Ph.Eur.
USP / Ph.Eur.
IP
USDMF
COS (CEP) / EDMF
DMF requirement
depends on the
target market
USP
Ph.Eur.
USP / Ph.Eur.
IP
US
Europe
Depends on the
target market
Indian (if not
available, then
US or Europe)
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
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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
API
Excipients
Reference product
Packaging
materials
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Regulatory Dossier
 Regulatory approach:
Parameters
US
Europe
Other markets
India
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
TSE/BSE, OVI
statements
TSE/BSE
Depends on the
target market
No such requirement
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
Stability data
Input materials
Packaging materials
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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
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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
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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
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Quality Assurance: Common Regulatory Compliance Issues
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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)
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Quality Assurance: Common Regulatory Compliance Issues
 Excipient
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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)
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Quality Assurance: Common Regulatory Compliance Issues
Formulation development
 Pre-formulation
 Improper API characterization
• Intrinsic solubility
• pH dependent solubility
• Saturation solubility
• Particle size
• Polymorph
• Bulk density
• Hygroscopicity study
• Impurity profile etc.,
 Wrong choice of reference product (e.g. Not selecting innovator product)
 Reference product not matching with the proposed market (e.g.: European
product selected for US market)
 Inadequate drug excipient compatibility studies
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Quality Assurance: Common Regulatory Compliance Issues
 Formulation development

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







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)
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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
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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
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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 Maharashtra
gradeCollege
polymers
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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
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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)
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Quality Assurance: Common Regulatory Compliance Issues
Stability Study
 Inadequate batch size (e.g.: less than 100,000 units or 1/10th
of the commercial batch size whichever is higher)
 Inadequate number of batches (e.g.: minimum 1 batch for
US, 2 batches for Europe etc.)
 Chamber temperature and humidity condition not appropriate
to the target market (e.g.: Zone I & II and Zone III and Zone
IV conditions are different)
 Inadequate data at the time of submission (e.g.: 3 months
data for US, 6 months data for Europe)
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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
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Stability
Global climatic zones
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
Zone
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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
Australia, New Zealand
Fiji, Papua - New Guinea
Australian / Oceanic
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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)
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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
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Quality Assurance: Common Regulatory Compliance Issues
Regulatory audits
 Training of personnel
 Facility upkeep
 Equipment upkeep and preventive maintenance program
 Area and environmental monitoring
 QA systems, documentation control and traceability
 Vendor approval procedure
 Inventory control and storage
 Change controls, deviations
 OOS
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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
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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
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Quality Assurance in Life Cycle Management
Post Approval Changes
Formula
Batch size
Process
Site Change
Equipment Change
Source / Spec & test procedure
API / Excipients / Pkg Materials
Multiple Changes
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Quality Assurance in Life Cycle Management
Post Approval Changes (US SUPAC)
Post approval changes
Level 1
Reporting
Annual Report
Changes Being Effected (CBE)
Level 2
Changes Being Effected in 30 days (CBE-30)
Level 3
Changes Being Effected (CBE)
Changes Being Effected in 30 days (CBE-30)
"Scale-Up and Post-Approval Changes"
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Quality Assurance in Life Cycle Management
Post Approval Changes (Europe)
Category
Reporting
Minor
Type 1A
Moderate
Type 1B
Major
Type II standard
Critical
Type II complex
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Quality Assurance in Life Cycle Management
Post Approval Changes (Other markets)
Other markets
Notifications e.g. Australia
India
No such requirement
Part A: Non-assessable changes
Part B: Self-assessable changes
Part C: Changes requiring approval
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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”
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Regulatory Authorities
 India: DCGI & State Drug Administration
 European Union: EMEA and national
 USA : Food and Drug Administration (FDA)
 Australia : Therapeutic Goods Administration
 Newzeland : Medsafe
 South Africa: Medicines council control
 Japan : Ministry of Health & Labour Welfare
 Switzerland : Swissmedic
 Brazil : ANVISA (The National Health Surveillance Agency)
 Mexico: COFEPRIS (The Federal Commission for the Protection against Sanitary Risk)
 Chile : ISP - Instituto de Salud Pública de Chile
 Columbia: INVIMA – Instituto Nacional de Vigilancia de Medicamentos
Alimentos Carrera 68 D No. 17 - 11 / 21
 Argentina: ANMAT - set in 1992 Argentine National Administration of
Drugs, Food & Medical Technology
France: Agence Française de Sécurité Sanitaire des Produits de Santé
Germany: Federal Institute for Drugs and Medical Devices
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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
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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
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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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Thank You
E-mail: [email protected]
Cell No: 00919742431000
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