| | | |  | | - Hausen, B. M., B. Post, Allergische Reaktionen auf Osmaron B in Melkfett, Akt. Dermatol., 18, 108, (1992)
- Hausen, B.M., Brinkmann, J., John., W., Encyclopaedia of the contact allergens, ecomed-Verlag, (1996)
- Herbst, R. A., H. I. Maibach, Contact dermatitis caused by allergy to ophthalmic drugs and contact lens solutions, Contact Dermatitis, 25, 312, (1991)
- Kägi, M. K., Falafel-Burger-Anaphylaxie, Allergologie, 15, 56, (1992)
- Kägi, M. K., B. Wüthrich, Campari-Orange anaphylaxis due to carmine allergy, The Lancet, Vol. 344, July 2, (1994)
- Lepp, U. et al., Litchi, ein neues Nahrungsmittelallergen, Allergologie, 15, 56, (1992)
- Nebenführer, L., Repräsentative Untersuchung chemischer Allergene in Ungarn, Dermat. Gesell., Nov. (1992)
- Nebenführer, L. et al., Vegyi allergenek representativ felmerese Magyarorszagon, Borg. Venerol. Sz., 5, 205, (1993)
- Nekam, K., Andrasofszky, Z., Gönczi, Z., Tornoczi, L., Papp, G., Gyeney, L., Viranyi, M., Allergography of Salomvar, Hungary, Int. Arch. Allergy Immunol., 118, 242, (1999)
- Pirker, C., T. Möslinger et al., Ethylmercuric chloride: the responsible agent in thiomersal hypersensitivity, Contact Dermatitis, 29, 152, (1993)
- Schata, M., W. Jorde, Allergische Reaktion durch alpha-Amylase in Backmitteln, Allergologie, 15, 57, (1992)
- Strohal, R., Specificity and Sensitivity of Epicutaneous Test Substances Manufactured by Booth-Hermal and brial - a Comparative Study, (2002)
Jürgen Brinkmann Qualification and standardisation of patch tests
for skin testing of contact allergens Lecture on the occasion of the 53rd anniversary of the Institute for Medical Research and Occupational Health, Academy of Science and Arts, Zagreb, Croatia, 05.12.2003 brial allergen GmbH, Greven, Germany Abstract The misbranding of raw materials for the manufacturing process of patch tests and the counterfeiting of the final product of these test materials have gained increasing importance in the last decade with respect to the production process in the pharmaceutical industry (1,4).
To guarantee the performance and safety of a semi-solid pharmaceutical testing form, it is important to make oneself acquainted with the different quality standards and official requirements demanded by the national and international regulations (3).
Moreover it will be necessary to get an idea about the major factors which influence the quality of patch tests and therefore finally the quality of the medical allergic diagnosis. Introduction The quality of patch tests mainly depends on three factors:
The quality of the manufacturing process according to the regulations of the World Health Organization (WHO) (4), the binding instructions of PIC (Pharmaceutical Instruction Convention) (5) and the EU GMP Guide which consist of very precise instructions how to manufacture in every possible case (6).
The second factor influencing the test quality is to be seen in those pharmaceutical and technical parameters of the pharmaceutical preparation which influence the right diagnosis (7).
When considering the above mentioned aspects the right test concentration will be the final result.
The quality of the staff members with their value pattern and personal beliefs and the way how they put the philosophy of their company into action will be the third factor to ensure a good pharmaceutical quality.
Apart from these facts which can be described as progress in personality development the aspects of technical training and scientific education have to be considered (8).
Quality aspects required by the authorities
Patch tests have to be of the highest quality: the correct allergic diagnosis depends on it.
It is no longer sufficient to test the quality of the final product, but it is absolutely necessary that each step of the whole manufacturing process has to be monitored as required by the latest regulations of the EU authorities the so called Annex 15 to the GMP Guidelines (9).
The regulations that govern the terms of the manufacturing process are steadily enlarged. Originally based on the best practice in industry, they have been updated as technology and practice have further been developed. In order to get a manufacturing licence, pharmaceutical companies have to pass several inspections by the regional government authorities and in addition they are checked by the Paul-Ehrlich-Institute (PEI), the highest authority in the EU for immunological affairs. These examinations and revisions have the aim to guarantee the compliance with the GMP Guidelines.
Today an EU GMP Guide has received statutory authority and defines GMP as that part of any Quality Assurance (QA) System which ensures that patch tests are consistently produced and controlled with respect to the quality standards appropriate to their intended use and as required by the product specifications.
In the following I will report on some significant passages from the GMP Guide. The final version of Annex 15 to the EU Guide to Good Manufacturing Practice describes the principles of qualification and validation which are applicable to the manufacturing process of patch tests. It is a main issue that the mode of production determines the kind of validation work which is necessary to guarantee the control of the crucial items of the respective operations (10).
What does validation mean? Validation is defined as the "Action of proving, in accordance to the principles of GMP, that any procedure, process, equipment, material, activity or system actually leads to the expected results" (GMP 1997) (11). The key elements of a qualification and validation programme should be defined and documented. This documentation may be considered as a Validation Master Plan (VMP).
Process validation is the means of ensuring and providing documentary evidence that processes - within their specified design parameters - are capable of consistently producing a finished product of the required quality. The requirements and principles outlined in the Annex 15 are applicable to the manufacture and packing of pharmaceutical dosage forms. They take into consideration the initial validation of new processes, the subsequent validation of modified processes and the re-validation (12).
Every manufacturing process contains a number of factors that may affect product quality. These factors will be identified during the development of a product and will influence process optimisation studies.
Process validation should normally be completed prior to distribution and sale of the drug product. The technical term for this case is prospective validation.
In cases in which this is not possible, it may be necessary to validate processes during routine production: in this case a concurrent validation has to be done.
Processes which have been in use for some time should be validated in form of a retrospective validation. In theory a validation work needs only to be carried out once for any given process. In reality a process never takes place under the same conditions. Changes occur in components like raw materials and packing materials, equipment is modified, technical affairs are improved and besides that it cannot be assumed that the process environment remains as during the initial validation.
A documented programme exists to review the state of validation and it is necessary to determine the point of tome for re-validation.
At last, a risk assessment approach is a necessary precondition to determine the scope and extent of the validation process. When all these parameters have been collected and generated, they are submitted to the regulatory authority, with all development, manufacturing and stability information, as a licence application. The regulatory authority reviews all the evidence and decides whether or not to grant a licence. It should be noted that if one product receives a licence, hundred have failed at some stage during research and development process. It requires a huge investment on the part of the pharmaceutical companies to bring a new patch test on the market.
Qualification of patch testing against the background of pharmacokinetic parameters (13)
The development of patch tests was for a long time based on experience. The relevant aspects for the diagnostic value of an allergic item are variables of the antigen which are substance-specific and concentration-dependent. On the other hand physic-chemical factors in the special form of the diagnosis medicament influence the rate of release from the ointment base.
The diagnostic relevance depends on various factors, namely the rate of dissolution of the antigen, the rate of diffusion in the matrix and the distribution behaviour between ointment and skin. Knowledge of these regularities and factors will assist in the selection of a suitable test concentration and it will promote the understanding of the mutual interdependencies between the physic-chemical parameters in the form of the diagnostic medicament and the immunologic reaction.
Neither a rational nor a reliable diagnosis of a contact allergy can be made without being familiar with the pharmacokinetic factors of the respective allergen. The task of the pharmaceutical technology is to use the pharmacokinetic examinations for a better understanding and optimising the mode of manufacturing patch tests with regard to their chemical composition and mode of application on the skin. Patch tests mainly consist of suspended antigens stored in an appropriate fatty matrix which is normally white Vaseline. This way, the antigen's rate of dissolution in the basis and its transport through the matrix are decisive factors for the time that passes until the allergic reaction at the skin is produced. Therefore the knowledge of the dissolving behaviour, the lipid/hydro distribution coefficient and the particle size are vital for the technological research. It is the release rate from the ointment basis that determines the beginning, the duration, the intensity and the end of an immunologic allergic reaction (14).
These regularities can clearly be demonstrated when one uses suspension ointments because their dissolving process is the longest phase compared with that of the subsequent absorption into the skin.
The knowledge of these fundamental physic-chemical processes and respective pharmacokinetic speed parameters is vital for a further qualifying process of already existing patch tests and for a better understanding of the immunologic processes. Mathematical models serve to describe the variables which are important for the processes taking place and to validate the results found. Numerous mathematical models have been developed on the basis of the above mentioned interdependence in order to comprehend the absorption process and the passage through biological membranes (15).
But the main question is the practicability of such abstract models which can be made more complex by adding more parameters, however, only to such an extent that the limits between fiction and reality remain obvious. Knowledge of the basic molecular processes which take place in patch tests enables us to influence the subsequent immunologic steps in the human organism.
The recurring question about the antigen's correct test concentration - which is still of highest significance in the field of test quality - has got a new meaning and a stronger importance in the light of the before mentioned interdependencies. Our main objective is to improve the quality of allergy diagnostics by optimising patch tests on the basis of a better knowledge of these laws including all parameters relevant to the rapidity and validity of an allergic reaction.
In-vivo trials support to determine the unknown correlations by describing blood level data of an antigen with the help of an appropriate mathematical function. Thus the functional relation between the molecular processes in the suspension ointment - such as degree of saturation, rate of dissolution in the vehicle and the permeation coefficient - is helpful to improve the quality of patch testing.
Standard for the "qualified person"
One of the principle roles in pharmaceutical manufacturing is that of the "qualified person". No batch of pharmaceutical product may be released for sale or supply prior to certification by a qualified person who testifies that all specifications are in accordance with the requirements of the GMP Guide. Finally the production of patch tests is highly controlled, research and examination of pharmaceutical factors are well studied and steadily qualified, and technical training and scientific education of employees are on a high level. But on the other hand there is a lack of any comparable regulations and requirements for development in personal qualification and personal character.
For many people this aspect seems to be a by-product but to my mind this qualification is of highest importance for any company.
The final decision regarding the handling of any pharmaceutical process is based in the end on the competence, understanding and decision-making of the people working in this field. High qualified processes normally found in every pharmaceutical department, cannot only be determined by a simple yes-or-no-decision. In any way we have to take into consideration the far reaching effects connected with every decision. The attitude of men with reference to economic, personal, technical, social and ecological issues is often driven by one's individual interests, personal wishes and private needs. Moreover, we have to reflect that people mainly focus on those pieces of information, which are in accordance with their personal situation which is for example determined by their school education, their training on the job and their actual way of life. These factors and circumstances lead to individual differences in judgement and assessment of a given situation, of people and processes in a pharmaceutical company. For equalising these facts with the objection to generate highly qualified decisions a binding company philosophy has to be founded. This philosophy has to take into consideration the needs of the company, those of the employees and customers and furthermore possible negative consequences and effects for our environment.
In the brial company we have come to the conclusion, based on long-term experiences, that the standard of material and technical quality is highly correlated with the development in personality and character of our employees (16). Our professional activities, human resources management and company philosophy are founded on the biophilia postulate of the Jesuit Rupert Lay (17).
Hence, corporate responsibility and responsible leadership are the manifestation of our principle "management by participation". We therefore pride ourselves of having developed a corporate culture dealing with inner and outer environment. Our corporate image that has arisen from this over the years corresponds with the theory of a "self-learning organisation" (18, 19, 20).
The realisation of a "self-organising company" with respect to the above mentioned theory requires the introduction of a series of restructuring measures. This process takes several years with both the management and the staff being involved in it. The implemented measures comprise, among others, the personal support of each stuff member. This includes the introduction of perception training and a behaviour analysis, in connection with aspects of leadership. This means communication and presentation training, conflict management, team work training and social ethics.
To my mind the faculty of lifelong learning and the ability and necessity to take decisions weigh heavily in a globalising world. The basis for the personnel development of our team members are clear and transparent working and operation processes in accordance with the requirements of a TQM (Total Quality Management) (21) quality concept and the DIN EN ISO standards (22). The reduction of our hierarchical organisational structures which has automatically resulted from the above mentioned issues has brought about notable changes with regard to our company culture: The internal decision-making has become faster and a management team which performs all management tasks and represents our company was formed. Thanks to the self-control within our management team, several, formerly necessary control measures have furthermore become needless and could be abolished. The decisive factor for a successful implementation of all these measures is the development of the communication ability and social behaviour between our staff members. In addition we carry out communication trainings in order to promote the self-critical analysis of organisational processes within our team. Our company philosophy is shaped by common norms and values which form the basis for dealing with each other within and outside our company. In this way, a corporate identity is created in which the uniqueness of each single staff member finds its expression. Due to this way of working and learning together in an atmosphere of confidence and safety both the staff and the management have got more freedom to concentrate their attention and activities on the quality of our goods with regard to our of customers' and patients' contentment. In this field of management studies and development of leadership qualities we are exploring a new theory of organisation with the intention to create a self-organising company.
As a model we take those structures of nature which are to be seen in analogy to immunologic patterns and behaviour of our body's defence system and the corresponding cell interaction and communication structures in our organism (23).
References
1. WHO Drug Information. 2001; 15(1): 2-5.
2. International Federation of Pharmaceutical Manufactures Associations (IFPMA). Counterfeiting. Download file on http:/www.ifpma.org
3. World Health Organization. Quality Assurance of Pharmaceuticals. Volume 2: Good Manufacturing Practices and Inspection. Geneva; 1999.
4. World Health Organization. GMP: Supplementary Guidelines for the Manufacture of Pharmaceutical Excipients. WHO Technical Report Series. 1999; 885.
5. PIC - Draft: Internationally Harmonised Guide for Active Pharmaceutical Ingredients. Good Manufacturing Practice (API Guide). Brussels: EFPIA; 1997.
6. GMP Audit Guideline for Distributors of Bulk Pharmaceutical Excipients. International Pharmaceutical Excipients Council. 2000.
7. Amico LA, Caricofe RB, English JD, Goodson GW, Lewis LD, Franz RM. Pilot Plant Operation. In: Swarbrick J, Boylan JC, editors. Encyclopedia of Pharmaceutical Technology. New York (NY): Marcel Decker Inc.; 1995;12:187-207.
8. Lay R. Über die Kultur des Unternehmens [Corporate culture, in German]. Düsseldorf, Vienna, New York (NY): Econ Verlag; 1994.
9. GMP Guidelines. Available from: URL: http://eudrams1.is.eudra.org/F2/eudralex/vol-4/pdfs-en/v4an.15.pdf
10. Food and Drug Administration. Division of Manufacturing and Product Quality. Office of Compliance. Guideline on General Principles of Process Validation. Rockville (MD); 1987.
11. Auterhoff G. EG-Leitfaden einer Guten Herstellungspraxis für Arzneimittel [EU Guide to Good Manufacturing Practice, in German]. 5th ed. Aulendorf: Editio Cantor Verlag; 1998.
12. Bias-Imhoff U, Glanzmann G, Woiwode W. Annual Product Review, ein Verfahren der retrospektiven Produkt- und Prozeßvalidierung [Annual Product Review, a procedure of retrospective product and process validation, in German]. Pharm. Ind. 1992; 54(2):177-82.
13. Brinkmann J. About the reliability of allergy tests. 2000. Available from: URL: http://www.brial.com/en/unternehmen/veroeffentlichung_en.asp
14. Martin AN et al. Physikalische Pharmazie [Physical pharmacy, in German]. 4th ed. Leuenberger H, editor. Stuttgart: Wissenschaftliche Verlags-Gesellschaft; 2002.
15. Brinkmann J. In-vivo-Untersuchungen zur Freisetzungskinetik in Arzneiformen [In-vivo trials referring to release behaviours in ointments, in German] [dissertation]. Bonn: Rheinische Friedrich-Wilhelms-Universität; 1975.
16. Brinkmann J. QMS und Firmenphilosophie [QMS and corporate philosophy, in German]. Available from: URL: http://www.brial.com/de/funternehmen.asp
17. Lay R. Kommunikation für Manager [Communication for manager, in German]. Düsseldorf, Vienna, New York (NY): Econ Verlag; 1991.
18. Seiffert H, Rodnitzky H, editors. Handlexikon zur Wissenschaftstheorie [Philosophy of science, in German]. 2nd ed. Munich: Ehrenwirth; 1994.
19. Gouillart FJ, Kelly JN. Business transformation. Vienna: Ueberreuther Verlag; 1995.
20. Puschmann NO. Systemtheorie [System theory, in German]. Unna; 2000.
21. Töpfer A, Mehdorn H. Total Quality Management. 4th ed. Neuwied, Kriftel, Berlin: Luchterhand-Verlag; 1995.
22. DIN - Deutsches Institut für Normung e.V., editor. DIN EN ISO Norm 9000-1. Qualitätsmanagement und Elemente eines Qualitätsmanagementsystems, Teil 1: Leitfaden [DIN EN ISO Standard 9000-1. Quality management and elements of a quality management system, Part 1: Guidelines, in German]. Berlin: Beuth Verlag; 1994
23. Brinkmann J. Allergie im Quantensprung [Quantum leaps in allergies, in German]. Landsberg: Ecomed; 1999.
Jürgen Brinkmann About the reliability of allergy tests Qualification of epicutaneous contact allergens against the background of mathematic abstractions Summary
The development of patch-test-allergens was for a long time based on experience. The properties of relevance for the diagnostic value of an allergenic substance are, on the one hand, variables of the antigen which are substance-specific and concentration-dependent, and on the other physico-chemical factors in the form of the medicament which influence the rate of release from the ointment base. The diagnostic relevance depends on various factors, namely the rate of dissolution, the rate of diffusion in the matrix and distribution behaviour at the interfacial boundary.
Knowledge of these regularities and factors will assist in the choice of a suitable test concentration and help in understanding the mutual interdependencies between the physicochemical parameters in the form of the medicament and the immunological reaction in the biophase.
Hausen, B. M., Brinkmann, J., Don, W.
Encyclopaedia of the contact allergens About the quick and reliable tracking of contact allergens Our concise descriptions will help you to do so. Allergies are currently experiencing a boom. Though their immunologic processes are very clear, it is still a problem to track and thus avoid the substance causing the allergy. This encyclopaedia will make that easier. It provides the reader with concise and useful surveys and recommendations for further readings with regard to over 350 substances and groups causing allergies. In addition, it contains more than 80 contact allergen descriptions with practical and useful information. These data have been very carefully investigated and include information on physicochemical parameters, occurrence and spread of the allergen, sensitization rate and potency, cross reaction and group reaction etc. This way, you have at hand all important information in no time.
And, since moreover numerous potent contact allergens are hidden in our flora, the book also contains concise descriptions of more than 80 allergy plants, providing the reader with all important botanical and allerologic background information. Numerous colour pictures help you with the quick identification of the plant.
J. Brinkmann, Alfred Messmann
"Quantum leaps in allergies" or "Learning from nature"
 What allergies have to do with the "dream of the dreaming cell". New prospects with regard to allergy processes. Normally, allergies are considered and treated as a disease. However, if thinking and perception do a quantum leap and are being inspired by the concept of the Dreambody, we can ask ourselves whether allergies could also be dreams ... only waiting for being discovered and recognized as such.
A fascinating journey through the world of science - starting with quantum physics with its observa-tion effect, followed by the psychoneuroimmunology and including the Dreambody and perception concept according to C. G. Jung and A. Mindell.
To what it serves? To a new and thorough understanding of immunologic systems. New prospects with regard to the "Healing of allergies". And, last but not least, a new, holistic view of health and disease.
Specificity and Sensitivity of Epicutaneous Test Substances Manufactured by Booth-Hermal and Brial - a Comparative Study Study period: September 1, 2002 - March 31, 2003 Patient group:
85 patients recruited (52 females, 33 males, aged 15 - 83 years), 70 patients suitable for evaluation. Study course - materials and methods:
Clinical indication for epicutaneous testing, patient education and consent of patient, use of Finn-chambers, sticking of the Hermal/Brial substances onto each patient's back (H10-20/B10-20, etc.), classical epicutaneous test (after 48 h removal of adhesive test stripes according to good practice in allergology (Praktische allergologische Diagnostik, Ring, et al.), photographical documentation after 48 h and 72 h. Tested substances: · Booth-Hermal (H) European epicutaneous test standard series
Cobalt (II)-chloride, 6H2O 1%, nickel (II)-sulphate, 6H2O 5%, benzocaine 5%, colophony 20%, n-Isopropyl-N`-phenyl-p-phenylendiamine 0,1%, potassium dichromate 0.5%, mer-capto mix 1%, epoxy resin 1%, Peru balsam 25%, p.-tert. butylphenol-formaldehyde resin 1%, paraben mix 16%, perfume mix 8%, mercuric amide chloride 1%, cetostearyl alcohol 20%, zinc-diethyldithiocarbamate 1%, soft-white paraffin 100%, formaldehyde (in water) 1%, chloromethylisothiazolone (3:1 in H20) 0.01%, thiomersal 0.1%, quarternum 15 1%, Germall 115 2%, dibromodicyanobutane/phenoxyethanole (1:4) 1%, bronopol 0.5%, composites mix 6%
· H - Standard series, supplement
Clotrimazole 5 %, pantothenyl alcohol 5 %, sodium fusidate 2 %, sodium bisulfite 1%, stannous(II)-chloride 0.5 %, hexamethylentetramine 1 %, phenyl mercuric acetate 0.05 % · Brial (B) European epicutaneous test standard series
Cobalt (II)-chloride, 6H2O 1%, nickel (II)-sulphate, 6H2O 5%, benzocaine 5% , colophony 20%, IPPD n-Isopropyl-N-phenyl-p-phenylendiamine 0.1%, potassium dichromate 0.5%, mercapto mix 1%, epoxy resin 1%, Peru balsam 25%, p.-tert. butylphenole formaldehyd resin 1%, paraben mix 16%, perfume mix 8%, mercuric (II)-amide-chloride 1%, ce-tostearyl alcohol 20%, zinc diethyldithiocarbamate 1%, soft-white paraffin 100%, formal-dehyde (in water) 1%, chloromethylisothiazolone (3:1 in H20) 0.01%, thiomersal 0.1%, quaternium 15 1%, imidazolidinyl urea Germall 115 2%, dibromodicyanobutane-phenoxyethanole (1:4) 1%, bronopol 0.5% · B ExStandard series, supplement
Clotrimazole 5 %, pantothenyl alcohol 5 %, sodium fusidate 2 %, sodium bisulfite 1%, stannous chloride 0.5 %, hexamethylentetramine 1 %, phenyl mercuric acetate 0.05 % Test substances: summary:
H - 28 substances standard series, 7 supplement
B - 23 substances standard series, 7 supplement Results:
Total number of tested substances - 4550 (B: 2100, H: 2450) Specificity:
· Total number of positive substances - 63/1.3% (= 126 responses for each B and H substances)
· Joint positive substances - 59/2.8% (= 118 reactions for the same B and H sub-stances)
· Different reactions - 4/0,19% (prior to follow-up testing of 2 test subjects 6): Pat. TM: Cobalt - H neg., B pos.; colophony - H pos., B neg.
Pat. KR: Formaldehyde - H pos., B neg.
Pat. SR: Bronopol - H pos., B neg.
(see illustrations) Sensitivity:
· Total number of pos. substances with responses of various reaction intensities - 13/0.61% Cobalt H + / B ++
Nickel H ++ / B +; H ++ / B +++; H +++ / B ++; H +++ / B ++
Benzocaine H ++ / B +
Colophony H ++ / B +
Peru balsam H +++ / B ++
Perfume mix H +++ / B ++
Cetostearyl alcohol H + / B ++
Methylisothiazolone H + / B ++; H +++ / B ++
Imidazolidinyl urea H ++ / B +
i.e. H in 9 out of 13 cases stronger reaction than B, 3 of them with nickel
Evaluation:
The most important parameter here, specificity, was found to be remarkably high, and even more so, since, according to some reports, the results differed when applying one and the same substance manufactured by one and the same company to different parts of the skin. Within the framework of the present study, the products to be tested were applied directly next to each other. In this case, too, specificity was very good. However, it should be mentioned that, owing to the fact that it is impossible to apply precisely the same quantities of test substances onto the Finn-chambers, the significance of the vary-ing intensity of the reactions is limited. Generally speaking, the tests revealed excellently homogenous results which clearly demonstrated that both manufacturers provide the same quality standard.
Feldkirch, June 10, 2003 Prim. Univ.-Doz. Robert Strohal
Department Head
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