2. Definition
The term quality control refers to the sum of all
procedures undertaken to ensure the identity and
purity of a particular pharmaceutical product. Such
procedures may range from the performance of simple
chemical experiments which determine the identity
and screening for the presence of particular
pharmaceutical substance to more complicated
requirements of pharmacopoeial monographs.
3. The quality of a product may deviate from the standard
required so carrying out analysis is important in order to
determine the quality.
Testing a pharmaceutical product involves chemical,
physical, and some time microbiological evaluation or
test.
Counterfeit medicines; The WHO defines a counterfeit
drug as a product that is with intent and illegally
mislabelled with respect to its identity and/or source.
Counterfeiting of medicinal products, active
pharmaceutical ingredients or product labels are
criminal offences, which may endanger patient health.
4. Counterfeit medicines may:
► contain no active ingredient
► contain the wrong active ingredient (e.g. a cheap
antibiotic instead of an expensive antibiotic)
► contain an incorrect (usually low) quantity of the active
ingredient
► be in low–quality packaging
► be manufactured using low–quality active ingredient or
excipient
► be manufactured under poor standards of good
manufacturing practice (GMP) compliance.
5. ► Counterfeit
products that contain no active ingredient
and those that contain the wrong active ingredient or the
correct active ingredient in the wrong amount can be
detected by carrying out appropriate identification and
quantitative tests. In situations where resources for
accurate and precise quantitative testing are limited, for
example in underdeveloped countries, basic tests,
including semi–quantitative tests, may be sufficient to
detect these types of counterfeit medicines.
► It may also be possible to identify products as being
counterfeit by their general appearance (color,
markings, etc.); particularly when the appearance
differs from a genuine batch of the product.
6. ► For
this reason, laboratories that regularly undertake
checks for counterfeit medicines maintain a stock of
genuine reference products for comparison.
Examination of the labelling should also be carried out
to check the accuracy of the information presented.
Labels of products made by counterfeit manufacturers
may contain errors that are evident to an expert.
► The quality of the packaging materials and of the
printing should also be inspected carefully and, if
possible, compared to that of a genuine batch of the
product.
7. Analytical process
► It
has been estimated that £ 10 billion is spent
each year on analysis in the UK alone and such
analytical processes can be found in various
industries as those producing food, beverages,
cosmetics, detergents, metals, paints, water,
agrochemical, biotechnology products and
pharmaceutical products. With such large
amount of money being spent on analytical
quality control, great spent must be placed on
providing accurate and precise analysis
8. Differentiation of analytical process
► Analytical
process may be categorized into five groups
based on the objective;
► Standard methods: This may be national standard
procedures, or international guidelines ( e.g. American
society for testing and material (ASTM), international
organization for standardization (ISO), international
union of pure and applied chemistry (IUPAC), etc.) and
standards, or procedures described by legal regulations,
► Comparable laboratory procedures: quantitative
analytical processes which vary in procedure from
standard methods, but are verified as equivalence to
using standard methods.
9. ► Other
quantitative analytical procedures which have
various uses and objectives in the laboratory out side of
governmentally regulated areas. These also include the
latest analytical procedures for which standards have
not yet been established
► Field methods: analytical processes which can be
performed out side the laboratory. With the aid of
objective measurement methods, field methods can
bring quantitative or semi-quantitative results
depending on previous handling of the sample and
quality assurance procedures
10. Quality of analytical process
► The
appropriate analytical process for obtaining the
answer to a specific question must not always be the
scientifically "best" procedure. However, it is important
that the results of an analysis, obtained through
adherence to legal regulations, should if necessary be
defensible in court, or in other word legally binding.
11. Precision requirements of analytical procedures as related to
analytical problem
Question
Is a substance present or not
Quality required for analytical process
Yes/no decision; a sufficiently sensitive orientation test is
applicable.
In which range of concentration is the
substance present
An orientation test indicating a corresponding gradation
of concentration regions is applicabl
Dose the concentration lie far below a
verifiable threshold limit?
A highly precise analytical results is not necessary;
orientation test and field methods are applicable
Has the threshold limit been exceeded?
A highly accurate (meaning both precision and trueness)
analytical result is required, i.e. only reference procedure
and if available comparable laboratory procedures are
applicable.
In what concentration, ± confidence
interval, is the substance in question
present in the sample?
A highly accurate (meaning both precision and trueness)
analytical result is required. If the analytical result is
legally binding, only standard methods or comparable
laboratory procedures are an acceptable. Otherwise, other
analytical procedures whose reliability has been proven
are applicable.
12. ► The
objective of analytical work is the achievement of
reliable analytical results of a defined quality. Quality
characteristics of analytical process are therefore:
Specificity; the ability of analytical process to register
only the desired analyte, while other components or
characteristics present in the sample (known as the
matrix) do not influence the results.
Sensitivity: the change in measured value per change in
analyte.
Accuracy: is the sense of both trueness (lack of
systematic errors) and precision (measurement of
differences between results, as obtained by repeated use
of an established analytical process on the same
sample). Imprecision is caused by random errors.
13. Four phase modules of analytical quality
assurances
► The
chronology of quality assurance characteristics is
reflected in a 4-phase model of analytical quality
assurance using statistical method, as described below:
► Phase 1: the quality characteristics of a new analytical
process in need of calibration are determined and if
necessary the process is improved and documented.
► Phase 11: preparative quality control. An analytical
process whose quality characteristics have already been
documented is made operational for routine analysis.
This includes achieving and maintaining sufficient
analytical quality test before routine analysis begins.
14. ► Phase
111: performance of all internal laboratory
quality assurance measures of routine analysis,
accompanied by
► Phase 1V: external laboratory quality assurance in the
form of inter laboratory tests and external audits.
15. Quality Assurance of pharmaceutical products
It is important in many spheres to have reliable, ►
interchangeable data on the recovery, identification and
quantification of drugs. In the pharmaceutical industry,
quality control and assessment (QC and QA) are
required to monitor production and assess the quality,
safety and efficacy of its products. In clinical analysis,
QC and QA is vital to the quality and safety of patient
care, to the diagnosis and control of therapy for the
individual patient, and for research and public health
purposes.
16. ► For
toxicologists and pathologists, QC and QA help to
distinguish between therapeutic and overdose levels and
to determine the cause of death. In law enforcement, it
is used to provide information to link drugs offences, to
identify drugs distribution networks and to provide
evidence of possession or misuse for the courts. It is
also essential for monitoring individuals on drug
rehabilitation programmers
17. ► Medicinal
products should be safe and efficacious.
Manufacturers of medicinal products are required by
law to possess marketing authorizations from
government regulatory agencies in countries in which
their products are marketed and to manufacture their
products in compliance with Good Pharmaceutical
Manufacturing Practice (GMP) standards. These
requirements involve conducting appropriate quality
control tests to check that the product conforms to a
specification that assures its safety and efficacy.
► Typical specifications include tests to verify the
chemical composition and physical properties of the
medicine and to ensure that the medicine is not
contaminated by micro–organisms or other substances.
18. Although medicinal products are subject to
quality–control testing by the manufacturer,
they may also have to be checked
independently to:
1. determine or confirm their composition
2. assess their suitability for use
3. investigate defects
4. identify unknown medicinal products
5. identify contaminants
6. determine if the products have been adulterated
7. establish if the products are counterfeit.
19. ► In
most cases that involve checking of the quality of a
medicinal product, it is preferable to use the test
methods in the product specification defined in the
manufacturer’s marketing authorization for the product.
This is because the product specifications, including the
test methods and acceptance criteria, have been
assessed by the government regulatory agency as being
valid and justified. Some manufacturers publish their
analytical methods in the scientific literature.
Consequently, it may be worthwhile to check the
literature or maintain a library of published methods.
20. ► Alternatively,
in certain circumstances, manufacturers
may provide the independent laboratory with the test
methods, acceptance criteria and reference materials.
► If the laboratory does not have access to the authorized
finished product specification, including the test
methods and acceptance criteria, pharmacopoeial
monographs can be used, where applicable
► In the absence of a pharmacopoeial monograph,
alternative approaches are required to obtain as much
information as possible about the quality of the
medicinal product
21. ►
This requires the development of valid test methods to
measure relevant quality parameters and the
application of generally accepted criteria to assess the
quality. However, if the laboratory uses different
analytical techniques to those used by the
manufacturer [e.g. a high performance liquid
chromatographic (HPLC) technique instead of an
ultraviolet (UV) spectrophotometric technique], the
results may differ significantly from those obtained by
the manufacturer, particularly if high levels of
impurities are present
22. Pharmacopoeial specification and methods
►
Pharmacopoeias are good sources of the specifications and
standards with which a wide range of commonly used drug
substances, excipient, packaging materials and finished products
must comply throughout their shelf–life. The principal
pharmacopoeias are the European Pharmacopoeia , British
Pharmacopoeia
► National pharmacopoeias of some countries, for example Japan,
China and individual European countries, may provide
specifications for pharmaceuticals that are available only in those
countries. The International Pharmacopoeia published by the
World Health Organization is intended for use by WHO member
states who wish to establish pharmacopoeial requirements for
pharmaceuticals used in their country
23. ► The
specifications in monographs of pharmacopoeias
are intended to be applicable to drug substances,
excipient and finished products from different
producers. Although the monographs contain the
essential tests that provide verification of the suitability
of the product for use, the monographs do not attempt
to control unique aspects of individual products.
► Consequently, drug substance and finished product
specifications in marketing authorizations of individual
products may be based on the requirements of a
relevant pharmacopoeia, but may also contain
additional tests or tighter acceptance criteria
24. ► This
is particularly true of finished product
specifications for the release of batches of products onto
the market (release specifications are used in Europe,
but not in the USA). For these, tighter acceptance
criteria may be required at the time of release to ensure
that the product remains within specification during its
shelf–life. Since samples tested by an independent
laboratory are often obtained from the marketplace, the
shelf–life acceptance criteria in pharmacopoeias provide
a suitable means by which the quality of medicinal
products can be judged.
25. ► Pharmacopoeial
monographs for medicinal products
provide good models upon which the testing of non–
pharmacopoeial products should also be based when a
general check of their quality is required. Typical
pharmaceutical specifications for dosage forms include
the following types of tests to provide assurance of their
quality, safety and efficacy:
► Identity test to confirm the identity of the active
ingredient(s) and, if appropriate other important
constituents (e.g. preservatives)
26. 1.
2.
3.
4.
5.
Assay of the active ingredient(s) and, if appropriate
other constituents
Homogeneity (e.g. uniformity of content for tablets
and capsules)
Release of the active ingredient from the formulation
Drug–related impurities and other contaminants
Microbiological tests (e.g. sterility tests for injectable
and ophthalmic products
Pharmacopoeias contain useful chemical, physical and
microbiological information about drug substances,
excipient and dosage forms. Examples include
molecular structures and formulae, relative molecular
masses, melting and boiling points, spectroscopic data
and solubility in various solvents.
27. ► Pharmacopoeial
methods should always be considered
when the testing of pharmacopoeial articles is required.
Even if the test methods in the marketing authorization
differ from those in the relevant pharmacopoeia, the
article must also comply with the standards of the
pharmacopoeia,
including
the
use
of
the
pharmacopoeial test methods, if it is covered by a
monograph in the pharmacopoeia.
► In most circumstances, pharmacopoeial methods can be
assumed to be valid for the materials covered by the
monographs. This is because they are intended for use
by a wide variety of laboratories, sometimes on an
infrequent basis.
28. ► One
of the criteria for the selection of the methods is
that they should be robust. Nevertheless, it is good
practice to carry out additional tests (e.g. a recovery
test) to demonstrate that the method is suitable for the
sample.
► If a test method is required for a pharmaceutical product
for which there is no pharmacopoeial monograph, it
may be possible to use or adapt the test methods in a
monograph of a similar material. In these
circumstances, however, relevant validation tests should
be carried out, such as recovery, precision, robustness,
selectivity and/or specificity and (for trace amounts, e.g.
impurities) limits of detection and quantification, to
provide confidence in the suitability of the adapted
method.
29. ► Pharmacopoeial
monographs generally do not rely on a
single analytical technique, but instead contain a
number of tests based on different analytical
methodologies (e.g. identity tests that use spectroscopic
techniques and colour reactions, tests for impurities
using chromatographic techniques and assays using a
non–selective titrimetry or UV spectrophotometric
technique). Pharmacopoeial authorities consider that
this approach provides the optimum level of assurance
about the quality of the product.
30. ► For
many substances and products it is possible to
combine the identity test, tests for impurities and assay
into a single chromatographic test. Indeed, many
manufacturers, including those of pharmacopoeial
products, adopt this approach for economic reasons. For
similar reasons, an independent laboratory may choose
to develop a single chromatographic test to check
identity, impurities and assay in surveillance
programme that involve large numbers of samples.
However, it is important to weigh the cost benefits of
this approach against the risks of failure to detect sub–
standard products (e.g. those that contain impurities not
detected by the single test).
31. ► Pharmacopoeial
monographs may contain, in addition
to product–specific test methods, a number of general
tests applicable to a wide variety of materials in the
pharmacopoeia. Examples of these are melting and
boiling point determination, heavy metals test, sulfated
ash test (test for residue on ignition in the USP),
disintegration testing of solid dose products, tests for
microbial contamination, preservative efficacy tests,
sterility tests and the Karl Fischer determination of
moisture. These pharmacopoeial methods have been
accepted as standard test methods and, consequently,
can be applied by laboratories to a wide range of non–
pharmacopoeial materials, provided appropriate
validation has been carried out.
