Alternative Methods Used in the Development and Safety Testing of Drugs Biologicals and Medical Devices Table 101

As outlined above, the number of experimental animals used by the drug industry in Germany has decreased during the past 25 years by more than 90% (see Fig. 10.2). This development is typical for the international drug industry, and is due to a general change of models that are used in the life sciences. Research in pharmacology is no longer centered around animal models of disease but rather is focused on molecular models. Biochemical pharmacology has been replaced by molecular pharmacology, which is shifting towards molecular genetics. The new molecular methods allow HTS of several thousand new drug candidates each month such that, today, animal models are only to monitor the efficacy and safety of the most promising lead chemicals before they enter clinical trials in humans.

Table 10.1 In-vitro tests which have replaced test animals in the quality control of biological drugs and in toxicology.

Purpose of testing

In-vitro method

Animal test

Degree of replacement

Accepted by regulatory authorities (country)

Quality control: biological drugs

Pregnancy test (immune assay)

Frog test

Complete replacement

Worldwide

Pyrogenicity test (limulus-(LAL)-test) (human cytokine TNF-a; ELISA)

Rabbit test

Replacement for protein-free solutions

Replacement for all applications

US-, EU- and Japan-Pharmacopoeia

E U - Pharmacopoeia submitted

Vitamins and hormones (vitamins, oxytocin, calcitonin, parathormone, sexual hormones)

Bioassay in chicken, rats, and mice

Complete replacement

E U - Pharmacopoeia

HPLC, immune assays

Insulin-determination (HPLC)

Convulsion test in mouse

Complete replacement

US- and EU-Pharmacopoeia

Insulin-determination (HPLC)

Blood glucose determination in mouse and rabbit

Complete replacement

US- and EU-Pharmacopoeia

Toxicity testing

Eye irritation (HET-CAM test; BCOP test; isolated chicken eye; isolated rabbit eye

Draize test in rabbit's eye

Replacement for severely irritating materials

EU according to OECD Test Guideline 405 Germany, Belgium Netherlands, U.K.

Phototoxicity (3T3 NRU phototoxicity test)

Phototoxicity tests in rabbit, rat, and guinea pig

Complete replacement

OECD Test Guideline 432

Skin corrosion (human skin constructs)

Corrosivity testing on rabbit skin

Complete replacement for corrosive materials

OECD Test Guideline 431

Skin penetration (human skin)

Skin penetration test on the skin of rats

Complete replacement

OECD Test Guideline 428

Delayed neurotoxicity of organophosphates (NTE-esterase determination in neuroblastoma cells)

OECD: neurotoxicity test of organophosphates in chicken

Partial replacement for esterase inhibitors

Worldwide according to OECD Guidelines 418 and 419

Due to progress in molecular genetics and biotechnology during the past 20 years, most hormones and other biologicals are no longer extracted from human and animal tissues but rather are produced by bacteria and cell lines. Insulin is an excellent example of this process as, in the past, it had to be extracted from the pancreas of cattle and pigs, and the potency of the extracts standardized in tests on rats and rabbits. In addition, safety tests had to be conducted on animals to detect impurities resulting from the extraction and purification procedures. For reasons of quality control, both potency and safety tests had to be conducted on each batch of insulin, and consequently, companies producing insulin conducted animal tests continuously in order to ensure the quality and safety of the drug.

Today, in the treatment of diabetes, bovine and porcine insulin have been replaced by pure human insulin produced by bacteria or genetically engineered mammalian cell lines. Therefore, extraction procedures are no longer needed, there is no contamination from the tissues of the donor species and, consequently, animal tests needed for quality control are no longer necessary. In contrast, the production of human insulin today is conducted according to the high standards of good manufacturing practice (GMP), which includes quality control of the final product by sensitive analytical methods. Experience has proven that this type of testing is sufficient for providing both doctors and patients with the highest quality of human insulin, which is free of contamination. For the reasons described, animal tests are today no longer conducted to ensure the safe use of insulin in diabetic patients.

Likewise, many other hormones and biologicals which previously required extraction from human or animal tissues are today produced by applying advanced technologies at the highest level of purity. Hence, most ofthe animal tests required to standardize the quality of these materials need no longer be conducted. Thus, the humanity criterion proposed by Russell and Burch has indeed become true in the production of hormones and other biologicals.

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