Pre-clinical safety drives drug development

Convincing proof and documentation of a drug’s quality, safety and efficacy is a prerequisite for regulatory authorities worldwide when issuing marketing authorisation for a new product. Quality and safety are decisive factors in determining how likely a new pharmaceutical ingredient or drug preparation is to reach the clinical phase for demonstration of efficacy. There is a very fine line between success and failure in this phase of drug development.

The Research and Consulting Company (RCC) Ltd was founded in 1977 in Switzerland as an independent, privately owned company. Its highly experienced staff are dedicated to efficient product development and giving the client the necessary support for a successful market launch of a new pharmaceutical.

The RCC team of specialists understands the commercial realities and requirements for both new biopharma start-ups and top pharma companies, and can customise the most efficient programme for pre-clinical development for individual customers. This approach has been incorporated into RCC’s fast-into-man® drug development concept, which represents a fast and cost-effective way for a new drug to reach the clinical phase I.

On approval of the project plan by the client, a project leader is appointed to oversee the implementation of the plan in laboratories and test facilities. Lines of communication and information exchange are set up to facilitate timely and appropriate decision-making. In the laboratories and test facilities, experienced study directors and teams of well-trained technicians who are experts in their field realise the tests and studies in due time, ensuring that results are available promptly and within budget.

It is very important to characterise the quality of a new active ingredient or drug at the beginning of the pre-clinical development programme. Insufficient specifications with wide acceptance criteria, inadequate supporting data, missing tests and inadequate or improperly validated analytical procedures are just some of the factors that might lead the regulatory authorities to refuse an application for marketing authorisation or question the results of studies.

Consequently, RCC’s analytical department offers a broad range of services to characterise the quality of drugs, from early development to quality control of marketed products. The laboratories are equipped with modern instruments covering a broad range of technologies. The techniques and expertise of the staff comprise small molecules and biomolecules, such as RNA, DNA, proteins and peptides. All tests can be performed under GLP or GMP as required by the client.

Standard pharmacopoeial and physicochemical testing is carried out according to European Pharmacopoeia and US Pharmacopoeia, and analytical methods for new and existing compounds can be developed and validated in line with specific guidelines. Stability testing according to ICH guidelines and quality control of active ingredients and drug products can be realised under GMP.

Analyses of active ingredients and metabolites in plasma, urine and tissues are enabled by well-equipped laboratories. From a simple new chemical entity to marker substances in complex phytopharmaceutical extracts, appropriate and sensitive analytical methods have been developed and validated in different biological matrices.

Passing the regulatory test

For the assessment of the toxicological profile of a drug, RCC carries out a wide range of regulatory toxicology studies to support the pharmaceutical industry and to meet the expectations of the regulatory authorities. Studies on single-dose toxicity, maximum tolerated dose, local tolerance and repeat-dose toxicity, which can last from two to 52 weeks are routinely carried out, as are regulatory carcinogenicity studies and carcinogenicity studies with genetically modified animal models (p53).

Special techniques for toxicological studies are developed and validated at RCC to meet the wishes of clients as well as changing regulatory requirements. For example, in-house experts at RCC developed asthma models for studies of inhalation toxicology in rats and dogs. These studies are frequently used by clients all over the world and widely accepted by the regulatory authorities.

The studies on toxicological profiles of active ingredients and pharmaceuticals require strong support from pathology and histopathology to ensure a scientific interpretation of results. Histopathology processes approximately 30,000 organs every month.

The early screening of several lead substances to select candidates for a pre-clinical test programme is one of the most critical points in the drug development process. RCC has established a set of techniques to make drug discovery more successful. All of these tests and techniques are fast and cost-effective, require only small amounts of substances, and are carried out under non-GLP conditions, but without any negative impact on the reliability of results.

These tests involve investigating the metabolic stability of a compound and generating preliminary results on absorption, distribution and elimination, preferably in rats. The technique of automated blood sampling plays a special role, allowing up to eight blood samples to be collected from one rat under stress-free conditions, as well as overnight sampling. In this way, reliable pharmacokinetic parameters can be obtained at a very early stage of development.

Another critical point is the possible interaction of a drug candidate with other drugs on the level of the Cytochrom P450 system and the transport systems for xenobiotica (PGP-Glycoprotein). Once a candidate has been selected and the pre-clinical test programme is underway, drug metabolism studies using radio-labelled material or unlabelled drugs can be carried out. Whole body autoradiography and real-time (quantitative) PCR are also available.

Last but not least, the data and results of all tests and studies must be evaluated and presented in a convincing manner to the regulatory authorities regulatory affairs group when applying for marketing authorisation. The experienced drug regulatory affairs group offers services covering the full range of human and veterinarian medicinal products, such as new active ingredients, generics, herbal medicinal products and biotech products.

Regulatory affairs managers prepare all parts of registration dossiers, sit in on negotiations with the authorities, organise the follow-up in terms of submitting documents, and handle deficiency lists and variations.

The high quality of RCC’s integrated service in all fields of pre-clinical development is supervised and maintained through effective quality control. The company guarantees the highest standards of animal welfare. Its highly evolved corporate culture is based on a strong sense of responsibility for the work it does and a commitment to reliability and punctuality.