Quality control of pharmaceutical products

Quality control

of medicinal products

Siham abdoun

Msc., PhD

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.

Definition

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.

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.

►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.

► 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.

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

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.

►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

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.

Precision requirements of analytical procedures as related to

analytical problem

Quality required for analytical processQuestion

Yes/no decision; a sufficiently sensitive orientation test is

applicable.

Is a substance present or not

An orientation test indicating a corresponding gradation

of concentration regions is applicabl

In which range of concentration is the

substance present

A highly precise analytical results is not necessary;

orientation test and field methods are applicable

Dose the concentration lie far below a

verifiable threshold limit?

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.

Has the threshold limit been exceeded?

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.

In what concentration, ± confidence

interval, is the substance in question

present in the sample?

►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.

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.

►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.

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.

► 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

►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.

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.

► 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.

►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

► 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

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

►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

►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.

► 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)

1. Assay of the active ingredient(s) and, if appropriate other constituents

2. Homogeneity (e.g. uniformity of content for tablets and capsules)

3. Release of the active ingredient from the formulation Drug–related impurities and other contaminants

4. Microbiological tests (e.g. sterility tests for injectable and ophthalmic products

5. 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.

► 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.

►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.

► 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.

► 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).

► 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.

END