Advanced Search

Royal Decree 288/1991, Of March 8, Which Regulates Immunological Medicinal Products For Human Use.

Original Language Title: Real Decreto 288/1991, de 8 de marzo, por el que se regulan los medicamentos inmunológicos de uso humano.

Subscribe to a Global-Regulation Premium Membership Today!

Key Benefits:

Subscribe Now for only USD$40 per month.

TEXT

Immunological drugs have a universally known health importance, since they are not only used in curative therapies but are also widely used for preventive and diagnostic purposes and, in healthy population.

The technical complexity of these medicinal products, the special characteristics in terms of raw materials, intermediate products and finished preparation, and the need to take measures to ensure their safety and (i) effectiveness, it makes it necessary to issue a specific regulation, harmonised with the provisions of Community Directive 89 /342/EEC, laying down additional provisions on immunological medicinal products consisting of vaccines, toxins, serums, and allergens (Official Journal of the European Communities of 25 May 1989).

This Royal Decree, issued on the basis of the powers of legislation on pharmaceutical products and the economic regime of Social Security, which attribute to the State Article 149.1.16 and Article 17 of the Constitution, Article 40.5 of Law 14/1986 of 25 April. General de Sanidad, and Article 39 of Law 25/1990 of 20 December of the European Medicines Agency, lays down the requirements necessary to ensure that the safety, efficacy and quality criteria for the authorization, production and control of the products are observed. immunological medicinal products, as well as the general criteria for their use with regard to the provision of the National Health System.

In its virtue, on the proposal of the Minister of Health and Consumer Affairs, the sectors affected, after favorable report of the Interterritorial Council of the National Health System in agreement with the State Council and after deliberation of the Council of Ministers at its meeting of 8 March 1991,

DISPONGO:

Article 1. º

1. For the purposes of this Royal Decree are immunological drugs, the serums, the vaccines, the toxins and the allergens included the individualized vaccines for a specific patient.

2.

the following definitions shall apply:

Serum: Agent used to produce passive immunity.

Vaccines: Agents used to trigger active immunity.

Toxins: Agents used to diagnose immunity status.

Allergen: Any product intended to identify or cause a specific and acquired modification of the immune response to an allergenic agent.

Individualized vaccines: They are prepared with immunising agents, at specific concentration and dilution based on the corresponding optional prescription for a given patient.

Art. 2. º

1. Immunological medicinal products, manufactured industrially, have the legal status of proprietary medicinal products and are therefore subject to authorization and registration in the Ministry of Health and Consumer Affairs and to the other requirements of the Current legislation imposes on that class of medicines, with specific forecasts that incorporates this Royal Decree or can incorporate the provisions that develop it.

2. The individual vaccines shall be governed by the provisions of Article 8. of this Royal Decree.

Art. 3. º

To ensure permanently the homogeneity of lots and products, processes and procedures used in the manufacture of immunological medicinal products, must be duly authorized by the Ministry of Health and Consumption, and adjusted to the Good Manufacturing Standards that are included in Annexes I and II to this Royal Decree.

Art. 4. º

1. Manufacturers shall make available to the health authorities responsible for the implementation of the legislation on pharmaceutical products, the protocols for the production and control of immunological medicinal products when they are required for this. They shall also provide for their control the raw materials, intermediate products or final batches of the immunological medicinal products when they are requested.

2. The Ministry of Health and Consumer Affairs may, in the interest of public health, subject to prior authorization the placing on the market of each batch of the following bulk or finished products of the immunological medicinal products:

Live vaccines.

Immunological medicinal products intended for primary immunisation of children and other groups of special risk.

Immunological drugs used in Health Campaigns.

immunological medicinal products manufactured with new technologies, modified technologies or which present a novelty character for a given manufacturer, during the time limit imposed on the corresponding authorization of the marketing.

3. The prior authorisation shall involve the review of the production and control protocols and, where appropriate, the carrying out of the analytical tests deemed appropriate.

The required authorisation shall be granted, when the Ministry of Health and Consumer Affairs has documented that the lot has been formed by the competent authority of another Member State of the European Economic Community.

4. The "Carlos III" Health Institute shall, within the maximum period of 60 calendar days from the time of the collection of samples by the inspection services, inform the General Directorate of Pharmacy and Sanitary Products of conformity or not of batches submitted to prior authorization.

Elapsed time without negative pronouncement. The batch shall be understood to be placed on the market.

Art. 5. º

The following considerations shall be taken into account in the dossiers accompanying the application for authorisation and registration of an immunological medicinal product:

(a) The quantitative description of immunological medicinal products shall be expressed en masse, in international units, in units of biological activity or, as far as possible, in protein content according to the type of immunological product in question.

(b) In any case, the qualitative and quantitative composition of the active constituents shall be expressed in units of biological activity or protein content.

Art. 6. º

The name or mark of the medicinal product shall always be accompanied by the common or scientific name of the active constituents.

Art. 7. º

The technical information sheet and the packaging material for immunological medicinal products, in addition to the requirements laid down for proprietary medicinal products, shall include:

(a) The information sheet and package leaflet, sufficient information on the precautions to be taken by the persons handling or administering them, as well as the precautions to be taken by patients.

b) In the carton and label, the symbols and phrases that warn of the need for cold conservation.

Art. 8. º

1. The elaboration, distribution and dispensing of the individual vaccines will be anti-allergic, bacterial or self-vaccine, and will obey a medical prescription for a particular patient.

2. The manufacturer's individual vaccine manufacturers must have prior authorization granted by the State Health Administration or the Autonomous Communities which have the responsibility for implementing the product legislation. pharmacists. The authorisations granted by the Autonomous Communities shall be communicated to the Ministry of Health and Consumer Affairs.

This authorization shall be granted when it is verified that the Entity has sufficient minimum means, materials, technicians and personnel for its proper manufacture and control, established by the Ministry of Health and Consumption and under the responsibility of a qualified superior technician according to the current regulations.

3. Manufacturing and control processes and procedures shall comply with the criteria of the Good Manufacturing Standards and shall be validated by the relevant pharmaceutical inspection services.

In any case, manufacturing and control processes and procedures will be protocolized.

4. Individualized anti-allergic vaccines will be developed from industrially manufactured allergens as set out in Article 2. of this Royal Decree.

5. The manufacturer of such individualized preparations shall take appropriate measures to identify in each preparation the office of pharmacy or pharmaceutical service applicant, the prescriber, patient, composition, manufacturing process and controls performed.

6. The conditioning material shall clearly identify at least the prescriber, patient and quantitative composition of the preparation, route of administration, manufacturing reference number and expiry date, as well as the Entity manufacturer and the need for cold storage.

An explanatory leaflet shall be accompanied by the instructions for correct administration and the precautions to be taken.

Art. 9. º

In the manufacture, distribution and preservation of immunological medicinal products, the particular temperature conditions necessary to avoid any alteration or deterioration shall be observed.

ADDITIONAL PROVISIONS

First.

The entry into force of this Royal Decree is subject to the prior authorisation of lots referred to in Article 4. °, 2, the following vaccines and suspensions:

Attenuated anti-polio vaccine concentrates.

Viral vaccines.

Vaccines against tetanus, diphtheria, and tosferin are both monovalent and polyvalent.

The attenuated antitificant vaccine.

Second.

1. Immunological medicinal products authorised as proprietary medicinal products for use by the Social Security Funds shall continue to be accepted in respect of the supply and other conditions of the provision, the general arrangements laid down for those.

2. Individual vaccines for funding by Social Security funds will follow the following regime:

(a) They shall be offered under the conditions which shall be determined for the State Administration.

Conditions and formalities for inclusion in the offer of the pharmaceutical provision of Social Security shall be established in accordance with the criteria marked by the Interterritorial Council of the National Health System.

(b) Iran with its packaging of an identification label containing the data deemed necessary for the control of the supply of social security and which must be adhered to in the prescription. moment of being delivered to the beneficiary by the Farmacêutica who disthought them.

c) The price will be determined specifically.

d) One year after the inclusion of the individual vaccines in the offer of the pharmaceutical provision of the Social Security, the concessions of this offer will be reviewed with the criteria marked in the legislation in force. From this review, periodic reviews will be carried out every five years.

TRANSIENT PROVISIONS

First.

Within one year of the entry into force of this Royal Decree, the current Entities of the individual vaccine manufacturers will adapt their activities to their forecasts.

Second.

However, the current manufacturers of individualized vaccines will communicate their operation within three months of the entry into force of this Royal Decree to the Health Administration of the State or of the Autonomous Communities competent for the implementation of the legislation on pharmaceutical products. The latter shall communicate this information to the Ministry of Health and Consumer Affairs.

Third.

Within the same period of three months the manufacturers currently authorized to manufacture individual vaccines will formulate the offer for admission to the financing from the Social Security funds.

Fourth.

Within one year, counted from the entry into force of this Royal Decree, laboratories that manufacture industrially immunological medicines will adapt their activities to the forecasts of the same.

FINAL DISPOSITION

The Minister of Health and Consumer Affairs is empowered to amend by Order the rules of correct manufacture of immunological medicinal products in order to adapt them to material, tenological or scientific advances and requirements.

Given in Madrid to March 8, 1991.

JOHN CARLOS R.

The Minister of Health and Consumer Affairs,

JULIAN GARCIA VARGAS

ANNEX I

Good manufacturing and quality control standards for human use vaccines

These rules facilitate compliance with the Standards of Good Manufacturing and Quality Control of Medicinal Products, approved by Order of 19 April 1985 ("Official State Gazette" of 30), in their specific adaptation to the development and control of human-use vaccines.

1. General considerations

1.1 All strains used in the manufacture of vaccines must correspond to those authorised and declared for the production of the vaccines in question.

1.2 Any product covered by this standard must be adequately identified with a batch key, which shall be entered in all product packages corresponding to that lot.

The batch identification key will be precept in the production protocols and their meaning will be reflected in the "pattern guide" of manufacture.

2. Definitions

For the purposes of these rules, the following definitions shall apply:

2.1 Seed: Original strain of the germ that is part of the vaccine.

2.2 Siembra: Product obtained by growing the seed in an appropriate medium.

2.3 Seed Lot: The homogeneous product obtained in each crop procedure.

2.4 Bulk Suspensions: Product resulting from the suspension of the vaccine in appropriate fluids or fluids.

2.5 Final product: Fully elaborated, dosed and packaged vaccine that requires further conditioning for distribution and sale.

2.6 Final Product Finished: Final Product Conditioning for Distribution and Sale.

3. Manufacturing

3.1 All manufacturing processes shall be duly protocolised in accordance with the rules laid down in the Order's number 7 of 19 April 1985.

3.2 The "Pattern Guide" for manufacturing and control shall include at least the following data and documents to be recorded in the Register documentation:

Identity tests of the strains.

Safety tests of the substrates.

Product quality control and manufacturing protocol.

Production system and process controls.

Analytical protocols that include the product acceptance specifications and the results obtained in each of the tests performed with the expression of the method used.

3.3 Packaging containing any of the products covered by this standard shall be clearly and accurately labeled with the data which, in an unequivocal manner, allows to know its nature.

3.4 Laboratories producing the final product from bulk suspensions, prepared by other laboratories, shall incorporate in their documentation the production protocols for these suspensions and the authorisation of the the Control Authorities of the country in which they occur.

3.5 The laboratories producing the final finished product, from the final product produced by other laboratories, must incorporate in their documentation the production protocols for the finished product and the finished product. authorization of the Control Authorities of the country in which they occur.

4. Quality control

For each stage of production, the producer laboratory shall carry out the checks to which it is obliged, in accordance with the provisions of the Register of Specialty.

5. Inspection and control by the Health Administration

5.1 Inspections and sampling.

5.1.1 By the Pharmaceutical Inspection Services it will be verified that production and control is carried out in accordance with the "Pattern Guide" of Manufacturing and Control and the protocols of each one are completed and archived. lot.

5.1.2 In exceptional circumstances and prior to the lifting of the regulatory act, samples of seed or seed lots, by the Pharmaceutical Inspectorate, shall be obtained for their remission and study in the Institute of Health "Carlos III". The production process may be continued without waiting for the results of the checks carried out.

5.1.3 The Pharmaceutical Inspectorate, after lifting the regulatory act, shall take samples of the bulk suspensions produced or imported, for referral and opinion by the "Carlos III" Health Institute, accompanied by the production protocols. The production process may be continued without waiting for the results of the checks carried out.

5.1.4 Finalised the final product development or reception phase, the producer laboratory will request from the Pharmaceutical Inspection Services the collection of the production protocols, samples of the final finished product, in statistically representative number of the batch size. These samples and documentation will be sent to the "Carlos III" Health Institute.

In the case of influenza vaccine and due to the exceptional circumstances of its marketing, the producer laboratories may request the collection of the final product samples before the end of the test corresponding production, being able to send these protocols later.

5.1.5 In the minutes raised in the sampling, the existence of the certificate issued by the Health Authority of the country of origin in respect of the conformity of the batches of materials shall be reflected in the cases where appropriate. are imported.

5.2 Control in foreign trade.

5.2.1 The import or export of any product or preparation affected by this Royal Decree, will require in accordance with the provisions of Article 1 (1), (d), and Article 3. of the Order of 7 May 1985 (" Bulletin State Officer ' of 20), the health authorisation granted by the Subdirectorate-General for the Evaluation of Medicinal Products.

5.2.2 In the import operations, the Health Inspection of Medicinal Genres, in addition to the vefrifications and reports provided for in the Order of 7 May 1985, will proceed to the seal of the goods for shipment to the the importer laboratory and shall immediately communicate to the General Sub-Directorate of Pharmaceutical Control and Peripheral Services, those circumstances for the performance of subsequent actions.

5.2.3 The Pharmaceutical Inspection Services shall unseal the goods and proceed to the sampling provided for in point 5.1.

5.2.4 When the import affects a pharmaceutical specialty totally finished and ready for sale to the public, the actions to be carried out by the Health Inspection of Medicinal Genres will be those established in this paragraph with the exception of the sealing of the goods.

6. Distribution and marketing

6.1 The authorization of finished product batches will involve the authorization of the previous products that you are part of.

6.2 The vaccine-producing laboratories may be distributed and placed on the market on the basis of the time limits laid down in Article 4 (4) of the Royal Decree. In the case of influenza vaccines this time limit shall be 30 days.

6.3 The laboratory will have documentary evidence of the distribution of the vaccines.

ANNEX II

Rules of correct manufacturing and quality control of allergens and individualized anti-allergic vaccines

1. General considerations

These Rules facilitate compliance with the Standards of Good Manufacturing and Quality Control of Medicinal Products, approved by Order of 19 April 1985 ("Official State Gazette" of 30), in their specific adaptation to the Manufacture and control of allergens and individualized anti-allergic vaccines.

2. Starting material

2.1 Raw materials. -For each raw material, the corresponding written specifications must exist in the laboratory.

The aim of these specifications is to maintain as much uniformity as possible in the quality of the different batches. It is therefore appropriate that the following paragraphs should be included in the specifications:

a) Description of the raw material.

b) Indications on obtaining, processing, and storage conditions.

(c) Control methods to be applied by the manufacturer of allergenic products to proceed where possible, to their identification, to check their degree of purity and to determine their allergenic composition.

d) Minimum requirements to be met by the raw material to be accepted by the manufacturer.

e) Storage conditions prior to processing or processing.

Data concerning raw materials should be included in the manufacturing guides.

2.1.1 Polenes. -The method of obtaining the polyes must be recorded, including the tests used for the detection of foreign polenes, spores, plant remains, and all kinds of possible foreign materials present.

Pollen collection should be supervised by staff with experience in Botany.

The minimum requirements that the polyes must meet in order to be accepted as raw materials are:

Maximum permitted content of spores, 1 per 100; maximum permitted content of other contaminations (particles of the same or different species and plant remains), 10 per 100. The content of polenes of other species must not exceed 1 per 100.

If any of these specifications cannot be met, the reasons must be indicated.

2.1.2 Hongos .. -Crop conditions should be described, as well as the morphological characteristics of the raw material (mycelium and spores, only spores, only mycelium), and its content in culture medium.

The cultivation of fungi intended for the preparation of allergens should be supervised by personnel with the appropriate experience.

In specific cases, mycotoxin control will be done.

2.1.3 Expensive.-The conditions of cultivation, the characteristics of the material as well as its contents in mites and in the culture medium must be described.

The cultivation of mites intended for the preparation of allergens should be supervised by personnel with the appropriate experience.

2.1.4 Epidermal derivatives. -The animal species used must be specified, including data on the health of the animals from which the allergenic material is obtained.

If dead animals or parts of these dead animals are used, the conservation methods that have been used prior to the collection of the raw material should be specified.

The method used for the collection of the raw material should be described.

Epidermal derivatives should only come from healthy animals, who do not suffer any type of infection, and who have not received any antiparasitic treatment or any medication, until the time of waiting imposed for that medication or treatment.

Hair collection will be performed according to methods that do not damage the living animal (brushing, combing, sucking).

If dead animals are used, the conservation method must ensure that the decomposition processes do not affect the collected epithelium.

2.1.5 Insect Veneno. -The method of obtaining the poison should be described.

In order to be used in the preparation of allergens, the poison must be extracted from the poison bags of the insects by means of methods that ensure the proper quality of the raw material.

For the preparation of extracts, whole bodies of insects may also be used. In this case it should be reflected in the manufacturing guide.

The collection of insect venom should be supervised by staff with the appropriate Entomology experience.

2.1.6 Other allergens. -If for the production of allergenic preparations, materials other than those described above are used, such as: Food, wood, grain flour, domestic powder, etc. The raw materials used should be described as closely as possible.

The specifications of each raw material should set the composition of the material to be used.

2.2 Other ingredients. -Ingredients such as: saline solutions, tampons, preservatives, stabilizers, etc., and those used as auxiliaries in the manufacturing process such as: Degreasing agents, solutions extraction, etc., must present a level of quality comparable to that required for ingredients described in the Pharmacopoeia.

Same quality level must present the solutions that accompany the finished allergenic product to be used as a solvent or diluent of the same.

In the preparation of allergens the use of ingredients that present immunogenic or allergenic action should be avoided.

3. Manufacture and control

3.1 General documentation. The complete process followed in the production must be described, step by step, in detail.

Each of the operations that make up the manufacturing process: For example, milling, extraction, clarification, filtration, dialysis, etc., must be clearly defined, detailing the conditions under which they are carried out, and from which point is operated in aseptic conditions.

Intermediate products must be properly identified in the process protocol.

Detailed controls must appear in process, and the points of the same where the samples are to be taken for realization.

It is advisable that in the production process a purification method be included to remove the components with molecular weight below 10,000 Daltons since they are not normally immunogens. However, in some particular cases where these components have not been shown to be harmful and may be essential for the activity of the product, this purification may be omitted.

If the allergen is purified or fractionated, the principles on which the purification or fractionation is based should be cited, and the methods used and their application described in detail.

3.2 Basic chemical documentation. The documentation should contain information about the product development and the chemical and/or immunochemical characterization of the preparation.

As far as possible. information must be gathered to demonstrate that the allergen is representative of the starting material. This information is particularly important in the case of highly purified allergenic preparations.

The manufacturing methods used should be kept in writing, as detailed as possible, and with corresponding bibliographic references.

The methods and properties must be included in the quality specifications (point 4.3).

3.2.1 Chemical/immunochemical characterization.-When considered of interest, data on protein and carbohydrate content shall be included.

In the case of highly purified and concentrated allergenic preparations, it is recommended to include the activity relationship between the purified and concentrated allergen and the raw allergen.

During the development of the manufacturing process the properties of the product concerned with its protein content must be determined, applying, in each case, the methods considered most appropriate. For example, the methods applied may be: "micro-kjeldhal", radial immunodiffusion, cross immunoelectrophoresis (CIE), isoelectrofocus (IEF), polyacrylamide gel electrophoresis with sodium dodecylsulfat (PAGESDS), layer filtration gel fine (TLGF), etc.

3.2.2 Allergen activity. -This section defines the principles on which the standardization of allergens is based and the establishment of reference samples for the standardization of production.

The methods used should be described in detail, attaching evidence of their specificity and accuracy. On the basis of these tests, the units in which the power of the batches produced are valued shall be defined.

3.2.2.1 Biologically standardized Alergenes. -There are different methods for determining the biological potency of an allergen, with its common characteristic being the preparation of a reference allergen perfectly. characterized and appraised "in vivo" by skin tests. Successive batches of production are valued, in comparison with the reference allergen, by means of "in vitro" techniques in order to ensure the uniformity of the batches in terms of their allergenic activity.

The "in vitro" test used most often consists of the application of the "RAST" technique, based on the measurement of the binding of the allergen to the specific IgE of the serum of sensitive patients.

Another of the "in vitro" tests used is the determination of the amount of histamine released by isolated leukocytes from sensitized patients.

The use of other biochemical and immunochemical methods may be valid, provided that their reliability and accuracy are demonstrated in the determination of allergenic allergen activity.

3.2.2.2 Non-standardized Alergenes biologically. -In some cases, the biological assessment of the allergens is not possible due to lack of adequate reagents, or because of technical impossibility. In these cases, the uniformity of production must be maintained on the basis of only a standardization of the production (initial quantity of the extracted material) or a chemical assessment of the protein content of the extract obtained, by means of methods which ensure the uniformity of the lots as to their concentration. These methods have been used until the emergence of more sophisticated biochemical and biological techniques and, although they do not ensure uniformity in the allergenic activity of products, they are still useful in cases in which the There is no appropriate biological method.

a) Weight/volume ratio. -It is the simplest method of expression of the potency of an allergenic preparation. It is given by the relationship between the dry weight of the material used and the volume of extraction liquid used in its preparation.

b) Protein nitrogen. -The amounts of proteins extracted for the same weight/volume ratio are not always the same. To avoid these differences in the extracts, the determination of the protein nitrogen thereof has been established as a method of standardization.

The "Protein Nitrogen Unit" (PNU) is defined as the amount of extract containing 10 milligrams of nitrogen of protein origin, precipitated with phosphoggistic acid, and valued by applying Kjedahl's method.

c) Other methods. -There are other chemical or immunochemical methods capable of determining the concentration of allergenic extracts and their use will be feasible as long as their reliability has been demonstrated.

3.2.2.3 Purified Alergenes. -Previous indications are not applicable for well-defined and purified allergens, as in these cases, the specific activity should be determined as activity per unit of mass.

3.3 Specifications. -Quality specifications must include:

(a) Raw material specifications (point 3.1).

b) Process control specifications,

c) Intermediate product specifications.

d) Product specifications terminated.

These specifications, taken together, should establish: The identity, potency and purity of the products, as well as the technical and pharmaceutical characteristics of the preparations and the packaging.

The requirements stated in the quality specifications must be maintained throughout the period of the preparation.

Special requirements for the date of manufacture should be described.

Compliance with quality specifications will be verified by applying different control methods. The control methods should be described separately and with sufficient detail to enable their reproducibility.

The selected control methods must allow the characterization of the preparations and minimize the variability between different batches.

In the case of special formulations of allergenic preparations (modified or polymerized allergenic extracts, gel adsorbed extracts and mixtures of different extracts), in which the tests of identity and potency are not they can be directly applied to the final products, quality and standardization controls must be carried out on the appropriate intermediate products.

3.4 Determination of the composition of the final product. -In cases where appropriate information and appropriate reagents are available, the allergenic composition of the extracts may be determined by the application of the different techniques, such as: Immunoelectrophoresis, (CIE), (CRIE), isoelectrofocus, (IEF), electrotransfer and immunodetection ("immunoblotting") , electrophoresis in polyacrylamide -SDS (PAGE-SDS), radial immunodiffusion (IDR), electroimmunoassay, etc.

The chemical composition of allergens and diluent and reconstituent solutions should be determined.

In cases of allergen adsorbed on aluminium hydroxide gel, it should be checked that the amount of aluminium they contain is less than the maximum allowed.

Also, the antimicrobial agents used to preserve the sterility of the preparation should be quantitatively determined.

3.5 Determination of the activity of the final product.-The standardization of the different batches of the same product must be carried out in accordance with point 4.2.2 and according to the bases described.

Reference preparations should be obtained and stored under conditions that ensure their stability. A freeze-dried preparation, preserved at 4 ° C, can be considered stable.

When there are well-characterized, national or international reference preparations, they must be used for the calibration of their own patterns.

3.6 Other tests. -In addition to those described, other tests to be performed on the finished product are: Loss by drying, sterility test, pyrogenics test (if applicable), toxicity test.

4. Stability and expiration date

Product stability must be properly documented.

The citation of bibliographic references on the stability of allergenic products is considered sufficient documentation to complete this section.

The stability of allergens, maintained in pre-fixed storage conditions during the period of validity, should be ensured. Reconstituted products or dilutions made from allergenic preparations, as well as reconstitution and dilution liquids, must be fixed at an expiry date in accordance with their stability.

5. Labelling of individualized anti-allergic vaccines

On the labelling of individual anti-allergic vaccines, the following data should be provided as technically as possible:

Name and composition of the preparation.

Administration path.

Name of the sick person to whom it is intended.

Name and address of the preparer lab.

Expiration date.

Prescriber physician.

dispensing pharmacy.

Identification key or reference number of the lab.

Individual allergen and anti-allergic vaccine entities should establish an appropriate system of self-control that can easily detect any error in the labelling of allergens.

6. Reference samples of the individual anti-allergic vaccines

Although the conservation of reference samples of the anti-allergic vaccines is not feasible because they are individualized formulations, it is necessary, however, to preserve representative reference samples of the extract. the mother or the last dilution allowing, if necessary, the traceability and reproducibility of the anti-allergic vaccine in question. The number of these samples shall be representative of two treatments.

7. Safety of allergens

The determination of allergen safety will be performed by abnormal toxicity studies and non-specific irritant testing.

7.1 Studies of abnormal toxicity. -These trials should be carried out in two species of animals (mice and guinea pigs or rats) to be injected with doses between 300 and 3,000 times higher than the highest dose expected for use. clinical, but without exceeding the volumes of 1 millilitre for the mice and 5 millilitres for the guinea pigs. The animals are kept under observation for a week.

At the end of the observation period, no animal should lose weight. After slaughter, the animals must be subjected to a macroscopic anathomological post-mortem analysis.

7.2 Test for non-specific irritant capacity. -For the performance of these tests (subcutaneous test in mice, rats or guinea pigs, irritation of the conjunctiva in rabbits, etc.), the use of the relevant animals is recommended. laboratory, although additional information may be obtained by studying the molecular weights of the components of the preparation.

For preparations intended for skin testing of the 'pricktest' type, toxicological data may be reduced to the study of non-specific irritant capacity.

For certain preparations intended for sensitising treatments, the performance of the safety test shall not be required provided that it has been previously carried out in the batches of the extracts and diluents used in the clothing.

In allergen preparations obtained from fungi or house dust, additional toxicological tests may be carried out.

8. Bibliography

It is advisable to collect as much literature as possible in support of the processes and methods used in the production and quality control of each of the allergens and individualized anti-allergic vaccines. ready.