COSMETICS

COSMETICS BSL BIOSERVICE
Interdisciplinary and international
BSL BIOSERVICE Scientific Laboratories GmbH, which came into being in 1996 as a result of a management buyoAut of various preceding institutions (commencement 1984, Dr Müller-Lierheim AG; 1990 ANAWA AG Munich; 1995 ANAWA BIOSERVICE GmbH), is now an independent and private contract research oragnisation that has specialised in the broad field of biological trials of drugs, medical products, cosmetics, biotechnological substances and chemicals.
The laboratories have in the meantime been certified for the fifth time in accordance with GLP (Good Laboratory Practice), most recently in 2000, and all tests have been performed in accordance with the internationally valid guidelines (ICH, EU, EPA, MHW, FDA). In addition, the laboratory was the first in the German-speaking countries to receive accreditation for testing of biocompatibility of medical devices in accordance with DIN EN 45001 / DIN ISO 17025.
Furthermore, BSL BIOSERVICE has been licensed by the WHO to perform in vitro and in vivo bioassays to determine biological activity.
Further typical quality characteristics are the licences in accordance with the Law on Protection against Infection regarding handling of microorganisms up to Risk Group 2 (L2 status) and the Federal Epidemics Law regarding handling of genetically modified organisms Stages 1 and 2 (S1-S2), as well as the permit regarding handling of radioactive substances. COSMETICS
Active membership in standards committees and participation in ring experiments at international level, as well as very close collaboration with universities and globally recognised experts guarantee the up-to-date state of science and technology in all tests performed by BSL BIOSERVICE.

The international and mostly long-standing circle of customers from the European countries, as well as all over the world, e.g. from the USA and Japan, currently includes over 500 clients, vouching for the high quality of services. COSMETICS
In line with its intensive customer-based orientation, the company places great value on flexibilAity, speed, adherence to deadlines and individual care.
The comparatively high proportion of 40% of academics (primarily biology graduates and veterinary surgeons) creates the high scientific quality of services and the direct attention to the customer on the part of the project manager in question.
The company is managed by Dr Wolfram Riedel, principal shareholder and managing director, and Dr Angela Lutterbach, company secretary and Head of Biological Trials.
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Biological trials – a conditio sine qua non
The efficacy and safety or harmlessness of a substance can only be elucidated in biological systems, and the complexity of the living organism makes it impossible to consider the issues of efficacy and safety independently of each other.

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For example, the risk of a substance can be defined at molecular, subcellular or cellular level. A harmful effect, however, can possibly only be made visible in a tissue, within an organ, or as a systemic effect in the entire organism.
All these organisational levels are thus to be examined individually, and depending on the question, tests are thus necessary at each stage, beginning with biochemical enzyme assays, for example, and concluding with clinical trials in humans (Tab. 1).
For ethical reasons, nobody would immediately test an unknown substance for efficacy and safety on humans before there was sufficient data from lower organisational levels or from trials in animals.

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Tab. 1: Biological trials at various levels
Level 1: The total organism
Level 2: Biological system groupings
(e.g. circulatory, nervous, immune systems etc.)
Level 3: Isolated organs
(e.g. heart, kidney, liver etc.)
Level 4: Basic biological systems
(e.g. cells, tissue, unicellular organisms etc.)
LevAel 5: Subcellular structural and functional units
(e.g. nuclei, mitochondria etc.)
Level 6: Biomolecules
(e.g. enzymes, transmitters, receptors etc.)

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Thus anyone presenting themself to their clients as a CRO for biological trials must, in addition to sound knowledge of their subject, have a wide range of investigative possibilities at their disposal in order to be capable of problem-oriented processing of the many issues from the fields of pharmaceuticals, medical products, biotechnology, cosmetics and chemistry.
The above contexts also make it clear that to elucidate biological matters, consultation and collaboration with interdisciplinary specialists such as BSL BIOSERVICE provides is practically imperative, not least because the institute has made it its aim to demonstrate its proximity to the customer by providing expert backup for trial results and thus contributing to the development or modification of a product.

The range of services in the field of biological trials

The extensive catalogues of services available, the website (www.bioservice.com) and personal consultation are better suited to that purpose.
However, by means of the following overviews of the biological trials for drugs, medical products, cosmetics and chemicals, an attempt will be made to demonstrate not only to the expert reader that comprehensive work in the institutes is a fundamental prerequisite. To cope with a programme such as this, knowledge of the subject and multidisciplinary expertise (Ill. 3) are essential and are available.
With its services, BSL BIOSERVICE is always ready to realise projects fast, at short notice and efficiently, and to process individual matters with a personal touch.
Despite the absolute necessity of animal trials, which are performed under strict adherence to the Animal ProtectiAon Law, the laboratory places the greatest value on application, development and establishment of alternative trial methods wherever possible. For example, one should mention in this context trial methods such as penetration and permeation behaviour on a skin model, skin corrosion, phototoxicity or the HET CAM Test instead of the Draize Test on rabbit eyes.

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Screening
Pharmacological screening is the start of the development of every active substance, and it constitutes the first stage by way of a filter or sieve in the search for a potentially active substance. The aim of screening is thus to develop so much 'permeability' that on the one hand as many active substances as possible are included and on the other hand the non-active substances are excluded. At this stage of development, involving biochemical or cytobiological processes, safety issues are still of secondary importance.
But toxicological screening calls for a fast and qualitative estimate of the potential danger of a substance or product classified as being active, ultimately in order to contribute towards cutting R&D costs.
In cooperation with the clients, BSL BIOSERVICE can develop and establish customised individual test systems in line with standardised guidelines.

Biological trials of drugs and chemicals
The most important examinations established at BSL BIOSERVICE can be found in Tab. 2.
The special expertise that can lie hidden behind every single trial can be clarified by means of a brief description of a few special tasks, by way of an example.

Skin penetration in vitro
In vitro test systems are developed and validated by BSL BIOSERVICE in order to simulate biological, chemical and physical conditions, and, for examinations, be able to transfer them to the circumstances to be found in the organism.

BSL BIOSERVIACE has at its disposal a specially developed system by means of which examinations of human skin or the skin of mammals can be performed under defined conditions.
The uppermost layer of skin – the stratum corneum – is known as the actual diffusion barrier.
The system is based on diffusion chambers developed in house that facilitate the application of extremely pure substances, as well as ointments, gels, creams or plasters.
The results of such examinations serve to optimise galenic formulations and serve for the interpretation both of data from clinical in vivo trials and of pharmacokinetic and toxicological factors of importance in the risk assessment of chemicals, pharmaceuticals and constituent substances of cosmetics.

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Tab. 2: Biological trials at BSL BIOSERVICE
Toxicology
– Systemic toxicity (acute, subacute, subchronic, chronic)
– Local tolerance
– Contact allergenicity
– Teratogenicity/reproduction toxicology
Mutagenicity / genotoxicity in bacteria and mammalian cells
Pharmacology
– Safety pharmacology
– Pharmacological methods and effects
– Bioassays in vitro and in vivo
– Skin penetration (rat, pig and human skin)
Immune system
– Immunomodulatory properties
– Antiasthmatic, antiallergic properties
Microbiological tests
– Antimicrobial efficacy
– Antibiotic assay
– Sterility
– Microbial impurities
– Organism differentiation
– Water samples
– Hygiene controls (HACCP concepts)
– Bacterial load
– Test for efficacy of antimicrobial preservation
– Detection of mycoplasms
Endotoxin determination, pyrogenic test

Ames TeAst
Bioassays
In a trial performed by 22 laboratories in 11 different countries worldwide, including BSL BIOSERVICE, the international standard for G-CSF (growth factor for granulocytes produced using genetic technology and used in very severe diseases in the fields of haematology and oncology) was ascertained using a large number of different bioassays and immunoassays (cf Journal of Immunological Methods 179, 117-126; 1995).
Further pharmacologically active substances such as recombinant cytokines, growth factors, viral vectors or antibodies (antibody fragments) are tested in the laboratory with regard to their biological efficacy.
Bioassays necessary for this purpose are developed and validated in accordance with a four-stage concept. They are as follows:
1. Selection of a suitable test system, and with cell-based bioassays the characterisation of the cells from various standpoints;
2. Assay development through definition of a suitable biological end point, the standards to be applied and suitable evaluation criteria and methods;
3. Prevalidation of the method, with proof of dose/effect relationships and
4. Validation in accordance with ICH guidelines, including statistical analysis of the results.

Antimicrobial efficacy trials
Dealing with test organisms for validation and quality assurance purposes is now part of everyday routine in every laboratory applying 'good microbiological practice'.
However, it is difficult if laboratory organisms other than the usual ones are required for special trials.
Particularly in the field of efficacy trials (determination of the antimicrobial efficacy of pharmaceuticals, determination of resistance behaviour etc.), special target organisms are required that, because of demanding culturing, containment and test conditions, call for exceptional microbiological expAertise.
For this reason BSL BIOSERVICE developed test systems and assumed overall charge of examinations to determine the antimicrobial efficacy of pharmaceuticals, even against such demanding trial organisms as anaerobic bacteria and protozoa (Arzneim. Forschung./Drug Res. 52, No. 9, 699-705; 2002).
To sum up thus far:
The service of biological trials for the development of substances supports licensing documentation in the field of drugs and notification in the field of chemicals, and includes batch release in quality control (Ill. 4).

Biological safety trials for medical products
BSL BIOSERVICE can claim to hold a leading position in Europe for safety trials of this nature.
In accordance with the new Medical Products Law (in force since 14.06.1998), the biocompatibility of medical products must be assessed to obtain a European licence.
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DIN EN ISO 10993 Part 1 – now used worldwide – serves as a guide to the procedure. The individual biocompatibility trials for surface products (skin, mucosa), externally communicating products (e.g. dentine, bloodpath indirect) and implants (tissue, bone, blood) are described in further sections of this ISO standard.
The trials performed at BSL BIOSERVICE in this context are roughly described in Tab. 3.
Although identity regarding biological trials definitely obtains for Tab. 2 and Tab. 3, a number of test systems are used for the individual areas, requiring special expertise such as is provided by BSL BIOSERVICE. It would thus always be rewarding for manufacturers of drugs or medical devices to establish contact with the institute.

Biological trials for cosmetics
Nowhere are consumer protection and animal protection so emotionally juxtaposed as in the field of cosmetics.
Whilst animal experiments are largely accepted asA being necessary in the field of drugs and for safety trials on chemicals, animal experiments in the field of cosmetics are to be completely replaced.

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Tab. 3: Biological trials for medical products
Cytotoxicity
– Direct cell-contact test
– Agar diffusion test
– Elution test
Mutagenicity / genotoxicity
Haemocompatibility in vitro and in vivo
Skin and mucosa tolerance
Sensitisation
– Maximisation Test (Magnusson/Kligman)
– Closed-patch Test (Buehler)
– Local Lymph Node Assay (LLNA)
Implantation
– Tissue tolerance
– Functionality
Systemic toxicity (acute, subacute, subchronic, chronic)
USP Plastic-class test
Microbiological examinations
– Endotoxin (LAL test), pyrogen test
– Sterility
– Bioburden determination (aerobic, optional and anaerobic organisms)
– Organism differentiation (bacteria, fungi)
– Examination of water samples (TVO, EP)
– Hygiene control (airborne organism count, surface-organism count, HACCP)
– Biovalidation of sterilisation processes
– Efficacy of antimicrobial products
– Trial regarding antimicrobial preservation
– Cleaning/disinfection of reusable instruments

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Not least for that reason, and because of BSL BIOSERVICE's individual obligation to pay the appropriate attention to animal protection, the company is increasingly investing in biological trials using in vitro test systems.
Whilst cyto-, photo- and genotoxicity per se are tested in vitro, test systems of this nature are also available for trials regarding local tolerance. In this context one should above all mention the test for photo irritation by meAans of a neutral red photograph, the test on red blood cells and the HET-CAM test (Hen's Egg Test Chorion Allantois Membrane) as an alternative to the Draize Test.
Microbiological examinations for cosmetics can be derived from Tab. 2 and Tab. 3.

Outlook
The extensive programme of biological trials for a great variety of products offers a sufficient basis for further future growth, whereby the company is not investing in growth at any price, but recommends itself by virtue of a long-term strategy on the basis of clear comprehensibility in terms of size, flexibility, speed and personally characterised proximity to the customer.
BSL BIOSERVICE offers a balanced and sound range of services that is of interest to all potential clients who are seeking and who appreciate individual service, individual contact and advice, as well as individual professional implementation of trials.

Summary
BSL BIOSERVICE is an independent CRO that concentrates on biological trials of drugs, medical products, biotechnological substances, chemicals and cosmetics.
The interdisciplinary and internationally accepted approach of the institute, with its various accreditations and certifications (GLP, DIN EN ISO 17025), guarantees high quality biological trials.
Biological trials with regard to a wide variety of issues call for extremely varied methods of examination, ranging from many in vitro methods through to carefully planned and implemented animal trials. The trials offered by BSL BIOSERVICE in this connection are clearly depicted in Tab. 2 and Tab. 3.
In addition, the company's services include extensive microbiological services through to batch release.
Any client who appreciates the advantages of the individuality of a commission institute will be well served by BSL BIOSERVICE.

Keywords:

COSMETICS, Genotoxicity, Cytotoxicity, Bioassay, Mutagenicity, Biocompatibility, Mikrobiologie, Microbiologie, Skin, Bioservice, Toxicity, Medical, Device, Testing, Notification, Legionellen, Cosmetics, Amestest, Bioburden, Chemicals, Steriltest, Steril test, Sensitisation, BSL, Permeation, Drug, GMP, Pharmacology, Endotoxin, LLNA, Sterilisation, chemicals testing, drug testing, medical device testing, notification chemicals, medical device biocompatibility, GLP toxicity pharmacology, GMP microbiologie, mutagenicity chemicals, genotoxicity chemicals, toxicity chemicals, Immunotoxicity, Immunogenicity.