How TOC analysis delivers results for drug makers

Total organic carbon (TOC) analysis remains a key backbone of the pharmaceutical production process. Here, Peter Morgan - technical product specialist at Elementar UK - explains how TOC analysers help to deliver reliable results for drug makers, and how new advances are keeping them at the forefront of the quality assurance (QA) process.

In a sector as stringently regulated as the pharmaceutical industry, defensibility of data is everything. The safety of even the most common production processes can never be taken for granted; the reliability of an organisation’s results, and the purity of its products, needs to be constantly demonstrated and documented to retain regulatory accreditation.

It is within these demanding circumstances that total organic carbon (TOC) analysis has emerged as a quality assurance (QA) gold standard, with regulators such as the US Food and Drug Administration (FDA) and the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) adopting it as a best practice method for evaluating organic contaminants throughout the pharmaceutical industry.

TOC analysers offer a proven way for manufacturers to guarantee the microbial integrity of therapies and prevent cross-contamination between product batches. Moreover, the latest technological improvements mean they are now able to do so in a way that is more efficient and reliable than ever, at a time when QA in drug development has arguably never been more pivotal.

TOC analysis - more important than ever?

One of the key reasons why TOC analysis is coming to the forefront of pharmaceutical manufacturing is the recent move away from exclusive blockbuster drugs, towards a model where more companies are producing a wider variety of medications.

In the past, most therapies would be manufactured exclusively by their patent holders using dedicated production processes, but recent waves of patent expiries have opened up the market to a glut of contract-based manufacturers producing multiple generic products within the same facilities, using the same equipment. At the same time, growing interest in personalised medicine means that the era of the one-size-fits-all therapy may be coming to an end, requiring an even more significant diversification of production approaches than has been seen so far.

As such, regulators are paying closer attention to product quality than ever, in order to ensure that production standards are being upheld and that compliance with their guidelines is being stringently documented. This paradigm shift has meant that reliable industry-standard verification methods like TOC analysis have an unprecedented opportunity to offer a reminder of their value.

Proven benefits of TOC analysis

TOC analysis has two primary applications in pharmaceutical production: for identifying and facilitating the removal of carbon impurities found in the products themselves, and for verifying the effectiveness of the cleaning work carried out between production batches.

The instruments operate by releasing the carbon contained within the sample in question by oxidising it, either by breaking it down through the use of UV/persulfate decomposition, or by placing it inside a high-temperature combustion furnace. This converts the carbon into carbon dioxide gas, which can then be identified using an IR detector.

Pharmaceutical manufacturers usually find that the UV/persulfate digestion method delivers the greatest benefit - drug production usually deals with relatively pure samples, without many instances of the kind of large solid mass that environmental scientists rely on furnace combustion-based TOC analysers to break down. In this context, the digestion-based approach proves to be cheaper and more efficient, as well as offering lower detection limits due to the fact that larger sample sizes can be analysed.

The use of TOC analysis in cleaning validation has been shown to deliver particularly considerable value for drug makers, allowing manufacturers to ensure that any containers or vessels used in the production have been decontaminated thoroughly before the next batch is produced. This can be done by testing the final rinse solution of washing water for TOCs, or by analysing a swab sample.

This method offers a number of benefits - it has been shown to prevent microbial build-up on equipment and stops the transfer of bio-burdens between products, enhancing lot integrity in a way that is quicker and more precise than other methods; moreover, because it is not ingredient-specific, it is ideal for situations where more than one type of impurity might be expected

New innovations solving existing challenges

As with any pharmaceutical industry methodology, TOC analysis remains a work in progress, with new solutions continuously emerging to solve the remaining challenges that manufacturers still face when carrying out this kind of work.

One common issue is the fact that most pharmaceutical production sites usually rely on UV/persulfate decomposition-based analysers, which makes it difficult to carry out any analysis that would require a combustion-based system. For instance, when analysing a large, solid swab sample that cannot be effectively dissolved - without investing in a separate piece of equipment that would only be used in specific circumstances.

However, technological innovations are now helping to bridge that gap: the acquray system, for example, is a newer UV/persulfate system that provides an add-on combustion furnace module, allowing labs to carry out occasional solid analysis using the same IR detection methods as the core digestion-based unit. As the market continues to evolve, new functionalities of this kind will continue to be added to TOC analysers to further improve their efficiency and reduce the amount of laboratory downtime to a bare minimum.

In this way, TOC analysis remains well positioned to continue meeting the demands of pharmaceutical manufacturers, even as the sector continues to diversify and embrace new operating models. Production strategies may change, but the importance of quality, purity and traceability is something that drug makers simply cannot allow to fall out of fashion - and TOC analysis is still one of the best ways of ensuring that doctors and patients can remain confident in the safety and effectiveness of their medicines.