Better, Faster, Cheaper, Safer Drugs - Getting Drugs to Market More Quickly And Cheaply

Main Category: Pharma Industry / Biotech Industry
Article Date: 29 Apr 2005 - 10:00 PDT

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Measurement scientists at the National Physical Laboratory are helping the pharmaceutical industry to get better drugs to market more quickly and cheaply - by reducing the time and cost of testing.

It can take up to fifteen years to develop a biopharmaceutical drug from original patent to mass market. This long development time drives up the cost of the drug, not the least because most patents last just twenty years, so restricting the drug's profitability to the patent's owner.

Biopharmaceuticals - biological molecules used as therapeutic agents - are manufactured by biotechnology and pharmaceutical companies to extremely high specifications set by regulatory bodies such as the Medicines and Healthcare products Regulatory Agency (MHRA). Success in the lucrative US market requires accreditation by the Food and Drug Administration (FDA).

Drugs that fail to comply with these regulations cannot be sold. Regulatory approval requires extensive testing including biological activity testing and clinical trials in patients. Testing continues after regulatory approval and product release to ensure quality and monitor long-term exposure effects.

The regulators need to have confidence in measurements made by the drugs industry, which in turn would like to keep measurements to the minimum required to produce safe and effective drugs in a cost-effective way. But only when there is less uncertainty in the data will regulators be satisfied with less testing.

NPL is working to bridge these two requirements as part of the new Measurements for Biotechnology (MfB) programme (2004-7) under the National Measurement System.

One of the programme's first projects aimed to quantify the accuracy of a common protein measurement technique - Circular Dichroism Spectroscopy.

This is a rapid method of determining whether a batch of protein biopharmaceutical has adopted its correct structure and consequently has a level of biological activity that is still traceable to material used in the clinical trials. Although potentially a valuable test, the technique is not widely used due to perceived inaccuracies.

NPL's mission was to find where inaccuracies were coming from. Samples of a standardised protein biopharmaceutical were sent for analysis by 27 different laboratories serving the pharmaceutical industry - with widely varying results.

"There was a range of errors," says Dr Marc Bailey from NPL's Quality of Life division. Some of the results were very good and some were very poor. Some of the results suggested the protein was partially unfolded and therefore inactive. Even those laboratories which provided good data could not provide an absolutely accurate set of circular dichroism spectra for the biopharmaceuticals.

"This is the sort of test outcome that could delay the approval of, or even lead to the discarding of, a batch of biopharmaceuticals which are biologically active and suitable for release," Dr. Bailey says. "Given the costs of manufacturing protein biopharmaceuticals, it is important to get these tests right."

The variations were mostly down to poor calibration and operation of the equipment, prompting NPL to develop the training and calibration services which will help laboratories to get reliable and consistent results.

Further quality assurance criteria for industry are being developed by NPL, with a number of MfB projects - in collaboration with the pharmaceutical industry - to develop new tests or validate existing procedures.

Projects (funded under the Measurements for Biotechnology programme)

-- The quantitation of host cell protein and DNA contaminants in biopharmaceutical products - validating new genomics and proteomics methods for this application.

-- Biopharmaceutical activity is currently determined by cell-based bio-assays. This project is seeking to determine the sources of uncertainty and validate alternate physicochemical methods.

-- Use of optical spectroscopies to determine the structure of protein biopharmaceuticals - working towards standard operating procedures and new calibration methods

Notes to editors

-- NPL runs the Measurements for Biotechnology programme in collaboration with LGC Ltd and the BioIndustry Association.

-- The MfB programme (http://www.mfbprog.org.uk) supports the UK's National Measurement System and is funded by DTI. It aims to develop a robust international biological measurement system, capable of sustaining a safe and competitive bioindustry.

-- There are four themes for 2004-07: Cell-based testing; Gene measurement; Product characterisation; and Protein measurement.

-- Progress made in the first years of the MfB programme (2001-04) is documented in Better Measurement for Biotechnology, produced by the BIA.

Further detail - background

Modern biopharmaceutical products include vaccines, therapeutic antibodies (including important anti-cancer agents) and other medical products such as human growth hormone.

Most of these products are produced by fermenting a 'broth' of selected or genetically-altered host organisms and then separating the target bio-active molecule from the fermentation mixture.

The target product, a complex and large organic compound and often a protein, is invariably produced along with other protein molecules or DNA fragments, which require separation and purification. Complete purification is normally economically (and technically) impossible so the pharmaceutical product usually contains less than1% contaminants, which may contain 1 - 100's of different protein molecules, depending on the process.

The product is subject to toxicity testing to ensure none of the contaminants are harmful. Other testing is required to give an estimate of the quantity of contaminants. As the production is a batch process each batch must be subject to rigorous safety testing. Animal testing is a regulatory requirement for toxicity testing during the early phase of product development. This can be costly, time consuming and has ethical issues.

What is NPL doing?

The Measurements for Biotechnology project will apply state-of-the-art techniques to analyse products and determine product profiles - i.e. identify and quantify the product/contaminant mixtures produced.

Product profiles will be determined for the material used for clinical trials - the human-based "gold standard" for drug approval against which production batch profiles can be compared. This could reduce the amount of testing required for each batch release.

The techniques include Quantitative Polymerase Chain Reaction for DNA analysis, and high performance liquid chromatography combined with mass spectroscopy for protein determination.

The idea is to produce new techniques that can be used at the production facility to provide accurate and precise quality control. In particular, the project will be working closely with the Food & Drug Administration (FDA) in the US to ensure the techniques are compatible with FDA requirements.

NPL is building good working relationships with the relevant regulatory authorities and expects to work with regulators and industry to develop methods that are fit-for-purpose and regulatory compliant.

The FDA is important because the US is the largest and most influential market for both established big pharmaceutical companies and new biotech start-ups.

New testing methodologies could give UK pharma industry a tangible competitive edge in terms of quality control, reduced testing costs and safety.

The new techniques improve manufacturing (reducing amount of testing/ reduced cost/ drive more consistency in production) without compromising safety. Many of the analytical methods applied to the testing of biopharma products have not changed since the start of the biotechnology industry in the 1970s. The science/analytical techniques have moved on considerably since then - it is time to apply them to production.

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