Marc-Antoine Kaag, Sampling strategy Product Manager, Millipore SAS, Molsheim, France-An affiliate of Merck KGaA, Darmstadt, Germany
Janmeet Anant, Ph.D. Senior Regulatory Consultant,MilliporeSigma, Burlington, MA-A business of Merck KGaA, Darmstadt, Germany
Microbial contamination during biopharmaceutical manufacturing of intermediates or the final product carries risks not only for the patient but also for the operator and the company. It can result in a lengthy shutdown of a facility for investigations to identify the root cause and prevent reoccurrence; and delay the production of much needed pharmaceuticals.
Traditional sampling methods tend not to be based on closed systems and therefore do not maintain a barrier to microbial contaminants entering the process during sampling. Thus the sampling process itself can cause contamination of a unit operation and possibly an entire batch. In addition, not all sampling methods fully align with regulatory guidelines. Unsurprisingly, the biopharmaceutical industry is increasingly switching to closed single-use sampling.
Regulatory guidelines for sampling
Several regulatory recommendations and citations relate to sampling. According to EU GMP Annex 1 revision March 2009, the bioburden should be monitored before sterilization and there should be working limits on contamination relating to the efficiency of the method immediately before sterilization. The Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) states that the filter efficacy studies must be considered when determining the acceptance criteria for the bioburden prior to filtration.
According to section 2.1 (preparation for sampling) of Annex 4 of the WHO guidelines, all sampling tools and implements should be made of inert materials so they do not interact, or react, with the sample itself. The section also states that using disposable, or single-use, sampling materials has distinct advantages. Section 2.2 (sampling operations and precautions) highlights the need for written procedures. They should cover operator health and safety during sampling and ensure that representative samples are taken in sufficient quantity for testing during the process and storage for later testing. Section 2.3 (storage and retention) states that the storage container should be sealed and preferably have a tamper-evident system in place.
FDA cGMP guidelines for Phase I drugs recommends using closed systems to minimize the contamination risk, and the sample to consist of appropriate, or adequate, quantities to perform additional later testing if required. The ICH Q7A Good Manufacturing Practice Guide for APIs, also adopted by the regulatory bodies of the EU, Japan and the US, states that the procedures used for in-process sampling should be designed to prevent contamination and ensure sample integrity. The WHO and European GMP guidelines also follow the ICH guidance in terms of in-process sampling and controls, highlighting the importance of preventing contamination during sampling. The WHO guidelines also stress the importance of training the personnel that carries out sampling.
The pros and cons of common sampling methods
Several sampling methods are being used in the pharmaceutical industry. The table lists the advantages and disadvantages of two methods that are not based on a closed system, Aseptic Connectors and Tube Welders, and of two fully closed-system ones, Steam in Place Sample Valve (SIP/Valve) and NovaSeptum® GO sterile sampling, where the device can be locked and containers sealed when not in use, keeping samples and the process safe. Some other methods exist, for example Open Sampling Valve and Septum Sampling, but are not considered here.
Closed aseptic process sampling offers several advantages over traditional methods, including ease of use, better alignment with regulatory requirements and limited investment needs. Closer alignment with regulations is achieved by better contamination control, the elimination of operator bias, the ability to collect representative samples, and improved operator safety.
When compared with SIP/Valve, the other common closed sampling method, NovaSeptum® GO offers several advantages: easy sampling, greater safety, container choice and configurations, single-use compatibility, adaptability and no need for dilutions or maintenance. Furthermore, the first sample can be drawn immediately, and the time between further samples is as little as two minutes. This makes the technique suitable for readily monitoring the manufacturing of your biologics.
To learn more about closed sampling systems for aseptic pharmaceutical manufacturing, visit: emdmillipore.com/ sterilesampling and https://youtu.be/-MlwxLJ8kjA
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