Modern science for better quality control of medicinal products "Towards global harmonization of 3Rs in biologicals": The report of an EPAA workshop.

This article summarizes the outcome of an international workshop organized by the European Partnership for Alternative Approaches to Animal Testing (EPAA) on Modern science for better quality control of medicinal products: Towards global harmonization of 3Rs in biologicals. As regards the safety testing of biologicals, the workshop participants agreed to actively encourage the deletion of abnormal toxicity tests and target animal batch safety tests from all relevant legal requirements and guidance documents (country-specific guidelines, pharmacopoeia monographs, WHO recommendations). To facilitate the global regulatory acceptance of non-animal methods for the potency testing of, e.g., human diphtheria and tetanus vaccines and veterinary swine erysipelas vaccines, international convergence on the scientific principles of the use of appropriately validated in vitro assays for replacing in vivo methods was identified as an overarching goal. The establishment of scientific requirements for new assays was recognized as a further means to unify regulatory approaches in different jurisdictions. It was recommended to include key regulators and manufacturers early in the corresponding discussions. Manufacturers and responsible expert groups, e.g. at the European Directorate for the Quality of Medicines and Health Care of the Council of Europe or the European Medicines Agency, were invited to consider leadership for international collaboration.

Import Testing: An Outdated Practice? Opportunities for Improved Access to Safe and Efficient Medicines.

Import testing of medicines is performed in the middle of the legitimate supply chain when a product enters a country. Risks, however, are identified in the illegitimate supply chain and in the trade within a country. Hence, import testing does not add any significant value to the quality and safety of drugs nor reduces risks, provided the manufacturers apply good practices, for example, Good Manufacturing Practices (GMPs) and Good Distribution Practices (GDPs). The consideration to implement additional regulations does not correlate with the increasing convergence between National Regulatory Authorities (NRAs) and international harmonization, for example, Pharmaceutical Inspection Co-Operation Scheme (PIC/S) and International Council for Harmonisation (ICH). This publication reflects the historical application of import testing and today's practice, concerns, and misconceptions of this redundant procedure. It explains why postmarketing surveillance testing is better suited to control the quality of medicines, addressing highly relevant concerns: counterfeits and supply interruptions.

Historical data analyses and scientific knowledge suggest complete removal of the abnormal toxicity test as a quality control test.

In the early 1900s, the abnormal toxicity test (ATT) was developed as an auxiliary means to ensure safe and consistent antiserum production. Today, the ATT is utilized as a quality control (QC) release test according to pharmacopoeial or other regulatory requirements. The study design has not been changed since around 1940. The evidence of abnormal toxicity testing as a prediction for harmful batches is highly questionable and lacks a scientific rationale. Numerous reviews of historical ATT results have revealed that no reliable conclusions can be drawn from this QC measure. Modern pharmaceutical manufacturers have thorough control of the manufacturing process and comply with good manufacturing practice rules. Contaminants are appropriately controlled by complying with the validated manufacturing processes and strict QC batch release confirming batch-to-batch consistency. Recognizing that product safety, efficacy, and stability can be ensured with strict QC measures, nowadays most regulatory authorities do not require the ATT for most product classes. In line with the replacement, reduction, and refinement (3Rs) initiative, the test requirement has been deleted from approximately 80 monographs of the European Pharmacopoeia and for the majority of product classes in the United States. For these reasons, it is recommended that the ATT should be consistently omitted world-wide and be removed from pharmacopoeias and other regulatory requirements.

Forced degradation of therapeutic proteins.

The scope of this paper is to review approaches used for forced degradation (synonym, stress testing) of therapeutic proteins. Forced degradation studies play a central role in the development of therapeutic proteins, for example, for candidate selection, molecule characterization, formulation development, assay development, and comparability studies. Typical stress methods are addressed within this review, such as exposure to elevated temperatures, freeze-thawing, mechanical stress, oxidation, light, as well as various materials and devices used in the clinics during final administration. Stability testing is briefly described as far as relevant to the discussion of forced degradation studies. Whereas stability-testing requirements are defined in regulatory guidelines, standard procedures for forced degradation of therapeutic proteins are largely unavailable, except for photostability. Possible selection criteria to identify appropriate stress conditions and recommendations for setting up forced degradation studies for the different phases of development of therapeutic proteins are presented.