Quality Control

Prepared by:
Perlita M. Crucis, RPh, MSPharm
April Mergelle R. Lapuz, RPh
2 Objectives:
At the end of the lecture, the students should be able to:
▹ Identify the different quality guidelines according to ICH; and
▹ Discuss the importance of harmonization in ensuring the quality of
pharmaceutical products.
3

LET’S REVIEW!
4 Quality

▹ Degree of excellence (Webster’s Dictionary)

▹ sum of all factors which contribute directly or indirectly to the
safety, effectiveness, and reliability of the product
5 Quality

▹ “Doing it right the first time and all the time”. (TQM)
▹ Excellence that is better than a minimum standard.
6 Quality
▹ Drug quality is our main business.

▹ Reality: Poor quality drugs do not meet official standards for:

▸ Strength
▸ Quality
▸ Purity
▸ Packaging
▸ Labelling
7 Drug quality in the world…

▹ Availability of substandard and counterfeit drugs in disturbing

proportion in many low-income countries
▹ Lack of reliable drug quality assurance systems in many
developing countries.
8 Implications
▹ Treatment failure
▹ Adverse effects
▹ Increased morbidity
▹ Mortality
▹ Development of drug resistance
▹ Wasted resources
9
10
11
QUALITY

ftUALITY ftUALITY
ASSURANCE CONTROL
12 Quality Control (QC)
▹ is the sum of all tests performed to determine the conformance of
the product to specification.
13 Quality Control

Routine: Non Routine:

RM and PM Analysis Calibration & Preventive
maintenance of instruments
Intermediate stage analysis
Preparation of
reference/working
Finished Product Analysis standards

Stability Studies Method development and

Validation
14 Quality Control
▹ Guarantees that the product:
▸ Is free ofimpurities
▸ Physically and chemically stable
▸ Contains the amount of active ingredients as stated in the
label
▸ Provides optimal release of active ingredients when the
product isadministered.
15 Quality Assurance (QA)
16 Quality Assurance (QA)
▹ Over-all organizational body designed to assure product quality.
▹ Sum of all processes performed to ensure that the product
possess all the characteristics it is intended to have.
17 Scope of QA/QC
No. Criteria QA QC

To prevent defects with a To identify defects in the

1 Focus
focus on process finished product.
To improve development and To identify defects after a
2 Goal test processes so that product is developed and
defects do not arise before it is released.
Establish a good QMS and Finding sources of quality
3 How assessment of its adequacy problems to continually meet
with continuous monitoring customer’s requirements.
18 Scope of QA/QC
No. Criteria QA QC

Prevention of quality Analytical techniques used to

4 What problems through planned maintain the product quality
and systematic activities. and process.
Of a specific team that tests
5 Responsibility Everyone on the team.
the product for defects.

6 As a tool QA is a managerial tool. QC is a corrective tool.

19 Quality Management System

▹ All manufacturing activities of a laboratory are

based on cGMP, AO 43, WHO guidelines, ISO,
EU.
20 cGMP
▹ Current Good Manufacturing Practices
▹ These regulations, which have the force of law, require that
manufacturers, processors, and packagers of drugs, medical
devices, some food, and blood take proactive steps to ensure that
their products are safe, pure, and effective.
▹ GMP regulations require a quality approach to manufacturing,
enabling companies to minimize or eliminate instances of
contamination, mix-ups, and errors.
▹ This in turn, protects the consumer from purchasing a product
which is not effective or even dangerous.
21 cGMP
22
23 Benefits

▹ Eliminates the risk of marketing unsafe product.

▹ Guarantees conformance to regulatory requirement
▹ Guarantees product efficacy
▹ Reduces operatingcost
▹ Reduces operatingloses
▹ Produces higher employee morale
▹ Motivates health care professional to sell or prescribed the
product.
24 Quality Responsibility

▹ Quality is the collective responsibility of every individuals in an

organization.
25 Quality by Design (QbD approach)

▹ Quality is not an add-on.

▹ Product quality criteria must be
established.
▹ Detailed specifications provide
quantitative parameters for
measurement.
▹ Written procedures document how
quality is attained and maintained.
▹ Continuous monitoring to confirm
quality is being built into the product.
26 Certification

▹ Certification is an affirmation or proof that the products or services

are approved and evaluated by a governing body that has the
ability to create reserved rights.
27 List of Certifying Agencies

▹ ISO (International Organization for Standardization)

▹ WHO (World HealthOrganization)
▹ FDA (Food and Drug Administration)
▹ ICH (International Conference on Harmonization)
▹ MHRA (Medicines and Healthcare products Regulatory Agency)
▹ ASTM (American Society of Testing and Materials)
▹ EPA (Environmental Protection Agency)
▹ TGA (Therapeutic Goods Administration)
▹ UKAS (United Kingdom Accreditation Services)
28 List of Certifying Agencies

Regulatory Authorities Standard Institutions

• WHO • ISO
• FDA • STM
• ICH • EPA
• MHRA • UKAS
• TGA
29

ICH Guidelines
30 ICH

▹ ICH is the “International Conference on Harmonization of

Technical Requirements for Registration for Pharmaceuticals for
Human Use”.

▹ It is a joint initiative involving both regulators and research-based

industry representatives of the EU, Japan and the US in scientific
and technical discussions of the testing procedures required to
assess and ensure the safety, quality and efficacy of medicines.
31 ICH Members

Representatives from the six co-sponsoring parties as well as three observers

and the International Federation of Pharmaceutical Manufacturers
Associations (IFPMA)
▹ Japan: Ministry of Health & Welfare (MHW) and the Japan Pharmaceutical
Manufacturers Association(JPMA)
▹ EU: European Commission (EC) and European Federation of
Pharmaceutical Industries’ Associations (EFPIA)
▹ USA: Food & Drug Administration (FDA) and the Pharmaceutical Research
and Manufacturers of America (PhRMA)
▹ Observers: WHO, EFTA, and Canada
32

ICH
Guidelines

Quality Safety Efficacy Multidisciplinary

guidelines guidelines guidelines Guidelines
33 Quality Guidelines
Stability Testing of New Drug Substances and
Q1A (R2)
Products
Stability Testing : Photostability Testing of New Drug
Q1B
Substances and Products
Q1C Stability Testing for New Dosage Forms
Bracketing and Matrixing Designs for Stability Testing
Q1D
of New Drug Substances and Products
Q1E Evaluation of Stability Data
Stability Data Package for Registration Applications
Q1F
in Climatic Zones III and I
 Analytical Validation (Q2)
34 Impurities (Q3A – Q3D)

Validation of Analytical Procedures: Text and

Q2 (R1)
Methodology
Q3A (R2 ) Impurities in New Drug Substances
Q3B (R5) Impurities in New Drug Products
Q3C (R5) Impurities: Guideline for Residual Solvents
Q3D Impurities: Guideline for Metal Impurities
35 Pharmacopeias (Q4 – Q4B)
Q4 Pharmacopoeias
Q4A Q4APharmacopoeial Harmonisation
Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in
the ICH Regions
Q4B 1R1 Residue on Ignition/Sulphated Ash
Q4B 2R1 Test for extractable volume of parenterals.
Q4B Annex 3R1 Test for Particulate Contamination: Sub-Visible Particles
Q4B Annex 4AR1 Q4B Microbiological Examination of Non-Sterile Products: Microbial
Enumeration Tests
Q4B Annex 4BR1 Microbiological Examination of Non-Sterile Products: Tests for Specified
Micro-Organisms
Q4B Annex 4CR1 Microbiological Examination of Non-Sterile Products: Acceptance
Criteria for Pharmaceutical Preparations and Substances for
Pharmaceutical Use
36 Pharmacopeias (Q4 – Q4B)
Q4B Anx 5R1 Disintegration Test
Q4B Anx 6R1 Uniformity of Dosage Units
Q4B Anx 7R2 Dissolution Test
Q4B Anx 8R1 Sterility Test
Q4B Anx 9R1 Tablet Friability
Q4B Anx 10R1 Polyacrylamide Gel Electrophoresis
Q4B Annex 11 Capillary Electrophoresis
Q4B Annex 12 Analytical Sieving
Q4B Annex 13 Bulk Density and Tapped Density of Powders General Chapter
Q4B Annex 14 Bacterial Endotoxins Test
 Quality of Biotechnological Products (Q5A –
37 Q5E)
Q5A(R1) Viral Safety Evaluation of Biotechnology Products Derived
from Cell Lines of Human or Animal Origin
Q5B Analysis of the Expression Construct in Cells Used for
Production of r-DNA Derived Protein Product
Q5C Stability Testing of Biotechnological/Biological Products
Q5D Derivation and Characterisation of Cell Substrates Used for
Production of Biotechnological/Biological Products
Q5E Comparability of Biotechnological/Biological Products
Subject to Changes in their Manufacturing process
38 Specifications (Q6A – Q6B)

Q6A Specifications : Test Procedures and Acceptance

Criteria for New Drug Substances and New Drug
Products: Chemical Substances
Q6B Specifications : Test Procedures and Acceptance
Criteria for Biotechnological/Biological Products

Good Manufacturing Practice Q7

Q7 Good Manufacturing Practice Guide for Active Pharmaceutical

Ingredients
39 Q8 – Q11
▹ Pharmaceutical Development Q8
▸ Q8(R2) Pharmaceutical Development
▹ Quality Risk ManagementQ9
▸ Q9 Quality RiskManagement
▹ Pharmaceutical Quality System Q10
▸ Q10 Pharmaceutical Quality System
▹ Development and Manufacture of Drug Substances Q11
▸ Q11 Development and Manufacture of Drug Substances
(Chemical Entities and Biotechnological/ biological entities.
40 Safety Guidelines
▹ ICH has produced a comprehensive set of safety Guidelines to uncover
potential risks like carcinogenicity, genotoxicity and reprotoxicity.

▹ A recent breakthrough has been a non-clinical testing strategy for assessing

the QT interval prolongation liability: the single most important cause of
drug withdrawals in recent years.
41 Safety Guidelines
S1 Carcinogenicity Studies
S2 Genotoxicity Studies
S3 Toxicokinetics and Pharmacokinetics
S4 Toxicity Testing
S5 Reproductive Toxicology
S6 Biotechnological Products
S7 Pharmacology Studies
S8 Immunotoxicology Studies
S9 Nonclinical Evaluation for Anticancer Pharmaceuticals
S10 Photosafety Evaluation
42 Safety Guidelines
▹ S1A-Need for Carcinogenicity Studies of Pharmaceuticals

▹ S1B-Testing for Carcinogenicity of Pharmaceuticals

▹ S1C(R2)-Dose Selection for Carcinogenicity Studies of

Pharmaceuticals
43 Efficacy Guidelines
▹ The work carried out by ICH under the Efficacy heading is concerned
with the design, conduct, safety and reporting of clinical trials. It also
covers novel types of medicines derived from biotechnological
processes and the use of Pharmacogenetics / genomics techniques
to produce better targeted medicines.
44 Efficacy Guidelines
▹ Clinical Safety E1 - E2F
E1 The Extent of Population Exposure to Assess
Clinical Safety for Drugs Intended for Long-Term
Treatment of Non-Life Threatening Conditions

E2A Clinical Safety Data Management: Definitions

and Standards for Expedited Reporting

E2B(R2) Maintenance of the Clinical Safety Data

Management including Data Elements for
Transmission of
Individual Case Safety Reports
45 Efficacy Guidelines
E2B(R3) Clinical Safety Data Management: Data Elements
for Transmission of Individual Case Safety Reports
E2C(R1) Clinical Safety Data Management: Periodic Safety
Update Reports for Marketed Drugs
E2D Post-Approval Safety Data Management:
Definitions and Standards for Expedited Reporting
E2E Pharmacovigilance Planning
E2F Development Safety Update Report
46 Efficacy Guidelines
▹ Clinical Study ReportsE3
E3 Structure and Content of Clinical Study Reports

▹ Dose-Response Studies E4
E4 Dose-Response Information to Support Drug Registration

▹ Ethnic Factors E5
E5(R1) Ethnic Factors in the Acceptability of Foreign Clinical Data

▹ Good Clinical Practice E6

E6(R1) Good Clinical Practice
47 Efficacy Guidelines

Studies in Support of Special Populations:

E7
Geriatrics

E8 General Considerations for Clinical Trials

E9 Statistical Principles for Clinical Trials

Choice of Control Group and Related Issues in
E10
Clinical Trials
Clinical Investigation of Medicinal Products in
E11
the Pediatric Population
48 Efficacy Guidelines
▹ Clinical Evaluation by Therapeutic Category E12
▸ E12 Principles for Clinical Evaluation of New Antihypertensive
Drugs
▹ Clinical Evaluation E14
▸ E14 The Clinical Evaluation of QT Interval Prolongation and
Proarrhythmic Potential for Non-Antiarrhythmic Drugs
▹ Pharmacogenomics E15 -E16
▸ E15 Definitions for Genomic Biomarkers, Pharmacogenomics,
Pharmacogenetics, Genomic Data and Sample Coding Categories
▸ E16 Biomarkers Related to Drug or Biotechnology Product
Development: Context, Structure and Format of qualification
submissions.
49 Multidisciplinary Guidelines
▹ Those are the cross-cutting topics which don’t fit uniquely into one of
the Quality, Safety and Efficacy categories.

▹ It includes ICH medical terminology, Common Technical Document

(CTD), Development of Electronic, Standards for the Transfer of
Regulatory Information(ESTRI)
50 Multidisciplinary Guidelines
M1 MedDRA Terminology
M2 Electronic Standards
M3 Nonclinical Safety Studies
M4 Common Technical Document
M5 Data Elements and Standards for Drug Dictionaries
M6 Gene Therapy
M7 Genotoxic Impurities
M8 Electronic Common Technical Document (eCTD)
51 Multidisciplinary Guidelines
▹ MedDRA Terminology M1
▸ MedDRA Medical Dictionary for Regulatory Activities
▹ Electronic Standards M2
▸ ESTRI Electronic Standards for the Transfer of Regulatory
Information
▹ Non clinical Safety Studies M3
▸ M3(R2)-Guidance on Non clinical Safety Studies for the Conduct of
Human Clinical Trials and Marketing Authorization for
Pharmaceuticals.
52 Multidisciplinary Guidelines
▹ Common Technical Document M4
▸ CTD The Common Technical Document
▹ Data Elements and Standards for Drug Dictionaries M5
▸ M5-Data Elements and Standards for Drug Dictionaries
▹ Gene Therapy M6
▸ M6-Virus and Gene Therapy Vector Shedding and Transmission
▹ Genotoxic Impurities M7
▸ M7Assessment and Control of DNA Reactive (Mutagenic)
▸ Impurities in Pharmaceuticals to Limit Potential Carcinogenic
Risk
▹ Electronic Common Technical Document (eCTD) M8
▸ Electronic Common Technical Document (eCTD)
53

PIC/S
54 PIC/S
▹ Pharmaceutical Inspection Cooperation Scheme

▹ Goal: To lead the international development, implementation and

maintenance of harmonized GMP standards and quality systems of
inspectorates in the field of medicinal products.
55 Main features of PIC/S
▹ Commenced operation on Nov. 2, 1995
▹ A “cooperative arrangement” between GMP regulatory authorities.
▹ A forum for:
▸ Networking and confidence building
▸ Exchange of information and experience on GMP
▸ Focus on Quality Systems for Inspectorates
▸ Focus on training of inspectors
▸ International harmonization of GMP
▹ No obligation for member authorities to accept inspection reports of
other members.
56 PIC/S Members
▹ Austria ▹ Greece ▹ Lithuania ▹ South Africa
▹ Australia ▹ Hong Kong SAR, China ▹ Malaysia ▹ Spain
▹ Belgium ▹ Hungary ▹ Malta ▹ Sweden
▹ Canada ▹ Iceland ▹ Mexico ▹ Switzerland
▹ Chinese Taipei ▹ Indonesia ▹ Netherlands ▹ Thailand
▹ Croatia ▹ Iran ▹ New Zealand ▹ Turkey
▹ Cyprus ▹ Ireland ▹ Norway ▹ Ukraine
▹ Czech Republic ▹ Israel ▹ Poland ▹ United Kingdom
▹ Denmark ▹ Italy ▹ Portugal ▹ USA
▹ Estonia ▹ Japan ▹ Romania
▹ Finland ▹ Korea ▹ Singapore
▹ France ▹ Latvia ▹ Slovak Republic
▹ Germany ▹ Liechtenstein ▹ Slovenia
57 Main Benefits for Members
▹ Training opportunities
▹ International GMPharmonization
▹ Networking
▹ High standards
▹ Sharing ofinformation
▹ Rapid AlertSystem
▹ Facilitation the conclusion of other agreements
58 Indirect Benefits for Industry
▹ Reduced duplication of inspections
▹ Cost-savings
▹ Export facilitation
▹ Enhanced marketaccess
59 Organizational Structure
 Some PIC/S Recommendation &
60 Guidance Documents
▹ Validation (master plan, process, cleaning)
▹ Validation of Aseptic Processes
▹ Inspection of Isolator Technology
▹ Sterility Testing
▹ Parametric release
▹ Guidance on Good Practices for Computerized Systems in Regulating GXP
Environments
▹ Inspection ofUtilities
▹ SOP on PIC/S inspection report format
▹ SOP on Rapid Alerts
 Typical PIC/S Inspection of a
61 Medicine Manufacturer
▹ Before theinspection:
▸ The need for inspection determined from computerized
schedule.
▸ Lead inspector assigned.
▸ Inspection teamselected.
▸ Company notified.
▸ Inspection team reviews documentation on file:
⬩ Site Master File, marketing authorizations, etc.
⬩ Complaints, recalls, product testing results, etc.
⬩ Last inspectionreport.
▸ Lead inspector prepares inspection plan (sent to company).
▸ Inspection conducted.
62 Sample Audit Plan
 Typical PIC/S Inspection of a
63 Medicine Manufacturer
▹ After the inspection:
▸ Assembly of inspection team (on site).
▸ Deficiency report prepared on-site (some PIC/S members only).
▸ Closing meeting with company:
▸ Objective evidence of corrective action assessed by lead inspector.
▸ If response judged OK, inspection closed out.
▸ If response not OK, refer to independent committee.
▸ Final Inspection Report prepared & sent tocompany after review by an
inspection manager.
64 Deficiency Report
65 PIC/S Classification of GMP deficiencies

▹ Critical Deficiency
▸ A deficiency that has produced, or may result in a
significant risk of producing, a product that is harmful to
the user.
66 PIC/S Classification of GMP deficiencies

Major Deficiency
▹ A non-critical deficiency that:
▸ has produced or may produce a product which does not comply with its
marketing authorization; and/or
▸ indicates a major deviation from the Code of GMP; and/or
▸ indicates a major deviation from the terms of the manufacturing license or GMP
approval (overseas manufacturers); and/or
▸ indicates a failure to carry out satisfactory procedures for release of batches;
and/or
▸ indicates a failure of the person responsible for QA/QC to fulfil his/her duties;
and/or
▸ consists of several other deficiencies, none of which on its own may be major, but
which may together represent a major deficiency and should be explained and
reported assuch
67 PIC/S Classification of GMP deficiencies

▹ ”Other” Deficiency (or Minor Deficiency)

▸ A deficiency that cannot be classified as either critical or
major, but indicates a departure from good manufacturing
practice.
▸ A deficiency may be “other” either because it is judged as
minor, or because there is insufficient information to
classify it as major or critical.
▸ One-off minor lapses or less significant issues are usually
not formally reported, but are brought to the attention of
the manufacturer.
68 PIC/S Inspection Report Format
69

ISO
70 ISO

▹ International Organization for Standardization

▹ ISO is an independent, non-governmental international
organization with a membership of 164 national standards
bodies, with a Central Secretariat in Geneva, Switzerland, that
coordinates thesystem.
▹ The current version of the standard is known as the ISO 9000
series.
71 Features of ISO 9000 Series

▹ ISO:9000 series standards call for integration for all activities

which have a direct or indirect effect on the quality of a
product orservices.
▹ It defines the basic concepts and specifies the procedures and
criteria to ensure that the outgoing product meets the
customer’s requirements.
▹ The quality standards are designed to be user-friendly.
▹ ISO:9000 series standards tells the suppliers and manufactures
what is required of quality oriented working system.
72 Areas Covered by ISO Standards
▹ Management
▹ Responsibility
▹ Quality system
▹ Contract Review
▹ Design Control
▹ Document Control
▹ Purchasing
▹ Purchaser’s SuppliedProducts
▹ Product Identification and Traceability
▹ Process Control
▹ Inspection andtesting
▹ Inspection
73 Areas Covered by ISO Standards
▹ Measuring and Testing Department
▹ Inspection and Test Status
▹ Non-Conformity Control
▹ Corrective Actions
▹ Handling
▹ Storage
▹ Packing andDelivery
▹ Quality Records
▹ Internal QualityAudits
▹ Training
▹ Services and Statistical techniques
74 Benefits of ISO:9000

▹ It is internationally accepted series of quality standards.

▹ It helps in achieving consistency, economy and cost
effectiveness.
▹ It increases customers confidence.
▹ It reduces the need for inspection by the buyers.
▹ The ISO certification by a company is a source of motivation.
75 Concept of Quality Control

▹ Refers to the process of striving to produce a perfect product.

▹ Requires a series of measures requiring an organized effort.
▹ Prevent or eliminate errors at every stage in the production.
76

WHO Guidelines
77 WHO Guidelines

▹ The scientific groups formulated proposals and guidelines for

research in the field of drug development.
▹ These reports also provided the basis for the ICH-GCP.
78

End of Lecture!