C H A P T E R 4 - DOCUMENTATION

Principle
Good documentation constitutes an essential part of the quality assurance system. Clearly written documentation prevents errors from spoken communication and permits tracing of batch history. Specifications, Manufacturing Formulae and instructions, procedures, and records must be free from errors and available in writing. The legibility of documents is of paramount importance.
General
4.1. Specifications describe in detail the requirements with which the products or materials used or obtained during manufacture have to conform. They serve as a basis for quality evaluation. Manufacturing Formulae, Processing and Packaging Instructions state all the starting materials used and lay down all processing and packaging operations. Procedures give directions for performing certain operations e.g. cleaning, clothing, environmental control, sampling, testing equipment operations. Records provide a history of each batch of product, including its distribution, and also of all other relevant circumstances pertinent for the quality of the final product.
4.2. Documents should be designed, prepared, reviewed and distributed with care. They should comply with the relevant parts of the manufacturing and marketing authorization dossiers.
4.3. Documents should be approved, signed and dated by appropriate and authorized persons.
4.4. Documents should have unambiguous contents; title, nature and purpose should be clearly stated. They should be laid out in an orderly fashion and be easy to check. Reproduced documents should be clear and legible. The reproduction of working documents from master documents must not allow any error to be introduced through the reproduction process.
4.5. Documents should be regularly reviewed and kept up-to-date. When a document has been revised, systems should be operated to prevent inadvertent use of superseded documents.
4.6. Documents should not be hand-written; although, where documents require the entry of data, these entries may be made in clear, legible, indelible handwriting. Sufficient space should be provided for such entries.
4.7. Any alteration made to the entry on a document should be signed and dated; the alteration should permit the reading of the original information. Where appropriate, the reason for the alteration should be recorded.
4.8. The records should be made or completed at the time each action is taken and in such a way that all significant activities concerning the manufacture of medicinal products are traceable. They should be retained for at least one year after the expiry date of the finished product.
4.9. Data may be recorded by electronic data processing systems, photographic or other reliable means, but detailed procedures relating to the system in use should be available and the accuracy of the records should be checked. If documentation is handled by electronic data processing methods, only authorized persons should be able to enter or modify data in the computer and there should be a record of changes and deletions; access should be restricted by passwords or other means and the result of entry of critical data should be independently checked. Batch records electronically stored should be protected by back-up transfer on magnetic tape, microfilm, paper or other means. It is particularly important that the data are readily available throughout the period of retention,.
Documents required
4.10. Specifications
There should be appropriately authorized and dated specifications for starting and packaging materials, and finished products; where appropriate, they should be also available for intermediate or bulk products.
Specifications for starting and packaging materials
4.11. Specifications for starting and primary or printed packaging materials should include, if applicable:
a) a description of the materials, including:
- the designated name and the internal code reference;
- the reference, if any, to a pharmacopoeial monograph;
- the approved suppliers and, if possible, the original producer of the products;
- a specimen of printed materials;
b) directions for sampling and testing or reference to procedures;
c) qualitative and quantitative requirements with acceptance limits;
d) storage conditions and precautions;
e) the maximum period of storage before re-examination.
Specifications for intermediate and bulk products
4.12. Specifications for intermediate and bulk products should be available if these are purchased or dispatched, or if data obtained from intermediate products are used for the evaluation of the finished product. The specifications should be similar to specifications for starting materials or for finished products, as appropriate.
Specifications for finished products
4.13. Specifications for finished products should include:
a) the designated name of the product and the code reference where applicable;
b) the formula or a reference to;
c) a description of the pharmaceutical form and package details;
d) directions for sampling and testing or a reference to procedures;
e) the qualitative and quantitative requirements, with the acceptance limits;
f) the storage conditions and any special handling precautions, where applicable;
g) the shelf-life.
Manufacturing Formula and Processing Instructions
Formally authorized Manufacturing Formula and Processing Instructions should exist for each product and batch size to be manufactured. They are often combined in one document.
4.14. The Manufacturing Formula should include:
a) the name of the product, with a product reference code relating to its specification;
b) a description of the pharmaceutical form, strength of the product and batch size;
c) a list of all starting materials to be used, with the amount of each, described using the designated name and a reference which is unique to that material; mention should be made of any substance that may disappear in the course of processing;
d) a statement of the expected final yield with the acceptable limits, and of relevant intermediate yields, where applicable.
4.15. The Processing Instructions should include:
a) a statement of the processing location and the principal equipment to be used;
b) the methods, or reference to the methods, to be used for preparing the critical equipment (e.g. cleaning, assembling, calibrating, sterilizing);
c) detailed stepwise processing instructions (e.g. checks on materials, pretreatments, sequence for adding materials, mixing times, temperatures);
d) the instructions for any in-process controls with their limits;
e) where necessary, the requirements for bulk storage of the products; including the container, labeling and special storage conditions where applicable;
f) any special precautions to be observed.
Packaging Instructions
4.16. There should be formally authorized Packaging Instructions for each product for pack size and type. These should normally include, or have a reference to, the following:
a) name of the product;
b) description of its pharmaceutical form, and strength where applicable;
c) the pack size expressed in terms of the number, weight or volume of the product in the final container;
d) a complete list of all the packaging materials required for a standard batch size, including quantities, sizes and types, with the code or reference number relating to the specifications of each packaging material;
e) where appropriate, an example or reproduction of the relevant printed packaging materials, and specimens indicating where to apply batch number references, and shelf-life of the product;
f) special precautions to be observed, including a careful examination of the area and equipment in order to ascertain the line clearance before operations begin;
g) a description of the packaging operation, including any significant subsidiary operations, and equipment to be used;
h) details of in-process controls with instructions for sampling and acceptance limits.
Batch Processing Records
4.17. A Batch Processing Record should be kept for each batch processed. It should be based on the relevant parts of the currently approved Manufacturing Formula and Processing Instructions. The method of preparation of such records should be designed to avoid transcription errors. The record should carry the number of the batch being manufactured.
Before any processing begins, there should be recorded checks that the equipment and work station are clear of previous products, documents or materials not required for the planned process, and that equipment is clean and suitable for use.
During processing, the following information should be recorded at the time each action is taken and, after completion, the record should be dated and signed in agreement by the person responsible for the processing operations:
a) the name of the product;
b) dates and times of commencement, of significant intermediate stages and of completion of production;
c) name of the person responsible for each stage of production;
d) initials of the operator of different significant steps of production and, where appropriate, of the person who checked each of these operations (e.g. weighing);
e) the batch number and/or analytical control number as well as the quantities of each starting material actually weighed (including the batch number and amount of any recovered or reprocessed material added);
f) any relevant processing operation or event and major equipment used;
g) a record of the in-process controls and the initials of the person(s) carrying them out, and the results obtained;
h) the amount of product yield obtained at different and pertinent stages of manufacture;
i) notes on special problems including details, with signed authorization for any deviation from the Manufacturing Formula and Processing Instructions.
Batch Packaging Records
4.18. A Batch Packaging Record should be kept for each batch or part batch processed. It should be based on the relevant parts of the Packaging Instructions and the method of preparation of such records should be designed to avoid transcription errors. The record should carry the batch number and the quantity of bulk product to be packed, as well as the batch number and the planned quantity of finished product that will be obtained. Before any packaging operation begins, there should be recorded checks that the equipment and work station are clear of previous products, documents or materials not required for the planned packaging operations, and that equipment is clean and suitable for use. The following information should be entered at the time each action is taken and, after completion, the record should be dated and signed in agreement by the person(s) responsible for the packaging operations:
a) the name of the product;
b) the date(s) and times of the packaging operations;
c) the name of the responsible person carrying out the packaging operation;
d) the initials of the operators of the different significant steps;
e) records of checks for identity and conformity with the Packaging Instructions including the results of in-process controls;
f) details of the packaging operations carried out, including references to equipment and the packaging lines used; g) whenever possible, samples of printed packaging materials used, including specimens of the batch coding, expiry dating and any additional overprinting;
h) notes on any special problems or unusual events including details with signed authorization for any deviation from the Manufacturing Formula and Processing Instructions;
i) the quantities and reference number or identification of all printed packaging materials and bulk product issued, used, destroyed or returned to stock and the quantities of obtained product, in order to provide for an adequate reconciliation.
Procedures and records
Receipt
4.19. There should be written procedures and records for the receipt of each delivery of each starting and primary and printed packaging material.
4.20. The records of the receipts should include:
a) the name of the material on the delivery note and the containers;
b) the "in-house" name and/or code of material (if different from a);
c) date of receipt;
d) supplier's name and, if possible, manufacturer's name;
e) manufacturer's batch or reference number;
f) total quantity, and number of containers received;
g) the batch number assigned after receipt;
h) any relevant comment (e.g. state of the containers).
4.21. There should be written procedures for the internal labeling, quarantine and storage of starting materials, packaging materials and other materials, as appropriate.
Sampling
4.22. There should be written procedures for sampling, which include the person(s) authorized to take samples, the methods and equipment to be used, the amounts to be taken and any precautions to be observed to avoid contamination of the material or any deterioration in its quality (see Chapter 6, Item 13).
Testing
4.23. There should be written procedures for testing materials and products at different stages of manufacture, describing the methods and equipment to be used. The tests performed should be recorded (see Chapter 6, Item 17).
Other
4.24 Written release and rejection procedures should be available for materials and products, and in particular for the release for sale of the finished product by the authorized person(s) designated for the purpose.
4.25. Records should be maintained of the distribution of each batch of a product in order to facilitate the recall of the batch if necessary (see Chapter 8).
4.26. There should be written procedures and the associated records of actions taken or conclusions reached, where appropriate, for:
- validation;
- equipment assembly and calibration;
- maintenance, cleaning and sanitization;
- personnel matters including training, clothing, hygiene;
- environmental monitoring;
- pest control;
- complaints;
- recalls;
- returns.
4.27. Clear operating procedures should be available for major items of manufacturing and test equipment.
4.28. Log books should be kept for major or critical equipment recording, as appropriate, any validations, calibrations, maintenance, cleaning or repair operations, including the dates and identity of people who carried these operations out.
4.29. Log books should also record in chronological order the use of major or critical equipment and the areas where the products have been processed.

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C H A P T E R 3 - PREMISES AND EQUIPMENT

Principle
Premises and equipment must be located, designed, constructed, adapted and maintained to suit the operations to be carried out. Their layout and design must aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build up of dust or dirt and, in general, any adverse effect on the quality of products.
PREMISES
General
3.1. Premises should be situated in an environment which, when considered together with measures to protect the manufacture, presents minimal risk of causing contamination of materials or products.
3.2. Premises should be carefully maintained, ensuring that repair and maintenance operations do not present any hazard to the quality of products. They should be cleaned and, where applicable, disinfected according to detailed written procedures.
3.3. Lighting, temperature, humidity and ventilation should be appropriate and such that they do not adversely affect, directly or indirectly, either the medicinal products during their manufacture and storage, or the accurate functioning of equipment.
3.4. Premises should be designed and equipped so as to afford maximum protection against the entry of insects or other animals.
3.5. Steps should be taken in order to prevent the entry of unauthorized people. Production, storage and quality control areas should not be used as a right of way by personnel who do not work in them.
Production Area
3.6. In order to minimize the risk of a serious medical hazard due to cross-contamination, dedicated and self-contained facilities must be available for the production of particular medicinal products, such as highly sensitizing materials (e.g. penicillins) or biological preparations (e.g. from live micro-organisms). The production of certain additional products, such as certain antibiotics, certain hormones, certain cytotoxics, certain highly active drugs and non-medicinal products should not be conducted in the same facilities. For those products, in exceptional cases, the principle of campaign working in the same facilities can be accepted provided that specific precautions are taken and the necessary validations are made. The manufacture of technical poisons, such as pesticides and herbicides, should not be allowed in premises used for the manufacture of medicinal products.
3.7. Premises should preferably be laid out in such a way as to allow the production to take place in areas connected in a logical order corresponding to the sequence of the operations and to the requisite cleanliness levels.
3.8. The adequacy of the working and in-process storage space should permit the orderly and logical positioning of equipment and materials so as to minimize the risk of confusion between different medicinal products or their components, to avoid cross-contamination and to minimize the risk of omission or wrong application of any of the manufacturing or control steps.
3.9. Where starting and primary packaging materials, intermediate or bulk products are exposed to the environment, interior surfaces (walls, floors and ceilings) should be smooth, free from cracks and open joints, and should not shed particulate matter and should permit easy and effective cleaning and, if necessary, disinfection.
3.10. Pipe work, light fittings, ventilation points and other services should be designed and sited to avoid the creation of recesses which are difficult to clean. As far as possible, for maintenance purposes, they should be accessible from outside the manufacturing areas.
3.11. Drains should be of adequate size, and have trapped gullies. Open channels should be avoided where possible, but if necessary, they should be shallow to facilitate cleaning and disinfection.
3.12. Production areas should be effectively ventilated, with air control facilities (including temperature and, where necessary, humidity and filtration) appropriate both to the products handled, to the operations undertaken within them and to the external environment.
3.13. Weighing of starting materials usually should be carried out in a separate weighing room designed for that use.
3.14. In cases where dust is generated (e.g. during sampling, weighing, mixing and processing operations, packaging of dry products), specific provisions should be taken to avoid cross-contamination and facilitate cleaning.
3.15. Premises for the packaging of medicinal products should be specifically designed and laid out so as to avoid mix-ups or cross-contamination.
3.16. Productions areas should be well lit, particularly where visual on-line controls are carried out.
3.17. In-process controls may be carried out within the production area provided they do not carry any risk for the production.
Storage Areas
3.18. Storage areas should be of sufficient capacity to allow orderly storage of the various categories of materials and products: starting and packaging materials, intermediate, bulk and finished products, products in quarantine, released, rejected, returned or recalled.
3.19. Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean and dry and maintained within acceptable temperature limits. Where special storage conditions are required (e.g. temperature, humidity) these should be provided, checked and monitored.
3.20. Receiving and dispatch bays should protect materials and products from the weather. Receptions areas should be designed and equipped to allow containers of incoming materials to be cleaned where necessary before storage.
3.21. Where quarantine status is ensured by storage in separate areas, these areas must be clearly marked and their access restricted to authorized personnel. Any system replacing the physical quarantine should give equivalent security.
3.22. There should normally be a separate sampling area for starting materials. If sampling is performed in the storage area, it should be conducted in such a way as to prevent contamination or cross-contamination.
3.23. Segregated areas should be provided for the storage of rejected, recalled or returned materials or products.
3.24. Highly active materials or products should be stored in safe and secure areas.
3.25. Printed packaging materials are considered critical to the conformity of the medicinal products and special attention should be paid to the safe and secure storage of these materials.
Quality Control Areas
3.26. Normally, Quality Control laboratories should be separated from production areas. This is particularly important for laboratories for the control of biologicals, microbiologicals and radioisotopes, which should also be separated from each other.
3.27. Control laboratories should be designed to suit the operations to be carried out in them. Sufficient space should be given to avoid mix-ups and cross-contamination. There should be adequate suitable storage space for samples and records.
3.28. Separate rooms may be necessary to protect sensitive instruments from vibration, electrical interference, humidity, etc.
3.29. Special requirements are needed in laboratories handling particular substances, such as biological or radioactive samples.
Ancillary Areas
3.30. Rest and refreshment rooms should be separate from other areas.
3.31. Facilities for changing clothes, and for washing and toilet purposes should be easily accessible and appropriate for the number of users. Toilets should not directly communicate with production or storage areas.
3.32. Maintenance workshops should as far as possible be separated from production areas. Whenever parts and tools are stored in the production area, they should be kept in rooms or lockers reserved for that use.
3.33. Animal houses should be well isolated from other areas, with separate entrance (animal access) and air handling facilities.
EQUIPMENT
3.34. Manufacturing equipment should be designed, located and maintained to suit its intended purpose.
3.35. Repair and maintenance operations should not present any hazard to the quality of the products.
3.36. Manufacturing equipment should be designed so that it can be easily and thoroughly cleaned. It should be cleaned according to detailed and written procedures and stored only in a clean and dry condition.
3.37. Washing and cleaning equipment should be chosen and used in order not to be a source of contamination.
3.38. Equipment should be installed in such a way as to prevent any risk of error or of contamination.
3.39. Production equipment should not present any hazard to the products. The parts of the production equipment that come into contact with the product must not be reactive, additive or absorptive to such an extent that it will affect the quality of the product and thus present any hazard.
3.40. Balances and measuring equipment of an appropriate range and precision should be available for production and control operations.
3.41. Measuring, weighing, recording and control equipment should be calibrated and checked at defined intervals by appropriate methods. Adequate records of such tests should be maintained.
3.42. Fixed pipe-work should be clearly labeled to indicate the contents and, where applicable, the direction of flow.
3.43. Distilled, deionized and, where appropriate, other water pipes should be sanitized according to written procedures that detail the action limits for microbiological contamination and the measures to be taken.
3.44. Defective equipment should, if possible, be removed from production and quality control areas, or at least be clearly labeled as defective.
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C H A P T E R 2 - PERSONNEL

Principle

The establishment and maintenance of a satisfactory system of quality assurance and the correct manufacture of medicinal products relies upon people. For this reason there must be sufficient qualified personnel to carry out all the tasks which are the responsibility of the manufacturer. Individual responsibilities should be clearly understood by the individuals and recorded. All personnel should be aware of the principles of Good Manufacturing Practice that affect them and receive initial and continuing training, including hygiene instructions, relevant to their needs.

General

2.1. The manufacturer should have an adequate number of personnel with the necessary qualifications and practical experience. The responsibilities placed on any one individual should not be so extensive as to present any risk to quality.

2.2. The manufacturer must have an organization chart. People in responsible positions should have specific duties recorded in written job descriptions and adequate authority to carry out their responsibilities. Their duties may be delegated to designated deputies of a satisfactory qualification level. There should be no gaps or unexplained overlaps in the responsibilities of those personnel concerned with the application of Good Manufacturing Practice.

Key Personnel

2.3. Key Personnel includes the head of Production, the head of Quality Control, and if at least one of these persons is not responsible for the release of products the authorized person(s) designated for the purpose. Normally key posts should be occupied by full-time personnel. The heads of Production and Quality Control must be independent from each other. In large organizations, it may be necessary to delegate some of the functions listed in 2.5., 2.6. and 2.7.

2.4. ...

2.5. The head of the Production Department generally has the following responsibilities:

i. to ensure that products are produced and stored according to the appropriate documentation in order to obtain the required quality; ii. to approve the instructions relating to production operations and to ensure their strict implementation;

iii. to ensure that the production records are evaluated and signed by an authorized person before they are sent to the Quality Control Department;

iv. to check the maintenance of his department, premises and equipment;

v. to ensure that the appropriate validations are done;

vi. to ensure that the required initial and continuing training of his department personnel is carried out and adapted according to need.

2.6. The head of the Quality Control Department generally has the following responsibilities:

i. to approve or reject, as he sees fit, starting materials, packaging materials, and intermediate, bulk and finished products;

ii. to evaluate batch records;

iii. to ensure that all necessary testing is carried out;

iv. to approve specifications, sampling instructions, test methods and

other Quality Control procedures;

v. to approve and monitor any contract analysts;

vi. to check the maintenance of his department, premises and equipment;

vii. to ensure that the appropriate validations are done;

viii. to ensure that the required initial and continuing training of his department personnel is carried out and adapted according to need. Other duties of the Quality Control Department are summarized in Chapter 6.

2.7. The heads of Production and Quality Control generally have some shared, or jointly exercised, responsibilities relating to quality. These may include, subject to any national regulations:

- the authorization of written procedures and other documents, including amendments;

- the monitoring and control of the manufacturing environment;

- plant hygiene;

- process validation;

- training;

- the approval and monitoring of suppliers of materials;

- the approval and monitoring of contract manufacturers;

- the designation and monitoring of storage conditions for materials and products;

- the retention of records;

- the monitoring of compliance with the requirements of GMP;

- the inspection, investigation, and taking of samples, in order to monitor factors which may affect product quality.

Training

2.8. The manufacturer should provide training for all the personnel whose duties take them into production areas or into control laboratories (including the technical, maintenance and cleaning personnel), and for other personnel whose activities could affect the quality of the product.

2.9. Beside the basic training on the theory and practice of Good Manufacturing Practice, newly recruited personnel should receive training appropriate to the duties assigned to them. Continuing training should also be given, and its practical effectiveness should be periodically assessed. Training programs should be available, approved by either the head of Production or the head of Quality Control, as appropriate. Training records should be kept.

2.10. Personnel working in areas where contamination is a hazard, e.g. clean areas or areas where highly active, toxic, infectious or sensitizing materials are handled, should be given specific training.

2.11. Visitors or untrained personnel should, preferably, not be taken into the production and Quality Control areas. If this is unavoidable, they should be given information in advance, particularly about personal hygiene and the prescribed protective clothing. They should be closely supervised.

2.12. The concept of Quality Assurance and all the measures capable of improving its understanding and implementation should be fully discussed during the training sessions.

Personal Hygiene

2.13. Detailed hygiene programs should be established and adapted to the different needs within the factory. They should include procedures relating to the health, hygiene practices and clothing of personnel. These procedures should be understood and followed in a very strict way by every person whose duties take him into the production and control areas. Hygiene programs should be promoted by management and widely discussed during training sessions.

2.14. All personnel should receive medical examination upon recruitment. It must be the manufacturer's responsibility that there are instructions ensuring that health conditions that can be of relevance to the quality of products come to the manufacturer's knowledge. After the first medical examination, examinations should be carried out when necessary for the work and personal health.

2.15. Steps should be taken to ensure as far as is practicable that no person affected by an infectious disease or having open lesions on the exposed surface of the body is engaged in the manufacture of medicinal products.

2.16. Every person entering the manufacturing areas should wear protective garments appropriate to the operations to be carried out.

2.17. Eating, drinking, chewing or smoking, or the storage of food, drink, smoking materials or personal medication in the production and storage areas should be prohibited. In general, any unhygienic practice within the manufacturing areas or in any other area where the product might be adversely affected, should be forbidden.

2.18. Direct contact should be avoided between the operator's hands and the exposed product as well as with any part of the equipment that comes into contact with the products.

2.19. Personnel should be instructed to use the hand-washing facilities.

2.20. Any specific requirements for the manufacture of special groups of products, for example sterile preparations, are covered in the Supplementary Guidelines.

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C H A P T E R 1 - QUALITY MANAGEMENT

Principle
The holder of a manufacturing authorization must manufacture medicinal products so as to ensure that they are fit for their intended use, comply with the requirements of the marketing authorization and do not place patients at risk due to inadequate safety, quality or efficacy. The attainment of this quality objective is the responsibility of senior management and requires the participation and commitment by staff in many different departments and at all levels within the company, by the company's suppliers and by the distributors. To achieve the quality objective reliably there must be a comprehensively designed and correctly implemented system of Quality Assurance Incorporating Good Manufacturing Practice and thus Quality Control. It should be fully documented and its effectiveness monitored. All parts of the Quality Assurance systems should be adequately resourced with competent personnel, and suitable and sufficient premises, equipment and facilities. There are additional legal responsibilities for the holder of the manufacturing authorization and for the authorized person(s).
1.1. The basic concepts of Quality Assurance, Good Manufacturing Practice and Quality Control are inter-related. They are described here in order to emphasize their relationships and their fundamental importance to the production and control of medicinal products.
Quality Assurance
1.2. Quality Assurance is a wide ranging concept which covers all matters which individually or collectively influence the quality of a product. It is the sum total of the organized arrangements made with the object of ensuring that medicinal products are of the quality required for their intended use. Quality Assurance therefore incorporates Good Manufacturing Practice plus other factors outside the scope of this Guide.
The system of Quality Assurance appropriate for the manufacture of medicinal products should ensure that: i. medicinal products are designed and developed in a way that takes account of the requirements of Good Manufacturing Practice and
Good Laboratory Practice; ii. Production and control operations are clearly specified and Good Manufacturing Practice adopted; iii. Managerial responsibilities are clearly specified; iv. arrangements are made for the manufacture, supply and use of the correct starting and packaging materials; v. all necessary controls on intermediate products, and any other inprocess controls and validations are carried out; vi. the finished product is correctly processed and checked, according to the defined procedures; vii. medicinal products are not sold or supplied before an authorized person has certified that each production batch has been produced and controlled in accordance with the requirements of the marketing authorization and any other regulations relevant to the production, control and release of medicinal products; viii. satisfactory arrangements exist to ensure, as far as possible, that the medicinal products are stored, distributed and subsequently handled so that quality is maintained throughout their shelf life;
ix. there is a procedure for self-inspection and/or quality audit which regularly appraises the effectiveness and applicability of the quality assurance system.
Good Manufacturing Practice for Medicinal products (GMP)
1.3. Good Manufacturing Practice is that part of Quality Assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization or product specification.
Good Manufacturing Practice is concerned with both production and quality control. The basic requirements of GMP are that; i. all manufacturing processes are clearly defined, systematically reviewed in the light of experience and shown to be capable of consistently manufacturing medicinal products of the required quality and complying with their specifications:
ii. critical steps of manufacturing processes and significant changes to the process are validated;
iii. all necessary facilities for GMP are provided including:
a. appropriately qualified and trained personnel;
b. adequate premises and space;
c. suitable equipment and services;
d. correct materials, containers and labels;
e. approved procedures and instructions;
f. suitable storage and transport;
iv. instructions and procedures are written in an instructional
form in clear and unambiguous language, specifically applicable to the facilities provided;
v. operators are trained to carry out procedures correctly;
vi. records are made, manually an/or by recording instruments, during manufacture which demonstrate that all the steps required by the defined procedures and instructions were in fact taken and that the quantity and quality of the product was as expected. Any significant deviations are fully recorded and investigated;
vii. records of manufacture including distribution which enable the complete history of a batch to be traced are retained in a comprehensible and accessible form;
viii. the distribution (wholesaling) of the products minimizes any risk to their quality; ix. a system is available to recall any batch of product, from sale or supply; x. complaints about marketed products are examined, the causes of quality defects investigated and appropriate measures taken in respect of the defective products and to prevent re-occurrence.
Quality Control
1.4. Quality Control is that part of Good Manufacturing Practice which is concerned with sampling, specifications and testing, and with the organization, documentation and release procedures which ensure that the necessary and relevant tests are actually carried out and that materials are not released for use, nor products released for sale or supply, until their quality has been judged to be satisfactory.
The basic requirements of Quality Control are that:
i. adequate facilities, trained personnel and approved procedures are available for sampling, inspecting and testing starting materials, packaging materials, intermediate, bulk, and finished products, and where appropriate for monitoring environmental conditions for GMP purposes;
ii. samples of starting materials, packaging materials, intermediate products, bulk products and finished products are taken by personnel and by methods approved by Quality Control;
iii. test methods are validated;
iv. records are made, manually and/or by recording instruments which demonstrate that all the required sampling, inspecting and testing procedures were actually carried out. Any deviations are fully recorded and investigated;
v. the finished products contain active ingredients complying with the
qualitative and quantitative composition of the marketing authorization, are of the purity required, and are enclosed within their proper container and correctly labeled;
vi. records are made of the results of inspection and that testing of materials, intermediate, bulk, and finished products is formally assessed against specification. Product assessment includes a review and evaluation of relevant production documentation and an assessment of deviations from specified procedures;
vii. no batch of product is released for sale or supply prior to certification by an authorized person that it is in accordance with the requirements of the marketing authorization;
viii. sufficient reference samples of starting materials and products are retained to permit future examination of the product if necessary and that the product is retained in its final pack unless exceptionally large packs are produced.

DIAGNOSIS, TREATMENT AND PREVENTION OF LARYNGITIS

Diagnosing Laryngitis

Laryngitis is often a symptom of some other health problem, so finding out its root cause is the first step to getting better. If your doctor finds no other health problems, knowing why your throat is inflamed means you can take steps to avoid getting laryngitis in the future. When hoarseness is accompanied by a weak voice and lasts more than two weeks, your doctor may want to do a test on your throat to rule out cancer, especially if you're a smoker. This test, called a laryngoscopy, involves your doctor directly looking at your voice box with a mirror or a small flexible scope which goes down your nose.

Treating and Preventing Laryngitis

If your laryngitis comes from straining your voice, resting it and breathing in steam will probably ease the pain and inflammation and help you recover. On the other hand, if your laryngitis is a symptom of an infection, it won't go away until the infection clears up. If the laryngitis is caused by bronchitis or another bacterial infection, antibiotics may be needed and corticosteroids may be prescribed to stop the inflammation. Most infections are caused by viruses and do not require antibiotics. When acid reflux or allergies are the source of irritation, bringing these conditions under control will make you feel better quickly.

Avoiding voice strain and irritants is the best way to prevent simple attacks of laryngitis. If you get a cold or flu and it feels like you are getting laryngitis as well, avoid things that irritate your throat. Remember to pace yourself and try not to push your voice by talking if you don't have to. These steps may help to stop your laryngitis in its tracks. Quitting smoking is another important way to treat both acute and chronic laryngitis.

LARYNGITIS, CAUSES, SYMPTOMS, COMPLICATIONS

Laryngitis occurs when the part of the throat called the larynx becomes inflamed. When this happens, it causes a severe hoarseness that can make your voice "croak" or have to whisper when you talk. It can even lead to temporary loss of your voice. The inflammation is very common - most people have experienced it at one time or another - and is really a symptom that's been caused by some other factor or condition. Yelling too enthusiastically at a hockey game can cause it, but so can viral and bacterial infections or other illnesses. Finding out the real cause of laryngitis is an important part of getting your voice back. There are two types of laryngitis: acute and chronic.

Causes of Laryngitis

Acute laryngitis refers to hoarseness or loss of voice that appears suddenly after a night of singing and shouting, or being exposed to a lot of cigarette smoke. This condition usually improves when you avoid whatever has been irritating the throat (like cigarettes) and and when you rest your voice. The common cold and influenza (the flu) are common causes of acute laryngitis, but it can also be a symptom of bronchitis, pneumonia, and measles. Hoarseness may also be part of an allergic reaction.

Chronic laryngitis lasts longer than a week, and comes back over time. This condition can involve permanent changes in the lining of the throat. These changes could be due to repeated attacks of acute laryngitis like those sometimes experienced by professional singers, or happen because of repeated exposure to smoke, dust, dryness, or other irritants. Chronic laryngitis can also be caused by allergies and post-nasal drip or gastroesophageal reflux disorder (when harsh stomach acids rise up into the esophagus and cause burning). Rarer causes of chronic laryngitis include cancer of the throat, non-cancerous tumours on the vocal cords, and non-cancerous wart-like lesions called papillomas that grow in the throat.

Symptoms and Complications of Laryngitis

Many people with laryngitis get very hoarse or even lose their voice for a short time. You may feel a tickling or rawness in your throat and experience a constant need to clear it. Symptoms vary with how badly the throat is inflamed.

When other symptoms accompany the laryngitis - such as fever, general aches and pains, and throat pain - a viral or bacterial infection usually the culprit.

ALLERGIC DISEASE TREATMENT

Treatment of allergic disease is limited to only five choices:

1. Ignore the symptoms. This is fine if the allergic problem is minimal in nature.

2. Avoid the offending allergens. This is accomplished by cleaning up the environment for allergens and avoiding places where allergens occur naturally.

For Pollen: Close windows to keep pollen out and stay indoors as much as possible. Use air conditioning, both in you home and car. Participate in outdoor activities when the pollen counts are lowest.

For Dust Mites: Steam clean carpeting. Replace old or musty carpeting. Use a central vacuum or a regular vacuum with a HEPA filter. Wash pillows, sheets/pillowcases, comforters, bedspreads, stuffed animals, and clothing regularly-- 130ºF soapy water kills mites best. Do not leave piles of previously worn clothing in the bedroom. Cover mattresses and pillows with mite-impermeable covers. Clean out furnace ducts-- place filters over vents in the bedroom especially. Avoid fabric headboards and fancy drapes that require drycleaning.

For Mold: Fix leaky roofs or plumbing. Fix leaky showers and repair/replace moldy walls around showers, tubs, and toilets. Flush out overflow drains for sinks and tubs with bleach. Clean out the drain pan for the self-defrosting refrigerator. Make sure water drains away from your house adequately. Use a dehumidifier in the basement. Hose down concrete areas with dilute bleach or borax. Store items in plastic bins instead of cardboard boxes. Avoid using swamp coolers to decrease the temperature in your house. Dry out the mold in your automobile air conditioning ducts by turning the heat on high for a few minutes before getting in the car and then switching to air conditioning. Avoid dryer sheets and complicated cleaning chemicals. Decrease mold/yeast containing foods in the diet.

For Animals: Bathe pets regularly; give them away if absolutely necessary. Wash with animal shampoo. For cats, Dawn dishwashing liquid can be used to wash most cats. Keep animals out of bedrooms. Avoid sleeping with them.

Cleaning up the environment for allergens takes a fair amount of time and effort, but it is worthwhile.

3. Use antihistamines with or without decongestants. They prevent/decrease the tissue swelling from occurring with an allergic reaction. The newer ones are non-sedating. Regular use is required for best. Remember: The use of antihistamines when driving a car is as dangerous as drinking alcohol and driving!! There are only a few antihistamines that are considered to be TRULY non-sedating by the FDA.

4.Use Cortisone products. Corisone block the allergic reaction in a different way from antihistamines. Pill and spray forms are used to treat nasal, throat, and lung problems. Sprays are not generally absorbed systemically, so they are quite safe for nasal or pulmonary use. Systemic cortisone use usually has significant risks only if used for more than several weeks. The rare, random, serious risks of cortisone use, like aseptic necrosis of the hip, can occur after only dose of a systemic cortisone product.

5. Take allergy shots. Desensitization involves having small amounts of the allergens to which a person is allergic injected into the fat of the arm in slowly increasing doses, causing the body to develop a tolerance to these allergens. Starting with a small dose that has been deemed to be low enough so as not to cause a reaction, the dose is increased gradually over several months. During that time, symptoms generally diminish slowly. Treatment is usually necessary for several years (3-10). Shots start at 1 week intervals and gradually are stretched to 3-4 week intervals. The improvement in symptoms and quality of life is generally worth the effort and expense. Patients who have such diseases as chronic sinusitis that has required one or more surgeries generally require desensitization for optimal control. Because there is always a risk of an adverse reaction to any allergy shot (including asthmatic or anaphylactic reactions), a 20-30 minute wait in the office is required after the allergy shot. Shots may be administered in the office of the allergist or the office of most family physicians.

ALLERGY, ALLERGEN, ANTIGEN-ANTIBODY COMPLEXES

Allergic disease of the ear, nose, and throat areas presents itself in many ways. The most common allergic symptoms are congestion, runny nose, postnasal drip, watery eyes, and itching of the eyes or throat. Ear infections and sinus infections are often aggravated by allergies. Less commonly, hives, headaches, and Menière's disease can be caused or aggravated by allergies. People who cannot breathe through their noses adequately because of allergies do not sleep well, either. That can cause or aggravate sleep apnea which increases the risk of heart attacks in folks over 50, causing death in some.

Simple allergic reactions involve an allergen (Ragweed, dust mite, cat, etc) finding an antibody in the nose, mouth, or throat and creating antigen-antibody complexes, triggering the immediate release of histamine which causes congestion, itching, etc. Less common allergic reactions involve blood compliment or fixed tissue reactions, which are often delayed in onset, prolonged in duration, and involve parts of the body other than the nose, throat, and lungs. Mild allergic reactions are usually treated symptomatically with antihistamines or nasal sprays and don't require identifying the offending allergens. As allergic reactions get worse and interfere more with daily life, the need to identify the offending allergens becomes greater and treatment becomes more prolonged, more complicated, and more specific. Allergy testing is usually done either as a skin test or a blood test (RAST). Skin testing involves placement of a small amount of allergen in the skin of the arm, creating small wheals (bumps). These wheals are then observed for 10 minutes and the change in size and color is recorded. Inhaled allergens cause acute reactions that go away within a few hours with the exception of molds, which can create acute and/or delayed reactions. Delayed mold reactions, usually dark red bumps that occur 24-72 hours after the skin test was placed, are often important. Notify your allergist if you note delayed reactions to skin tests that were placed one or more days earlier.When you are scheduled for skin testing: Wear a short sleeved shirt. Make sure you have been off all drugs that might interfere with skin testing for an adequate period of time. This includes antihistamines, many antidepressants, and certain anti-acid stomach medications. Ask about your current medications when scheduling your appointment for skin testing. Check with the doctor who put you on antidepressants before stopping antidepressant medications! Make sure toe doctor know if you are on a beta blocker for any reason. Skin testing is not usually done on someone on a beta blocker.

Allergic disease of the head and neck presents itself in many ways. The most common allergic symptoms are congestion, runny nose, postnasal drip, watery eyes, and itching of the eyes or throat. Ear infections and sinus infections are often aggravated by allergies. Less commonly, hives, headaches, and Menière's disease can be caused or aggravated by allergies. People who cannot breathe through their noses adequately because of allergies do not sleep well, either. That can cause or aggravate sleep apnea which significantly increases the risk of heart attacks in folks over 50, causing death in some. Simple allergic reactions involve an allergen (Ragweed, dust mite, cat, etc) finding an antibody in the nose, mouth, or throat and creating antigen-antibody complexes, triggering the immediate release of histamine which causes congestion, itching, etc. Less common allergic reactions involve blood compliment or fixed tissue reactions. The latter create symptoms which are often delayed in onset, prolonged in duration, and involve parts of the body other than the head and chest. Mild allergic reactions are usually treated symptomatically with antihistamines or nasal sprays and don’t require identifying the offending allergens. As allergic reactions get worse and interfere more with daily life, the need to identify the offending allergens becomes greater and treatment becomes more prolonged, more complicated, and more specific.

Allergy testing is usually done either as a skin test or a blood test (RAST). Skin testing involves placement of a small amount of allergen in the skin of the arm, creating small wheals (bumps). These wheals are then observed for 10 minutes and the change in size and color is recorded. Inhaled allergens cause acute reactions that go away within a few hours with the exception of molds, which can create acute and/or delayed reactions. Delayed mold reactions, usually dark red bumps that occur 24-72 hours after the skin test was placed, are usually important. Notify your allergist if you note delayed reactions to skin tests that were placed one or more days earlier. RAST testing determines the amount of immunoglobulin E present in the blood for specific antigens. It is less invasive than skin tests, it doesn’t require the patient to be off medications, and it does not involve much of the patient’s time. Not all allergens, especially molds, can be tested accurately using RAST, so it cannot totally replace skin testing. If you are scheduled for skin testing: Wear a short sleeved shirt. Make sure you have been off all drugs that might interfere with skin testing for an adequate period of time. This includes antihistamines, many antidepressants, and certain anti-acid stomach medications. Ask about your current medications when scheduling your appointment for skin testing. Check with the doctor who put you on antidepressants before stopping those medications!

SINUSITIS DISEASE

Sinus disease is very common in industrialized countries. It contributes to significant respiratory disease, which is one of the largest causes of work loss in the United States.  It causes significant illness, including congestion, headaches, post-nasal drainage, and nasal polyps. Complications of sinus disease include face, eye, and brain abscesses, nerve injury to any of the cranial nerves(nerves to the face and head) near the sinuses, local bone destruction, spinal fluid leaks, and sometimes even death.

Proper treatment of sinus infections is necessary to prevent complications and decrease morbidity. Your otolaryngologist is the best trained physician/surgeon to diagnose and treat sinus problems. Early consultation with an otolaryngologist will help prevent the irreversible changes in the sinus mucosa and bone that occur when infection has been present for a long period of time.

Sinus disease is integrally related to multiple disease processes and environmental factors that affect the head and neck. Anatomical problems that interfere with a normal air flow and proper sinus drainage cause and aggravate sinus disease. Nasal septal deviation and anatomical abnormalities from old facial fractures are only two of these causes. Allergies, especially dust mite, mold, and animal allergy cause nasal swelling that interferes with normal air flow, obstructs sinus openings, and causes excessive mucous production that aggravates infection. GERD, gastrointestinal reflux disease, may also aggravate sinus disease. Sinus disease associated with nasal polyp formation is aggravated by the use of aspirin or aspirin-containing products, including the tartrazine dyes (yellow dye #5). Smoking also aggravates sinus disease.

Sinus disease occurs in several forms, but all are related to a combination of infection and the inability of air to get into sinus cavities from the nose. Similar to the ear and mastoid , the sinuses are air-filled spaces surrounded by thin bone and lined by mucosa. When the air is absorbed by the mucosa faster than air can get through the sinus openings (ostia) into the sinuses, a relative vacuum develops and fluid is pulled from the lining tissues of the sinuses into the sinus cavities.  This fluid easily becomes infected.  Allergy causes mucous glands to release thicker fluids (mucous), which can also become infected and which are harder to clean from the sinuses. Besides the toxic effect on the nasal tissues from the carcinogens in cigarette smoke, cigarette smoke paralyzes the hairs of the cilia of the nasal and sinus mucosa that move the mucous your nose normally produces into your throat. When normal mucous does not flow from your nose into your throat, it becomes infected more easily and adds to a "downward spiral" of problems that causes full-blown sinus disease.

Sinus surgery, opening the sinus cavities so air can reach the mucosa in a "functional" way, allows reversal of the disease process as long as the mucosal and bone of the sinuses has not been too badly damaged by the infections. FESS (Functional Endoscopic Sinus Surgery) has revolutionized sinus surgery. It has increased the completeness of disease removal at the same time as it has allowed simpler and less invasive procedures to eliminate the sinus infections/disease. Short endoscopes pass light into the nose and sinuses and magnify the field for the surgeon, allowing state of the art instruments to open the small sinus cavities and remove disease with the least surgical trauma to the remaining bone and mucosa. Less packing is needed with this kind of sinus surgery and there is less postoperative pain and drainage.

Control of allergic disease is imperative if sinus disease is to be cured and if reinfection is to be prevented. Allergy shots (desensitization) for dust mites, molds, and cat are often indicated if sinus disease is to be well controlled. Nasal steroid sprays help decrease nasal edema and open up sinus ostia, as well.

Chronic sinus disease may cause or aggravate nasal congestiion problems that can make sleep apnea worse. It can also cause problems that limit a patients ability to use CPAP on a consistent basis.

Gastrointestinal reflux (GERD) can irritate the lining of the throat, mouth, voice box, upper trachea (windpipe) as well as the back of the nose, the adjacent sinuse, and the openings ofthe eustacian tubes to the ears.. Reflux often occurs during the night when a person lies flat, but it can also occur during the day. It is a MAJOR factor causing and aggravating ear, nose, and throat diseases. Control of GERD is imperative.

Control of fungus infection in the nose and sinuses is often necessary to clear sinus infections and prevent their recurrence. Ask your otolaryngologist about this.

RESULT CALCULATIONS (KARL FISCHER METHOD)

The titrator automatically calculates the water content of the sample in the chosen
units. The drift measured from the start of the titration, the quantity of water introduced
by the solvent and the dilution parameters are also taken into account during
calculations. If a series of measurements is performed, the titrator will calculate the
mean value, the standard deviation and the uncertainty on the mean value.
The user is able to accept or refuse the last result obtained and check the impact it
might have on the mean result. A rejected result will remain in the GLP table with
the indication “rejected”.
Finally, the titrator includes specific QC parameter setting together with High-Low
alarms to help operators make the right choice in reviewing results.

GOOD LABORATORY PRACTICE (KARL FISCHER METHOD)

General remarks
Performing Karl Fischer titrations is more demanding than other volumetric titrations.
Radiometer Analytical titrators guide the user step-by-step to ensure reliable and
reproducible results are obtained every time.
The main difficulties of a Karl Fischer titration are:
• The omnipresence of water in the atmosphere. Leakage of water and
vapour in the cell during the titration will lead to an erroneous result.
Radiometer Analytical has designed a titration stand which is easy to use and
ensures operation without contact with the external atmosphere. An
electronically driven pump allows addition of solvent and emptying of the cell
without any leakage. The user should inspect the desiccant tubes regularly
and replace the desiccant when saturated.
• Side reactions will be detrimental to the accuracy of the titration. For example,
the reaction with iodine (ketones and aldehydes) or reactions which inhibit
the response of the indicating electrodes. In the first case, a specific reagent
should be used to reduce the influence of these side reactions and in the
latter, an oven is required.
The KF titration cell
It is recommended to always leave the cell on stand by, i.e. the titrator measures the
effect of ambient humidity during conditioning so that the KF cell is ready for
immediate use.
The built-in electronically driven pump assures the draining of the KF cell. In this
way, exchanges with ambient humidity as well as solvent handling are avoided.
Start the pump then press the emptying button. When the cell is empty, release the
button then stop the pump. To add solvent, start the pump then hold the solvent
button down until the solvent reaches the level marked on the cell.
The KF titration cell should be completely disassembled if not being used for
longer periods of time. The parts should be washed in methanol and then dried.
The parts can also be dried in an oven. The temperature of the oven must not
exceed 50°C. Higher temperatures are not recommended as this can lead to
deformation of plastic parts.
Stirring speed
The stirring speed should be selected to ensure a rapid mixing of the reagent
added, without introducing an excessive amount of air into the solution. Insufficient
stirring can easily lead to an over-titration whereas excessive stirring may disturb
the response of the electrodes.
Delivery tip and indicating electrode
The delivery tip should be placed after the indicating electrode following the
direction of rotation of the stirrer.
The burette
Most manufacturers titrant and solvent bottles can be connected directly to
Radiometer Analytical titrators using the bottle stoppers supplied.
The burette should be equipped with an absorption chamber filled with silica gel or
a molecular sieve for H2O absorption. This will preserve the titre of the titrant and
limit titrant consumption during the pre-titration of the solvent.
GLP
Even with all the precautions taken in order to preserve the titre of the KF reagent,
it is recommended to perform a calibration at regular intervals. The titrator alerts the
operator when a calibration is necessary. The calibration interval is entered by the
operator during programming. In the same way, when using dedicated PC software,
it is possible to enter a KF titre expiry date during programming of the KF reagent
library. The operator will then be prompted when it is time to replace the KF reagent.
Use of dedicated PC software allows unlimited archiving of results and data and
lets you consult your results and methods at all times. As many as 7 titrators can be
connected via a standard RS232C serial port.
Safety
A ventilation hood is advisable, particularly if a titrant containing pyridine is used.
Please note that, almost all KF titrants and solvents used are inflammable and
toxic.

THE WORKING MEDIUM (KARL FISCHER METHOD)

The solvent
The working medium (i.e. the solvent required), can be freely chosen by the user
depending on the dissolution properties of the sample to be investigated. For
methanol-based reagents, the stoichiometry 1:1 of the Karl Fischer reaction is only
fulfilled if there is more than 25% methanol in the reaction mixture. A methanol-free
working medium can be used, however it is important to determine the titre of the
KF reagent in the same working medium.
The modern solvents available today present a high buffer and dissolution capacity.
These solvents consist of sulphur dioxide, a base and methanol or ethanol.
The main advantages of these solvents are:
• A more rapid titration due to better reaction kinetics; an advantage especially
for the titration of large amounts of water.
• A better reproducibility, because the reaction environment is stable. The pH
and the sulphur dioxide concentration remain constant.
For the titration of samples producing side reactions (aldehydes, ketones and
silanols), it is necessary to use an appropriate solvent. Most reagent manufacturers
include the letter K in the commercial name of such solvents.
Note:
If you are using an ethanol-based Karl Fischer solvent (example: E-Solvent) and
you have difficulties balancing your cell, you may need to immerse the Pt-Pt
electrode for 2 min. in a 10% v/v TritonX-100 solution once a week. Then rinse with
dry methanol and gently wipe. This treatment allows the electrode to recover full
efficiency after a few minutes operation. 10% v/v TritonX-100 is available from
reagent manufacturers or can be prepared by diluting 10 ml of TritonX-100 in 100
ml of deionised water.
The titrant
The titrant consists of iodine dissolved in methanol or ethanol. We often find that
the titrant has three titres 1, 2 and 5 mg of water per ml titrant. Even if it is possible
to perform a titration with more than one stroke of the burette piston, it should be
avoided by an appropriate reagent titre and choice of sample size. This allows the
titration time to be reduced and therefore improves the reproducibility.
The titration of samples producing side reactions (aldehydes, ketones and silanols)
requires an appropriate solvent.
The following table gives the recommended maximum speeds for given reagents
and solvents. However, conditions may be modified with respect to the additives,
solvents e.g. chloroform, or samples added.
If the titrator indicates an excess of iodine at the end of the titration, the burette
speed should be halved (a speed below 5 ml/min is rarely used). It should be
remembered that the titration time is not necessarily proportional to the rate of
reagent addition. It is recommended to adapt the addition rate so that it is proportional
to the speed of the Karl Fischer chemical reaction. Increasing the speed may lead
to a momentary excess of non reacted iodine which puts a stop to the reagent
addition. The titrator must therefore wait until this excess has been consumed
before continuing the reagent addition.
Water determination using Radiometer Analytical titrators
1) Filling the burette with titrant
Place the reagent bottle in the bottle holder (if mounted) and connect the
suction tubing from titrant bottle to stopcock. Add desiccant to the absorption chamber
mounted on the bottle. To prepare the titrant, use the titrator burette functions “Bottle
exchange” or “New titrant”.
Note: replace the desiccant when saturated.
2) Filling the KF cell with solvent
Place the solvent bottle in the bottle holder (if mounted) and connect the tubing
from the solvent bottle to the KF cell. Fill the desiccant tubes for KF cell and KF
pump with an appropriate desiccant, e.g. silica gel. Start the pump then using the
titrator solvent button, add between 30 and 40 ml of solvent to the titration cell.
Radiometer Analytical has marked the KF cell to indicate the minimum level to
which solvent must be added.
3) Mounting the waste bottle
Label and identify the waste bottle and place the bottle at the rear of the titrator.
Connect the tubings, KF cell to waste bottle and pump to waste
bottle. Make sure that the tubing is correctly connected to the pump module. A bad
connection could release liquid into the pneumatic module and cause severe
damage. Start the pump then use the waste button to empty the cell.
Reagent Solvent Manufacturer Recommended speed
Recommended
current
HYDRANAL®-Composit 5 Methanol Riedel-de-Hahn 150 %/min = 15 ml/min AC 50 μA
HYDRANAL®-Composit 5K HYDRANAL®-Solvent K Riedel-de-Hahn 50 %/min = 15 ml/min AC 50 μA
HYDRANAL®-Titrant 1 HYDRANAL®-Solvent Riedel-de-Hahn 150 %/min = 15 ml/min AC 50 μA
HYDRANAL®-Titrant 2 HYDRANAL®-Solvent Riedel-de-Hahn 150 %/min = 15 ml/min AC 50 μA
HYDRANAL®-Titrant 5 HYDRANAL®-Solvent Riedel-de-Hahn 150 %/min = 15 ml/min AC 50 μA
HYDRANAL®-Titrant 5 HYDRANAL®-Solvent CM Riedel-de-Hahn 150 %/min = 15 ml/min AC 50 μA
HYDRANAL®-Titrant 5 E HYDRANAL®-Solvent E Riedel-de-Hahn 15 ml/min AC 20 μA
HYDRANAL®-Titrant 2 E HYDRANAL®-Solvent E Riedel-de-Hahn 15 ml/min AC 20 μA
HYDRANAL-Composolver E Ethanol Riedel-de-Hahn
Karl Fischer Réagent T Karl Fischer reagent S Merck 150 %/min = 15 ml/min AC 50 μA
Karl Fischer Reagent 2.5 Karl Fischer reagent S Merck 150 %/min = 15 ml/min AC 50 μA
Karl Fischer Reagent 5 Pyridine Merck 50 %/min = 5 ml/min AC 50 μA

4) Pre-titration
Pre-titration allows the removal of traces of water introduced with the solvent. It is
only necessary if the stand by function is not used.
5) Sample introduction
The titrator is ready to start titrating when the message "Introduce sample" appears
on the display.
In general, at least 5 mg/ml is allowed. With a newly filled KF cell, it is possible to
titrate 5 x 35 = 175 mg of water.
6) Titrating the water
If "Autostart" has been activated, the titration will start as soon as the water in the
sample is detected. Otherwise the titration will start as soon as the ✓ key is pressed.
The titrator constantly determines the speed of titrant addition which is adapted to
the titration. The introduction or simple confirmation of the sample addition can be
carried out by the operator in his own time. In fact, the titration may have finished
before the sample amount is introduced. The titrator waits for the input of the sample
amount before calculating the final result.
7) Result calculation
The titrator calculates the water content of the sample. The drift measured from
titration start and if necessary the quantity of water introduced by the blank, the
dilution factor etc.are also taken into account during calculations.
At the same time, the titrator will determine whether or not the result falls within the
acceptance range specified by the user during programming. This allows the user
to determine if the water content conforms to the specifications and if the result can
be used for statistical purposes.
8) Solvent renewal
It is possible to perform successive titrations in the same solvent. However, it is
important to ensure that the methanol concentration is above 25% and that pH is
maintained within the range 5 to 7.
Although it is advisable to renew the solvent after each analysis, successive titrations
may be performed using the same solvent. Due to the fact that the quantity of
sulphur dioxide present in the cell is limited, care must be taken to respect the
quantity of water that can be analysed using the volume of solvent present in the
KF cell. For further information, consult the reagent manufacturer's instructions for
use.

9) Restarting the titration using a new aliquot or return to the start of
a menu
The KF titration cell will remain permanently on stand by i.e. ready for immediate
use.
10) At the end of a series of titrations, the following statistical
calculations are performed:
• Mean.
• Standard deviation.
Use of an oven
The oven is necessary when:
• The solvent does not allow a sufficient dissolution of the sample.
• The sample interacts with the working medium.
• The sample inhibits the response of the indicating electrodes.
The preparation steps 1 to 4 for the titration are identical to the conventional method.
Use a specific method based on the preprogrammed "Oven KF method".
Remember to pre-titrate the cell after having turned on the gas flow.
1. The titrator prompts you to weigh an "advised" amount of aliquot. The
approximate value of this aliquot has been entered in the titrator beforehand.
2. Introduce the sample in the oven's cold zone.
3. Enter the "exact" amount of sample weighed.
4. The titrator will determine the drift value.
5. Move the sample to the oven's hot zone.
6. The titration will start automatically if the option “Autostart” has been selected.
The titrator will display the result until the end of the titration.
7. Withdraw the sample from the oven.
8. Start a new titration with another aliquot or return to the menu. The cell will
remain in stand by condition, i.e. ready for a new titration.
9. At the end of a series of titrations statistical calculations are performed.
The user is guided through all the stages in the titration by the titrator's, clear and
concise messages. In this way the quality of the analyses is optimised.

VOLUMETRIC TITRATION

General remarks
Volumetric Karl Fischer titration requires the determination of the titre (t) of the Karl
Fischer reagent. It is usually quoted in mg of water per ml of Karl Fischer reagent.
Modern reagents allow direct titration of water in the sample. The sample may be
introduced directly into the KF cell or after an extraction or dissolution with a suitable
solvent. The water concentration of the solvent must be determined previously in
order to be subtracted from the sample analysis.
In Radiometer Analytical titrators all these operations are simplified and the different
results are accounted for automatically.
The volumetric titration of water allows the analysis of water concentrations between
0.1% and 100%. If an aliquot contains less than 1 mg of water, coulometric
determination will result in a more accurate result. For reasons of precision, the
titre of the titrant should be chosen so that the titration is completed with a titrant
demand between 1 and 10 ml.
End point determination
The end point of the reaction is generally based on the detection of a slight excess
of iodine which occurs when water is no longer present in the KF cell. The iodine
excess can be indicated visually, photometrically or potentiometrically. The
potentiometric method is the most common for the majority of titrators currently on
the market.
Radiometer Analytical titrators allow the use of direct or alternating current. The
indicating electrode geometry and frequency of the alternating signal have been
optimised. The instrument does not operate with instantaneous potential values
but uses half the difference between two consecutive measurements.
E =
E(t) - E(t-1)
2 (IV)
In a conventional system with dc current, the electrodes are polarised,
and become the site for reactions other than the reaction iodine to iodide. This
leads to a drift in the potential difference between the electrodes and an end point
that may be erroneous.
- 6 -
Two curves for the same electrode are shown. Both have the same
amplitude but one is with direct current whereas the other is with alternating current.
It can be seen that with ac the potential is stabilised whereas with dc the potential
increases, showing the appearance of reactions other than the reaction iodine to
iodide.
The amplitude of the direct or alternating current and the value of the set point are
modified according to the resistivity of the reactive medium. Radiometer Analytical
offer more than a simple end point titration. The instrument controls the speed of
reagent addition in order to maintain the indicating electrode potential at a constant
value, thus an excess of iodine is never observed. This reaction control is achieved
with a self-adapting PID algorithm(1). The only input parameter is the maximum
allowed speed that only depends on the reaction kinetics of the reagent used.
Radiometer Analytical has tested most available reagents and the default value is
valid for the most commonly used ones. The table below gives the maximum advised
speed for the tested reagents.
Thanks to this principle, the titrator compensates the water introduced into the KF
cell by determining a drift value which is subtracted during the titration. In this way,
more accurate results are obtained, especially for low water contents.
(1) PID: Proportional Integral Derivative

pH CONSIDERATIONS (KARL FISCHER METHOD)

The Karl Fischer reaction can only take place in a certain pH range between 5 and
7. In this pH range, the reaction remains constant. If the pH drops too low, end point
attainment becomes sluggish or an end point will not be reached at all. If the pH is
too high, side reactions occur making the titration non-stoichiometric. We can
therefore say that errors occurring during a KF titration may be due to a change in
the pH of the titration solvent.
The pH of the titration solvent can be tested using a combined pH electrode and a
pH meter. The electrode is first calibrated with aqueous buffer solutions and
afterwards the pH of the titration solvent is measured.
Note: do not place the pH electrode directly into the KF cell because excessive
moisture will be introduced along with the electrode.
For further information, consult the users manuals of the main manufacturers of
Karl Fischer reagents.

CHEMICAL REACTIONS

The titration is based on the oxidation of sulphur dioxide by iodine in the presence
of water. It is the same reaction as the iodometric titration of sulphur dioxide in
water.
I2 + SO2 + 2H2O 􀃙2HI + H2SO4 (I)
In 1935, Karl Fischer published a description of “a new procedure for the titration of
water” using the above reaction in an anhydrous nonaqueous solvent. However, in
order to shift the equilibrium (I) to the right, it was necessary to neutralise the acids
produced. Originally pyridine was used as the neutralising base. Later on,
diethanolamine followed by imidazole were used as buffers.
Recent studies show that methanol, which is the most commonly used solvent,
contributes in the reaction. The Karl Fischer titration can therefore be described by
the two following reactions:
CH3OH + SO2 + RN => [RNH]SO3CH3 (II)
H2O + I2 + [RNH]SO3CH3 + RN -> [RNH]SO4CH3 + 2[RNH]I (III)
(RN designates the base used)
Ethanol-based reagents have recently emerged. These have the advantage of
being less toxic, offering more stable endpoints and faster kinetics.

INTRODUCTION

Water content needs to be determined at all stages of the manufacturing process
from raw materials to finished goods. The quality of the product depends on it. In
products such as kerosene, transformer insulation oil or brake oil, the presence of
unwanted moisture can have disastrous consequences.
In the pharmaceutical industry, it is essential to know the amount of water contained
in the ingredients of a drug in order to correctly predict its lifetime, stability and
effectiveness.
In the food industry, the water content of both raw materials and the finished foodstuff
needs to be carefully monitored.
The technique most commonly used for these analyses because of its rapidity,
accuracy and ease of use is Karl Fischer titration.
Thanks to their design and titration algorithm, Radiometer Analytical Karl Fischer
Titrators provide accurate results and clear sample information. Radiometer
Analytical makes it easy for the user to comply with Quality Control requirements
and follow Good Laboratory Practice.
The instrument is easy to program due to preset methods for titrations in the most
common samples. The last calibration results of titrants, blanks and samples are
stored. When used in conjunction with dedicated PC software, archiving of results
and methods is limited only by available storage space.