Foolproof testing times
Despite the requirement for validation in the pharmaceutical industry there is no standard sampling procedure for liquid preparations. Now, however, a novel, aseptic solution has been introduced.
The pharmaceutical and biotechnology sectors are amongst the most regulated manufacturing industries in the world and strict GMP procedures must be followed at every stage of manufacture. Indeed, no batch of medicinal product can be released to the market within the EC unless it has been signed off by a nominated Qualified Person who must certify that it has been manufactured and checked in compliance with the laws. The reason is obvious and probably best stated in the introduction to the "Rules and Guidance" for those laws – commonly known as "The Orange Guide" – which states: "The objective of GMP…is to assure the quality of the product for the safety, well being and protection of the patient". Pharmaceuticals cannot, therefore, be compromised on quality standards. Unsurprisingly, this results in repeated validation processes to ensure the product is of the required quality. However, despite this requirement, there is no standard procedure for sampling liquid preparations and the methods and equipment adopted vary widely with many "home made" systems being devised for the purpose. Some of these systems are controllable, but most consist of complex valve and piping systems which are inherently problematical.
Difficult to evaluate Firstly, it is actually difficult to validate the cleanliness and sterilisation of these devices as they invariably consists of at least two separate pieces of equipment and items such as valve trains are not easily cleaned and sterilised. Standard Operating Procedures (SOPs) therefore become complex, increasing the likelihood of human failure. The installations themselves also tend to be bulky and costly and what is a routine operation turns out to be inordinately time-consuming as the entire system must be cleaned and sterilised between each sampling. Typically the CIP, SIP and cooling time is three to four hours. Moreover, after sterilising the pipe/valve system and the mobile sample container, there is a considerable risk that steam condensate will be trapped inside the system. If the system is not pre-flushed, the sample will be diluted and therefore unrepresentative and if it is flushed, the degree of flushing must be validated. There is also a risk of returning false analytical values with biological processes which include heat sensitive components as the SIP process transfers substantial heat to the tank wall and shut-off valve. Finally, and perhaps most seriously, is the fact that complex systems with considerable human involvement are invariably exposed to a high risk of contamination. Particularly vulnerable are the manual connections, where, for example, environmental contamination may occur when traces of the product drip out during the removal of the sample containers. Minor mishandling during connection may also destroy the bioburden at the connection point thereby violating the sterilisation process. Chemical contamination of the sample can also occur due to the difficulty in cleaning the system thoroughly from the previous sampling. Sampling containers which are not specifically designed for the task of safe transfer of the sample to the laboratory may also create problems. Any of these scenarios can result in imprecise or false positive readings which can lead to quarantine, necessitating a repeat analysis and even products that are unacceptable. In any industry this would be a time-wasting, expensive exercise. In the pharmaceutical industry it can be a very costly process.
Rapid, accurate sampling Faced with this problem, Swedish aseptic process specialist, NovAseptic, set about developing a sampling system which avoided the requirement for manual connections and maintained the integrity of the sample from point of use to analysis. The result is a presterilised, disposable, totally enclosed sampling system for use in pharmaceutical, biotechnology and food industries where sterile, aseptic sampling is vital. As each unit is totally enclosed in a sterile environment and disposable, validation is simple and the potential for outside contamination and cross-contamination is eliminated. Moreover, apart from providing accurate samples, the enclosed system dramatically cuts the time taken to collect the sample as the requirement to carry out CIP/SIP procedures between each sampling – as is the case with traditional "through valve" configurations – is removed. The system is also easy to handle, set-up and dispose of which further speeds up the process, allowing quicker throughput to the laboratory and rapid return of the results. At the heart of the NovaSeptum is a self-sealing septum through which a stainless-steel needle connected to the sampling bag is pushed to collect the fluid sample. Firstly, the magazine – which holds up to nine disposable, presterilised units depending on the size of the holder – must be loaded. The unit is presterilised by radiation and the surface of the septum facing the product is sterilised by steam during routine SIP of the system, as in Fig 1. Sterility of the needle is assured as it remains enclosed in the silicon membrane until pushed through. Pushing the needle connected to the tubing and sampling unit releases it from its locked position and forces it through the septum membrane. The liquid sample then flows automatically through the tube and fills the sampling bag as shown in Fig 2. The provision of a representative sample is assured as each one is taken without flush directly from the batch. When the required liquid volume is collected – sizes from 20ml up to 1,000ml are available – the needle can be pulled out from the self-sealing septum and again locked in its outer position. The tube is then sealed and the bag removed leaving the tube and the septum unit in the magazine – Fig 3 – while the sampling bag is taken to the laboratory for analysis as in Fig 4. Various types of holder are available to connect the sampling device to the tank, including Tri-Clamp and Ingold fittings, and special adapters are available on request. Pipe connectable holders are also available if samples are required from a tubing system.
Wide applications The simplicity and adaptability of the system make it applicable to a wide range of applications, including sterility and pyrogenic testing, bacterial counting, chemical and pH analysis and fermentation. The unit can also be used for contamination-free transference of fluids into vessels and pipes, making it ideal for applications such as bioreactor starter inoculations and pH regulation. The units are assembled in Class M6.5 cleanrooms from FDA and USP Class VI approved materials and as well as being sterilised by irradiation with a minimum dose of 25 kGy, they are guaranteed to be pyrogen-free. In order to guarantee the quality and reliability of each unit, mechanical and microbiological tests are performed to ensure integrity and sterility and each is marked with a part number and LOT number for full traceability. With increasingly strict standards of manufacture and pressure on companies to reduce downtime and improve productivity, the NovaSeptum is a timely entrant to the market and represents a major advance in aseptic handling of samples. It may even spell the end for the "DIY" sampling device.