Quality Assurance of Pharmaceuticals - A Compendium of Guidelines and Related Materials - Volume 1
(1997; 248 pages) [French] View the PDF document
Table of Contents
Open this folder and view contentsIntroduction
Open this folder and view contents1. National drug regulation
Open this folder and view contents2. Product assessment and registration
Open this folder and view contents3. Distribution
Open this folder and view contents4. The international pharmacopoeia and related activities
Open this folder and view contents5. Basic tests
Open this folder and view contents6. Laboratory services
Open this folder and view contents7. International trade in pharmaceuticals
Open this folder and view contents8. Counterfeit products
Close this folder9. Training
View the documentTraining programme in drug analysis1,2
View the documentPlaces of training in drug quality control offered by the International Federation of Pharmaceutical Manufacturers Associations1
View the documentSelected WHO publications of related interest
View the documentBack cover
 

Training programme in drug analysis1,2

1WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirtieth Report. Geneva, World Health Organization, 1987 (WHO Technical Report Series, No. 748).

2 A group training course for recent science and pharmacy graduates in the practical and theoretical aspects of regulatory drug analysis.

1. Introduction

The establishment of a new drug control laboratory in a developing country and the subsequent expansion of its activities is dependent on the local availability of properly trained staff. This applies both to the supervisory personnel (including the head of the laboratory) and to the analysts who will perform the tests (either single-handed or with the assistance of technicians).

Staff for drug control laboratories are usually recruited from schools of pharmacy but may also come from institutions specializing in various other branches of science. These graduates have adequate theoretical knowledge to perform standard analytical tasks but need a period of practical in-service training before they can be allowed to work independently.

In large established drug control laboratories, the practical training of newly recruited staff is usually accomplished by their temporary attachment to experienced analysts for periods of apprenticeship. In addition, a new staff member is sometimes required to attend briefing sessions on such matters as the internal organization of the laboratory, analytical documentation and reporting, and safety measures. However, such training is often impracticable in small laboratories and is out of the question when a completely new laboratory is to be established.

The WHO Expert Committee on Specifications for Pharmaceutical Preparations, in its twenty-eighth and twenty-ninth reports, reviewed various aspects of the establishment and expansion of drug control laboratories in developing countries and came to the conclusion that the lack of adequately trained staff for governmental drug control laboratories is a major obstacle in the way of national programmes on improvement of drug quality (1, 2). The Committee is aware that some provision has already been made for individual training of drug analysts from developing countries (2). This arrangement, however, is more suited to the training of supervisory staff or of analysts who already have substantial professional experience and are under consideration for promotion to supervisory positions. The Committee has therefore focused its attention on group training (1, 2) of recent graduates and has further developed the basic ideas presented in the twenty-ninth report of the Expert Committee (2).

The syllabus is designed to train people for the facilities provided in the model governmental drug control laboratories described in section 2 of this report.1 However, the training provided would enable the participants to adapt readily to the requirements of work in industrial control laboratories.

1WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirtieth Report. Geneva, World Health Organization, 1987 (WHO Technical Report Series, No. 748): 12-13.

In order to ensure that the training is of direct relevance to analysts from developing countries, it should be carried out in a well-equipped drug control laboratory in a developing country that has specialists in each discipline on its staff.

2. Course objectives and types of training

2.1 Course objectives

The main objective of the proposed training is to provide basic practical guidance on the analysis of pharmaceutical products. It is not intended to produce highly qualified specialists in the whole field of drug analysis. Special skills can only be acquired through long experience in laboratory work.

As a national drug control laboratory is not usually involved directly in the sampling of pharmaceutical products, sampling has not been included in the curriculum.

2.2 Types of training

Separate courses are proposed for chemical, microbiological, and biological methods of drug control.

The course dealing with chemical methods of analysis is comprehensive and reflects the present preponderance of chemical and instrumental methods among analytical procedures. It does not, however, include instruction on the use of complex instruments, such as nuclear magnetic resonance spectrometers, mass spectrometers, or autoanalysers, these not being provided for in the model laboratories described in section 2 of this report.1 Instruments, such as polarographs, that are rarely used are discussed only from the theoretical standpoint.

The course on microbiological control emphasizes sterility testing, microbiological spoilage testing, potency tests for antibiotics and other specific drug substances, and the preparation and monitoring of culture media under local conditions. Methods used in the control of natural products are included, as well as the use of microscopic techniques for plant identification.

The biological control course is mainly concerned with pyrogen testing and specific safety tests. The testing of biological products such as vaccines and blood products is left out of consideration. Since many of the trainees admitted to the course will have received little formal training in pharmacology, sufficient theoretical knowledge must be provided to enable them to appreciate the objectives and importance of experimental work.

2.3 Educational background of trainees

The courses are intended for recent graduates in science or pharmacy with 3-4 years of education at university level. Among science graduates, preference should be given to those with detailed knowledge of analytical chemistry, biochemistry, or microbiology, but extensive practical experience is not required.

2.4 Training in more than one subject

Trainees desiring to be trained in more than one aspect of analysis should allow an interval of at least 1 year to elapse between courses, in order to ensure that each period of training is complemented by an extended period of practical experience.

3. Duration of training courses

3.1 General

It is envisaged that the courses in chemical control methods and in microbiological control should each last 6 months.

Since training in biological control is more restricted in its scope the syllabus can be completed in 3-4 months.

3.2 Teaching arrangements

The first week of each course provides an introduction to the general principles of quality control and analysis as they relate to procurement and distribution systems for pharmaceutical products.

It also develops a general awareness of all important aspects of quality control and a clear perception of the duties and responsibilities of an analyst. In particular it underscores the importance of instituting good laboratory practices in the interests of both efficiency and safety.

The practical training that follows also provides for discussions on the theoretical aspects of the use of instruments and the applicability and utility of individual methods, which it is recommended should occupy some 10-15% of the time available.

No guidance is given on the sequence of topics or the amount of time to be allocated to each. Detailed schedules can only be prepared locally on the basis of the facilities available.

In each course, the trainee, in addition to becoming familiar with the use of instruments and test methods, is expected to perform independently the full range of tests that he or she will subsequently meet in routine practice. Participants in the chemical drug control course should complete analyses of at least 25 pharmaceutical products, including both dosage forms and drug substances and in accordance with both pharmacopoeial monographs and manufacturer’s specifications.

3.3 Course certificate

Trainees who successfully complete the whole course should be awarded a certificate indicating the nature of the course and its duration.

4. Course programmes

4.1 Introductory subjects

• Introduction to a national drug regulatory system and the activities involved in pharmaceutical inspection.

• The reasons for drug quality testing, including in-process quality control (good manufacturing practice requirements) and the analysis of finished products.

• An introduction to the statutory instruments in force locally (e.g. a drug and cosmetics act).

• The role of governmental drug control laboratories in relation to drug surveillance programmes.

• An introduction to the use of regional/national and international pharmacopoeias; selection of requirements and test methods suitable for the product.

• Operation of an analytical laboratory.

• Duties and responsibilities of an analyst.

• Good laboratory practices in governmental drug control laboratories.

• Maintenance of analytical instruments.

• Safety procedures in analytical laboratories.

• Record-keeping; the importance of properly documented laboratory work; maintenance of laboratory notebooks and the preparation of certificates of analysis.

• Reference standards and working standards; their importance and maintenance.

• Storage and care of samples.

4.2 Chemical drug control training programme

 

Theoretical subject

Laboratory work

General

   

Checking and calibration of simple laboratory instruments, including analytical balances

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General quality standards and limit tests (sulfated ash, loss on drying, iron, arsenic, chloride, sulfate, lead, and heavy metals)

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Testing of packaging material

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Preparation of reagents for the quantitative analysis of pharmaceutical products

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Evaluation of test results and the concept of statistical evaluation of analytical results

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Physical tests

   

Melting point determination and the concept of mixed melting points

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Viscosity

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Refractive index

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Specific optical rotation

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Relative density

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Osmolarity

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Azeotropic distillation

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Gravimetric methods (test-tube methods)

   

Assay by the gravimetric method

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Potentiometric techniques

   

Determination of pH

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Ion-selective electrodes

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Titrimetric and related methods (employing both visual and potentiometric endpoint determination)

   

Acid-base

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Oxidation-reduction

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Non-aqueous

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Complexometric

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Karl Fischer

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Polarography

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Iodine value

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Saponification and acid values

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Nitrogen assay by the Kjeldahl method

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Oxygen combustion method

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Spectrophotometric techniques

   

UV/visible

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Infrared

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Flame photometry

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Atomic absorption

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Fluorescence (especially in the analysis of vitamins)

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Chromatographic techniques

   

Thin-layer

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Paper

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Column

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Gas-liquid chromatography

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High performance liquid chromatography

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Electrophoresis

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Pharmacognostic testing

   

Organoleptic examinations

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Microscopic examination of crude drugs

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Microchemical and phytochemical evaluation (alkaloids, glycosides, saponins, etc.)

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Physical evaluation (ash value, fluorescence, moisture content of crude drugs, extractive value)

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Physicochemical and chemical assay of crude drugs and galenicals

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Dosage-form testing

   

General test procedures

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The concepts of bioavailability and bioequivalence

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Disintegration

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Dissolution

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Uniformity of mass

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Content uniformity of single-dose pharmaceutical products

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Tablet hardness and friability

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Assay of preservatives in a parenteral preparation

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Verification of added colouring matter in tablets and oral liquid preparations

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Limit tests for particulate matter in large-volume parenterals

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Stability studies

   

Studies of the shelf-life of single-ingredient and multi-ingredient formulations at room temperature and at elevated temperature (accelerated decomposition) under different humidity conditions

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Control of products requiring enzymatic determination

   

Control of pharmaceutical products containing pepsin, trypsin, papain, diastase, and pancreatin

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4.3 Microbiological control training programme

Theoretical basis

• Morphology and fine structure of bacteria, fungi, and viruses; classification and nomenclature of bacteria; cultivation of microorganisms: nutritional requirements; ingredients, types, and preparations of culture media; physical conditions required for microbial growth; pure cultures and their characteristics; methods of isolating pure cultures; methods of preserving microorganisms.

• Effects of physical agents: pasteurization; sterilization by dry heat, moist heat, radiation and ethylene oxide; filtration; sterility testing.

• Effects of chemical agents; characteristics and classification of disinfectants; their selection and evaluation.

• Antibiotics and other chemotherapeutic agents; history of chemotherapy; classification of antibiotics; general chemical properties; mode of action; antimicrobial spectrum; development of resistance.

• Introduction to general biometry including the fundamentals of probability and significance calculations.

• Assay of antibiotics.

• Microbiological control of preparations not normally required to be sterile.

• Documentation and evaluation of test results.

Laboratory work

• General microbiology

- Preparation and dispensing of solid and liquid culture media.

- Sterilization of glassware.

- Small-scale preparation of sterile liquids.

- Aseptic transfer of microbial cultures.

- Microbiological method of testing the efficiency of a laminar-flow hood.

- Count of microorganisms: plate method and most-probable-number method.

- Study of the morphology of microorganisms by different staining methods:

(i) Gram staining;
(ii) spore staining;
(iii) capsule staining.

- Microbial limit tests for pathogenic organisms (Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, and Salmonella.

- Sterility test for injectables:

(i) containing no inhibitor;
(ii) containing inhibitors (membrane filter method).

- Isolation of microorganisms from locally available material; their maintenance; maintenance of reference microbial cultures.

- Microbiological spoilage testing.

- Testing the effectiveness of antimicrobial preservatives.

• Microbiological assay

- Assay of antibiotics by the agar diffusion method, using both small plates (Petri dishes) and large plates, by means of the following techniques (including statistical analysis):

- (i) 2 + 2 and 3 + 3 design for both large and small plates;

- (ii) 6×6 and 8×8 Latin-square design for large square plates.

- Turbidimetric assay of antibiotics, with due attention to the experimental design.

- Assay of vitamins by both turbidimetric and agar diffusion methods.

- Bioautographic technique.

- Determination of the effectiveness of disinfectants (Rideal-Walker coefficient).

4.4 Biological control training programme

Theoretical basis

• General introduction to pharmacology.

• Absorption, distribution, biotransformation, and excretion.

• Dosage forms; different routes of administration and their influence on the biological response.

• Pharmacological classification of drugs, with representative examples.

• Modes of action of drugs with examples: extracellular and intracellular effects, membrane effects, enzyme effects, action on specific receptors, interactions.

• Responses in isolated tissues and intact animals; graded responses (oxytocin on rat uterus, vasopressin on cat blood pressure).

• Nature, source, and effects of pyrogens.

• Determination of dose and solvent for the pyrogen test on rabbits.

• Introduction to general biometry, including the fundamentals of probability and significance calculations.

• Quantal responses: minimum lethal dose (toxicity of stibogluconate sodium), percentage of animals responding to different doses (insulin assay in mice).

• Recording and evaluation of test results.

• Ethical responsibilities in using animals and consideration of alternatives to animal testing.

Laboratory work

Animal house

- Selection, handling, and care of laboratory animals; safety considerations; demonstration and instruction.

• Pyrogens

- Preparation of pyrogen-free glassware, water, and solutions.
- Test for pyrogens in rabbits.
- In vitro Limulus amoebocyte lysate (LAL) test for the presence of endotoxins.

• Test for local irritation

- Subcutaneous and intramuscular irritation tests for drugs and implants.

• Test for abnormal toxicity.

• Test to be carried out in mice.

• Histamine-like substances

- Test of histamine-like substances on cat blood pressure (demonstration only).

• Bioassay.

• Insulin potency in mice.

• Heparin.

• Oxytocin (demonstration only).

References

1. WHO Technical Report Series, No. 681, 1982.

2. WHO Technical Report Series, No. 704, 1984.

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