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European Biopharmaceutical Review

TSE Certification - The Early Development Paradox

Ian Lafferty and Emma Mickley at R5 Pharmaceuticals discuss the TSE certification paradox in biotechnology-derived therapeutic formulation development and GMP manufacturing

Biotechnology-derived therapeutics, by their very nature, are administered parenterally, often intravenously. Furthermore, the processes by which they are manufactured involve a number of steps which can introduce potential infection risks, such as possible viral components. This article focuses on the requirement for TSE-free certification of biotechnology-derived products and how this can be a sticking point for small biotech companies in the earlier stages of product biomanufacturing development, namely formulation and final product process development.

Transmissible spongiform encephalopathies (TSEs) describes a range of rare but fatal neurodegenerative diseases resulting from the cellular build up of infectious proteins known as prions. Prions are non-living organisms that adhere extremely easily and vigorously to surfaces and are known to move from surface to surface during processing operations. Furthermore, they are highly resistant to protease treatments and other normal protein denaturation techniques such as heat. TSE diseases in animals include bovine spongiform encephalopathies (BSE) in cattle and scrapie in sheep and goats, while in humans it causes a range of diseases, the most well-known of which is Creutzfeldt- Jakob Disease (CJD) for which there is no known treatment. Across all species, TSE diseases are generally not fully diagnosed until post-mortem.


While the mechanism of transmission is still not fully understood, there have been clear incidences of cases resulting from the use of inadequately decontaminated neurosurgical equipment and medical treatments such as the administration of hormones prepared from human pituitary glands, corneal grafts and blood transfusions.

Although there are many natural barriers to interspecies transmission, BSE in cattle is clearly recognised as resulting from the feeding of infected meat and bone from other infected animals, with strong indications linking the consumption of beef from infected cattle by humans to CJD. As a consequence, the possibility of transmission via pharmaceutical products is a major concern and must be taken seriously.

After the issue was first identified in the late 1990s, the European Commission issued a number of directives, including a ban on a wide range of bovine materials, potentially including common biopharmaceutical reagents such as bovine serum albumin. Consequently, it quickly became obvious that this was not feasible in the case of medicinal product development and manufacture. Indeed, if it had actually been implemented, it would have resulted in more than 80 per cent of all pharmaceutical preparations being taken off the pharmacy shelves. Since then, a range of legislation and guidance has been issued by the regulatory authorities aimed at minimising the risks by using a process of risk assessment to take account of all the factors involved (European Directive 1999/82/EC).

These are based on three broad principles:

  • Control of the source animals: where it is not possible to avoid the use of animal materials by using synthetic or non-animal alternatives, then animals should be selected from: – non-TSE susceptible species – geographical regions known to be free of TSE – younger animals
  • Select animal tissue known to have a lower degree of infectivity, for example gelatine derived from bones and hide is preferable to materials sourced from blood or brain tissue
  • GMP control of all aspects of the manufacturing process from API and excipient manufacture to final product preparation and delivery, including rigorous quality systems to ensure full traceability and consistency of human and veterinary pharmaceutical products (plus cosmetics and neutraceuticals)


With respect to the formulation development and manufacture of biotechnology-derived drug and vaccine products, it is obviously impossible to avoid the use of animal-derived materials as they are integral parts of the API manufacturing processes, such as mammalian cell cultures and bacterial fermentation. Many of the materials involved in these bioprocesses are not the subject of regulations or licensing requirements, and it therefore falls to the biomanufacturer suppliers and users to follow best practices to ensure that the final products can be certified as TSE-free.

Other formulation excipients are not free from scrutiny either and it is often not obvious that they have an animal origin. These materials include fatty acids, fatty alcohols, amines, amides, fatty acid esters and oils incorporated or involved in the manufacture of plastics, lubricants and antioxidants. Also in the spotlight are greases and oils used to lubricate processing equipment and surfactants used in equipment cleaning.

Biotech products often require specific buffers to maintain therapeutic integrity, development of novel processing techniques or careful handling precautions once in final product form. Therefore the need for the early development of a robust formulation is essential. It is also key to design a formulation and a final product manufacturing process that is transferable to a larger scale for late-stage clinical trials as well as commercial manufacture.


For many reasons, including commercial considerations and the availability of specialist scientific expertise, a large proportion of biotechnology-derived product development is outsourced to contract formulation development and manufacturing organisations. The vast majority of development laboratories that support biological product development are also involved in clinical or commercial final product manufacture and therefore have GMP status at their facilities. In order to comply with the rules outlined above (for the control and traceability of animal-derived products) these contract development and manufacturing organisations must impose a strict set of raw material acceptance criteria and supplier approvals processes as part of their GMP quality system. In essence, this involves requesting TSE certification from all raw material suppliers and ensuring that any certification supplied is provided with due diligence. Many of these organisations actively advocate that they run a TSE-free or animal component-free facility and specifically refuse to allow any non-TSE certified material into their facilities.

However, application of these requirements generally precludes the introduction onto a site of any material, even for use in non-clinical formulation and process development, unless it can also meet the requirement of TSE certification, as to do so would compromise their GMP and TSE-free status by introducing risks (or often simply the perception of risk) due to cross contamination that in turn will deter subsequent potential clients from engaging them and their facilities as an outsourcing partner.

This situation can create a paradox as small biotechnology companies will often possess small amounts of their development drug substance, which is perfectly suitable for formulation development, but does not have the necessary TSE certification due to the fact that in the initial stages they may not have realised the necessity for raw material traceability or that cleaning procedures for equipment between batches and between products need to be well documented. Also, in many cases, they may not have even been aware that animal-derived material was involved in some early stages of their API manufacture. While the risk assessment process may be applied retrospectively, it is likely that gaps will exist in the availability of the necessary information. As a result, it is often difficult for these small, emergent and often virtual biotechnology companies, who need to scale up into early clinical trial manufacture, to identify possible contract research formulation development partners with the necessary expertise who can also manage their non-TSE certifiable material.

A flexible approach is important to accommodate these situations as the alternative can be a complete halt to a development programme while new APIs with the necessary certification can be manufactured – assuming they remain commercially viable at all.

One way to accommodate such issues is for contract development and manufacturing organisations to maintain a dual-site approach to their activities, whereby they have a GMP-regulated site for all compliant materials, development and manufacturing operations that can be performed with TSE-compliant materials and another completely remote and nonintegrated site for the handling of non- TSE-compliant materials. Both sites can obviously benefit from the same expertise and scientific skills, while employing strict quality procedures to ensure no product or equipment is transferred between GMP and non-GMP laboratories or sites. Once suitable formulation development and proof-of-concept batches have been developed using the non-TSE certificated materials, confidence will be sufficient to support the manufacture of more APIs with all the necessary safeguards to make it suitable for the clinical batch manufacturer.


For all small biotechnology companies, the best course of action is to be familiar with the various regulatory requirements so that they are aware of any potential pitfalls or delays as development candidates progress. Furthermore, it is obvious that contract houses offering biotechnology-derived therapeutic GMP support should also consider a dual, flexible model to allow non-GMP and non-TSE certified therapeutic formulation and manufacturing process simulation, prior to formal GMP manufacture and all of the regulatory requirements which that entails.

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Ian Lafferty is the Chief Technical Officer (CTO) at R5 Pharmaceuticals and has been an essential member of the R5 team since March 2009. Ian specialises in sterile product development and manufacture and was Manufacturing Director for six years at Nova Laboratories prior to joining R5. He has always worked in dosage form development and has gained considerable experience across most dosage forms during positions with West, AZ and MSD. Ian completed his BSc Hons degree at Liverpool John Moore University and his PhD at the Department of Pharmaceutical Sciences, De Montfort University.

Emma Mickley is the Director of Business Development at R5 Pharmaceuticals, joining the company in November 2009. Prior to her role at R5, Emma specialised in preclinical biopharmaceutical development including discovery and regulatory toxicology, ADME and safety pharmacology with positions at CXR Biosciences, Charles River Laboratories and Quintiles. Emma also worked at the consultancy firm, Wood Mackenzie, as an analyst in the Pharmaceuticals and Biotechnology team. She gained her First Class Honours degree in Pharmacology from Kings College, University of London and her PhD from the Department of Medicine, University of Edinburgh.

Ian Lafferty
Emma Mickley
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