Lecture 1

INTRODUCTION
TO QUALITY
CONTROL
PHARMACEUTICAL ANALYSIS I
Quantitative Pharmaceutical Chemistry

1
OBJECTIVES
1. identify the importance of quality control in the pharmaceutical industry
2. define terms relevant to quantitative pharmaceutical chemistry
3. Discuss the 10 Golden Rules of GMP

2
2
OUTLINE
1. Quantitative Pharmaceutical Chemistry Pharmacy
2. Definition of Terms 7. International Organization for
1. Quality Standardization
2. Quality Control 8. Total Quality Management
3. Quality Assurance 3. Organization of QA and QC
4. Good Manufacturing Practice 4. Functions and Responsibilities of QA and QC
5. Specifications 5. The 10 Golden Rules of GMP
6. References 6. Analyst of the Laboratory
1. USP/NF 7. Reagents
2. Monograph
3. Remington: The Science and Practice of 3
3
 Quantitative Pharmaceutical Chemistry

Test Interpret Decide Act

In any case, it remains the responsibility of the pharmacist to solve problems relating to
drug quality.
4
4
 DEFINITIONS
Quantitative Pharmaceutical Chemistry

5
 D e f i n i t i o n o f Te r m s
Quality
• …degree to which a specific product conforms to a design or specification
• …totality of features and characteristics of a product or service that bears on its ability to
satisfy stated or implied needs
• …fitness for use
• Even though quality cannot be defined, you know what it is.
• “making it right the first time”
• …when your customer returns and your products don’t.
• Quality = Productivity = Profitability
• …defined by the customer; customers want products and services that, throughout their
lives, meet customers’ needs and expectations at a cost that represents value

the sum of all factors which contribute directly or indirectly to the safety,
effectiveness, and reliability of the product
6
6
 D e f i n i t i o n o f Te r m s
Quality Control
Quality control guarantees within reasonable limits that drug product:
(1) is free from impurities
(2) is physically and chemically stable
(3) contains the amount of active ingredients as stated on the label
(4) provides optimal release of active ingredients when the product is administered

the day-to –day control of quality within a company, a department staffed with scientists and
technicians responsible for the acceptance or rejection of incoming raw materials and
packaging components, in-process tests and inspections, to assure that systems are being
controlled and monitored finally, for the approval or rejection of completed dosage forms
3 PILLARS OF DRUG PRODUCT
1. Safety
2. Efficacy
3. Quality
Safety and efficacy are not separable from quality but part of it. 7
7
 D e f i n i t i o n o f Te r m s
Quality Assurance
the overall organizational body designed to assure product
quality

Develop and follows standard operating procedures directed

toward assuring the quality, safety, purity and effectiveness of
drug products

• Testing: find defects in the product

• Quality Control: evaluate the quality, estimate if it meets
customer's expectations
• Quality Assurance: define and improve the quality related
processes and procedures to ensure quality

8
8
 D e f i n i t i o n o f Te r m s
Good Manufacturing Practice
• A system for ensuring that products are consistently produced and controlled according to
quality standards
• designed to minimize the risks involved in any pharmaceutical production that cannot be
eliminated through testing the final product
• cGMP covers all aspects of production from the starting materials, premises and
equipment to the training and personal hygiene of staff

9
9
 D e f i n i t i o n o f Te r m s
PIC/S GMP
• PIC/S Guide to Good Manufacturing Practice: Pharmaceutical Inspection Convention and
Pharmaceutical Inspection Co-operation Scheme (PIC/S)
• PIC/S is European whereas the previous GMP regulation are based from US FDA
• Founded by The European Free Trade Association (EFTA) in October 1970, a legal treaty
between countries
• Adopted to further facilitate the removal of barriers to trade in medicinal products

PIC/S Goal
“To lead the international development, implementation and maintenance of
harmonized GMP standards and quality systems of inspectorates in the field of
medicinal products”.

10
10
 D e f i n i t i o n o f Te r m s
The 10 Golden Rules of GMP
1 Get the facility design right from the start
2 Validate processes
3 Write good procedures and follow them
4 Identify who does what
5 Keep good records
6 Train and develop staff
7 Practice good hygiene
8 Maintain facilities and equipment
9 Build quality into the whole product lifecycle
10 Perform regular audits

11
11
 D e f i n i t i o n o f Te r m s
The 10 Golden Rules of GMP
1 Get the facility design right from the start

12
12
13
13
14
14
 -
( )

-
( )
-
( )

+
( )

+
( ) -
( ) -
( )

+
( )

15
15
 D e f i n i t i o n o f Te r m s
The 10 Golden Rules of GMP
2 Validate processes
"Establishing documented evidence that provides a high degree of assurance that a
specific process will consistently produce a product meeting its pre-determined
specifications and quality attributes”

16
16
 D e f i n i t i o n o f Te r m s
The 10 Golden Rules of GMP
3 Write good procedures and follow them
Procedures should be clear, concise and logical

17
17
 D e f i n i t i o n o f Te r m s
The 10 Golden Rules of GMP
4 Identify who does what
There should be no gaps or overlaps in responsibilities

18
18
 D e f i n i t i o n o f Te r m s
The 10 Golden Rules of GMP
5 Keep good records
If it is not written down, then it did not happen.

19
19
 D e f i n i t i o n o f Te r m s
The 10 Golden Rules of GMP
6 Train and develop staff
Companies need people who know how to do the job
right the first time, every time.

20
20
 D e f i n i t i o n o f Te r m s
The 10 Golden Rules of GMP
7 Practice good hygiene
The fight against contamination is a constant battle and is one that requires
the attention of every single employee, every day.

21
21
 D e f i n i t i o n o f Te r m s
The 10 Golden Rules of GMP
8 Maintain facilities and equipment
Regular equipment maintenance prevents equipment breakdowns, which
can be costly. It also reduces the risk of product contamination and
maintains the ‘validated state’ of the facility or equipment.

22
22
 D e f i n i t i o n o f Te r m s
The 10 Golden Rules of GMP
9 Design quality into the whole product lifecycle.
Quality by Design (QbD)

23
23
 D e f i n i t i o n o f Te r m s
The 10 Golden Rules of GMP
10 Perform regular audits.
• FDA
• Self – audit
• External audit
➔ CAPA – Corrective Action Preventive Action

24
24
 D e f i n i t i o n o f Te r m s
Specifications
• Exact statement of the particular needs to be satisfied, or essential characteristics that a
customer requires (in a good, material, method, process, service, system, or work) and
which a vendor must deliver

• Written usually in a manner that enables both parties (and/or an independent certifier) to
measure the degree of conformance

• A description of starting material, intermediate, bulk or finished product in terms of its

chemical, physical and microbiological characteristics, if any

• A specification shall include descriptive and or numerical clauses stating standards and
tolerated deviations, whenever applicable

• Lists of detailed requirements with which the products or materials used or obtained
during manufacture have to conform, they serve as a basis for quality evaluation

25
25
 D e f i n i t i o n o f Te r m s
Specifications
Specifications are divided generally into two main categories:

1. PERFORMANCE SPECIFICATIONS conform to known customer requirements such as

keeping the temperature within a specified range

2. TECHNICAL SPECIFICATIONS express the level of performance of the individual units

a. INDIVIDUAL UNIT SPECIFICATIONS which state boundaries or parameters of the unit
performance consisting of a nominal value and tolerance

b. ACCEPTABLE QUALITY LEVEL which states limits that are to be satisfied by most of the
units, but a certain percentage of the units is allowed to exceed those limits

c. DISTRIBUTION SPECIFICATIONS which define an acceptable statistical distribution for

each unit and are used by a producer to monitor its production processes

26
26
D e f i n i t i o n o f Te r m s
Specifications

27
27
D e f i n i t i o n o f Te r m s
Specifications

28
28
 D e f i n i t i o n o f Te r m s
Specifications
Example of specifications for finished products

For each batch of drug product, there should be an appropriate laboratory determination of
satisfactory conformity to its finished product specification prior to release.

Products failing to meet the established specifications or any other relevant quality criteria
should be rejected.
29
29
 D e f i n i t i o n o f Te r m s
USP/NF
• A combination of two compendia, the United States Pharmacopeia (USP) and the National
Formulary (NF)

• It contains standards for medicines, dosage forms, drug substances, excipients, biologics,
compounded preparations, medical devices, dietary supplements, and other therapeutics

• The current version of USP-NF standards deemed official by USP are enforceable by the
U.S. Food and Drug Administration for medicines manufactured and marketed in the
United States

Revisions
• Revised annually since 2002
• 2 supplements in a year
• Founded in 1820 (first pharmacopeia published)

30
30
D e f i n i t i o n o f Te r m s
USP/NF

31
31
D e f i n i t i o n o f Te r m s
USP/NF

32
32
D e f i n i t i o n o f Te r m s
USP/NF

33
33
 D e f i n i t i o n o f Te r m s
USP/NF
GENERAL CHAPTERS

• 1000 - 1999 for informational purposes only, contain no mandatory test assay or other
requirements applicable to any official article

• 1000 below Monograph and General Notices

• 2000 above apply only to articles that are intended for use as dietary supplements

34
34
 D e f i n i t i o n o f Te r m s
USP/NF
<1000 below> Monograph and General Notices
GENERAL NOTICES AND REQUIREMENTS

• The General Notices and Requirements section (the General Notices) presents the basic
assumptions, definitions, and default conditions for the interpretation and application of
the United States Pharmacopeia (USP) and the National Formulary (NF).

• Requirements stated in these General Notices apply to all articles recognized in the USP
and NF (the “compendia”) and to all general chapters unless specifically stated otherwise.

35
35
D e f i n i t i o n o f Te r m s
USP/NF

36
36
D e f i n i t i o n o f Te r m s
USP/NF

37
37
D e f i n i t i o n o f Te r m s
USP/NF

38
38
D e f i n i t i o n o f Te r m s
USP/NF

39
39
 D e f i n i t i o n o f Te r m s
USP/NF
<1000 – 1999> For Informational Purposes only
contain no mandatory test assay or other requirements applicable to any official article

40
40
 D e f i n i t i o n o f Te r m s
USP/NF
<1000 – 1999> For Informational Purposes only
contain no mandatory test assay or other requirements applicable to any official article

• The chapters in this section are information, and aside from excerpts given herein from
Federal Acts and regulations that may be applicable, they contain no standards, tests,
assays, nor other mandatory specifications, with respect to any Pharmacopeial articles.
The excerpts from pertinent Federal Acts and regulations included in this section are
placed here inasmuch as they are not of Pharmacopeial authorship. Revisions of the
federal requirements that affect these excerpts will be included in USP Supplements as
promptly as practical. The official requirements for Pharmacopeial articles are set forth in
the General Notices, the individual monographs, and the General Tests and Assays chapters
of this Pharmacopeia.

41
41
 D e f i n i t i o n o f Te r m s
USP/NF
<2000 below> Dietary Supplements
apply only to articles that are intended for use as dietary supplements

42
42
D e f i n i t i o n o f Te r m s
USP/NF
USP ANTHEM

43
43
 D e f i n i t i o n o f Te r m s
Monograph
• Monographs set forth the article's name, definition, specification, and other requirements
related to packaging, storage, and labelling.

• The specification consists of tests, procedures, and acceptance criteria that help ensure the
identity, strength, quality and purity of the article.

*An official article is an article that is recognized in USP or NF.

44
44
 D e f i n i t i o n o f Te r m s
Monograph
MONOGRAPH COMPONENTS
1. Molecular Formula 5. Assay
2. Added Substances 6. Impurities and Foreign Substances
3. Description and Solubility 7. Performance Tests
4. Identification 8. USP Reference Standards

45
45
 D e f i n i t i o n o f Te r m s
Remington: The Science and Practice of Pharmacy
• Revised every 5 years
• Latest edition 22nd (2010)

• For over 100 years, Remington has been the

definitive textbook and reference on the
science and practice of pharmacy.

46
46
 D e f i n i t i o n o f Te r m s
Remington: The Science and Practice of Pharmacy
V. 1. The science of pharmacy
1. Introduction
2. Pharmaceutical chemistry
3. Pharmaceutical analysis and quality control
4. Pharmaceutics (science of dosage form design)
5. Pharmaceutical dosage forms: manufacturing
and compounding
6. Pharmacokinetics and pharmacodynamics -
Monographs : Pharmaceutical and medicinal
agents.
V. 2. The practice of pharmacy
7. Fundamentals of pharmacy practice
8. The scope of pharmacy practice
9. Social, behavioral, economic, and
administrative sciences
10. Patient care
47
47
 D e f i n i t i o n o f Te r m s
Remington: The Science and Practice of Pharmacy

48
48
 D e f i n i t i o n o f Te r m s
ISO
• International Organization for Standardization (IOS)
• Organisation Internationale de Normalisation (OIN) – French
• “ISO” All purpose name derived from the Greek isos, meaning equal

International Organization
for Standardization

www.iso.org

49
 D e f i n i t i o n o f Te r m s
ISO
What standards do?
• make the development, manufacturing and supply of products and services more efficient,
safer and cleaner
• facilitate trade between countries
• provide governments with a technical base for health, safety and environmental
legislation, and conformity assessment
• share technological advances and good management practice
• disseminate innovation
• safeguard consumers, and users in general, of products and services

Why standards matter?

• Standards make an enormous and positive contribution to most aspects of our lives.
• Standards ensure desirable characteristics of products and services such as quality,
environmental friendliness, safety, reliability, efficiency and interchangeability - and at an
economical cost.

50
50
 D e f i n i t i o n o f Te r m s
ISO
ISO 9001 is for quality management
• Quality refers to all those features of a product (or service) which are required by the
customer.
• Quality management means what the organization does to ensure that its products or
services satisfy the customer's quality requirements and comply with any regulations
applicable to those products or services.

ISO 14001 is for environmental management.

• This means what the organization does to minimize harmful effects on the environment
caused by its activities, to conform to applicable regulatory requirements, and to achieve
continual improvement of its environmental performance.

ISO 9001 and ISO 14001 are generic standards.

51
51
 D e f i n i t i o n o f Te r m s
TQM
TOTAL QUALITY MANAGEMENT

• TQM functions on the premise that the quality of products and processes is the
responsibility of everyone who is involved with the creation or consumption of the
products or services offered by an organization.

• TQM requires the involvement of management, workforce, suppliers, and customers, in

order to meet or exceed customer expectations.

• Stresses a commitment by management to have a companywide drive towards Excellence

in all aspects of products and services

52
52
FUNCTIONS AND
RESPONSIBILITIES
Quantitative Pharmaceutical Chemistry

53
 QA VS QC
QUALITY ASSURANCE
• Establishes systems for ensuring the quality
of the product
• Final authority for product acceptance/
release or rejection
• Report to chief executive or president
• Quality monitoring or audit functions
(adequate systems, facilities and written
procedures)
QUALITY CONTROL
• Responsible for the day to day control of
quality w/in a company
• Staffed w/ scientists and technicians,
responsible for sampling and analytical
testing for incoming raw materials and
inspection of packaging components
including labeling
• Conduct in- process testing
• Inspect operations for compliance
• Conduct tests on finished dosage form
• Monitors product quality, testing product
complaint samples, evaluating product
quality
• Perform environmental monitoring
54
54
 QA VS QC
QUALITY ASSURANCE
• QA makes sure that we are doing the right
things, the right way.
• QA focuses on building in quality and hence
preventing defects.
• QA deals with process.
• QA is for entire life cycle.
• QA is preventive process.
QUALITY CONTROL
• QC makes sure the results of what we
have done are what we expected.
• QC focuses on testing for quality and
hence detecting defects.
• QC deals with product.
• QC is for testing part in SDLC.
• QC is corrective process.
55
55
 S E C T I O N S U N D E R T H E Q UA L I T Y C O N T R O L M A N A G E R

1. MATERIALS INSPECTION SECTION

2. ANALYTICAL LABORATORY

3. BIOLOGICAL TESTING LABORATORY

4. SPECIFICATIONS AND ANALYTICAL DEVELOPMENT

5. QUALITY COORDINATION OFFICE

56
56
 Sections under the Quality Control Manager
MATERIALS INSPECTION SECTION
• To sample and examine all raw materials received

• Conduct physical tests on all shipments of packaging materials and all

manufacturing, filling and packaging operations

• Maintain periodic examination on the quality of inventories throughout all phases

of storage, shipping and distribution

• Perform audit which is independent of the work done by product personnel

Note: inspection stations are placed in the area of operation, warehouse,

manufacturing and packaging areas

57
57
 Sections under the Quality Control Manager
ANALYTICAL LABORATORY
• For testing and approving raw materials, work in-process and finished product

• To perform chemical and physical analysis / tests and specifications may be found
in several sources as USP, NF, BP and Merck Index

58
58
59
59
 Sections under the Quality Control Manager
BIOLOGICAL TESTING LABORATORY
• Staff must be well trained and experience in both simple and complex
microbiogical procedures

• To perform and evaluate microbiological and pharmacological assays, sterility,

pyrogen and bacteriological tests, irritation, safety or acute toxicity tests

• Conduct environmental monitoring

• Sterile conditions should be provided for areas where biological tests are
conducted

• Noise should be precluded from areas where animals are used

60
60
 Sections under the Quality Control Manager
SPECIFICATIONS AND ANALYTICAL DEVELOPMENT
• Coordinate with research, product development, production, sales and
management towards improvements of product

• Establish specifications for raw and packaging materials

• Validate existing and tentative procedures of testing

• Establish specifications based on validation procedure

• Develop new assay methods for in-house use

• Develop and improve specifications for quality characteristics of the final product
being manufactured

61
61
 Sections under the Quality Control Manager
QUALITY COORDINATION OFFICE
• Documentation is its main responsibility

• Maintain and store records that represent the history of the batch from start to
finish: batch and master formula records, raw mat analytical record, printed and
packaging material inspection reports and retention files)

• Furnish data that will aid in analyzing product performance in the market: stability
studies and returned goods reports

• Investigate customer complaints

• Maintain and develop standard operating procedures

62
62
 Quality Functions

Control functions may vary in companies but basically these functions can be classified into
four categories

1. ANALYSIS FUNCTIONS

2. MONITOR FUNCTIONS

3. RECORD, REVIEW AND RELEASE FUNCTIONS

4. AUDIT FUNCTION

63
63
 Quality Functions
ANALYSIS FUNCTIONS
• Assures acceptability of the product

• Tests are made not only on the raw materials and packaging components but also
on the bulk product during processing and after packaging prior to release to
market

• Selected lots are subjected to shelf life to confirm expiration period

64
64
 Quality Functions
MONITOR FUNCTIONS
• To sample and examine materials while they are being processed

• Environmental monitoring: to control the microbial and particular matter content

of environmental air

65
65
 Quality Functions
RECORD, REVIEW AND RELEASE FUNCTIONS
• Carefully reviewing the batch record for the lot and assuring that all necessary
records are present and complete

66
66
 Quality Functions
AUDIT FUNCTIONS
• The production and quality control of quality products are governed by standard
operating procedures (SOP) which embrace the legal requirements set forth by the
cGMP

67
67
ANALYST IN THE
LABORATORY
Quantitative Pharmaceutical Chemistry

68
 A N A LY S T I N T H E L A B O R ATO R Y

1. SUCCESS AS AN ANALYST

2. ACCURACY AND HONESTY

3. AGREEMENT IN ANALYTICAL DETERMINATIONS

4. ECONOMY OF TIME

69
69
 Analyst In The Laboratory
SUCCESS AN ANALYST
• Manipulative skill acquired by experience

• Ability to follow directions under supervision of skilled analyst

• Has fundamental knowledge of theory

• Practical ability in the application of analytical methods

• Skill of technique, patience, neatness and accuracy

• Must not only use common sense in the laboratory but think throughout each step
of the procedure

70
70
 Analyst In The Laboratory
ACCURACY AND HONESTY
• All quantitative work be performed without even a slight loss of material or gain of
extraneous matter

• Absolute integrity is demanded of every quantitative analyst, the only person who
is familiar with the entire history of an analysis and who knows whether it is
worthy of full confidence

• At least 2 determinations of any analytical value are required (trials and replicates)

71
71
 Analyst In The Laboratory
AGREEMENT IN ANALYTICAL DETERMINATIONS
• Precision and Accuracy

72
72
 Analyst In The Laboratory
ECONOMY OF TIME
• Economical utilization of laboratory hours is best achieved through a preliminary
study of the work to be done, followed by a plan for its prompt execution.

• There is not such thing as “speed” in quantitative work.

• Economy of time is achieved not by haste, but by planning the work so that two or
more operations may be carried out at one time and especially by working so
accurately that is will be unnecessary to repeat a determination.

73
73
 Analyst In The Laboratory
ECONOMY OF TIME
1. Keep the desk scrupulously clean at all times

2. Clean all apparatus immediately after using it and put it in the desk

3. Label all solutions, filtrates, and precipitates systematically throughout the

analytical procedure

4. Keep two or more operations going at one time (while cooling a precipitate, ignite
another)

5. Utilize all time between operations in making calculations and writing up

experiments

74
74
 REAGENTS
Quantitative Pharmaceutical Chemistry

75
 Reagents
IDEAL CHARACTERISTICS OF REAGENTS
1. Pure
2. Conform to USP/NF requirements
3. AR grade

76
76
 Reagents
GRADES OF CHEMICALS
1. Reagent ACS
2. Guaranteed Reagent (GR)
3. Analytical Reagent (AR) / Reagent Grade
4. Primary Standard
5. Purified
6. Lab Grade
7. USP
8. NF
9. Technical

77
77
 Reagents
GRADES OF CHEMICALS
1. Reagent ACS
• Designates high quality chemical for laboratory use
• "A.C.S.," means the chemical meets the specifications of the American Chemical Society

2. Guaranteed Reagent (GR)

• Suitable for use in analytical chemistry
• Meet or exceed American Chemical Society (ACS) requirements where applicable

3. Analytical Reagent (AR) / Reagent Grade

• Highly purified chemicals

4. Primary Standard
• Used for standardization of solution to a very high degree of accuracy

5. Purified
• Defines chemicals of good quality where there are no official standards. This grade is
usually limited to inorganic chemicals 78
78
 Reagents
GRADES OF CHEMICALS
6. Lab Grade
• A line of solvents suitable for histology methods and general laboratory applications

7. USP
• Chemicals manufactured under current Good Manufacturing Practices and which meet
the requirements of the US Pharmacopeia

8. NF
• Chemicals that meet the requirements of the National Formulary

9. Technical
• A grade suitable for general industrial use; superficial purification, seldom use in
analytical work

79
79
 END.
Quantitative Pharmaceutical Chemistry

80