Validating Single-Use Systems

Editor's Note: This article is part of a special feature on single-use systems that was published in the October issue of PTE Digital.

There are a number of validation approaches that can be adopted — all of which incorporate the established approach of user requirement specification (URS), design qualification (DQ), installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ). Validating singleuse systems, however, requires a few changes of emphasis with respect to these specific steps.

For singleuse systems in general, validation can be performed in three areas. The first relates to the actual process operation itself. This will be dependent on the intended use, e.g., aseptic operations, short or longterm product hold, levels of process closure, the stage of clinical development and whether or not the product being produced is for commercial supply. A riskbased approach will determine the validation programme based on the end use and process requirements. Secondly, it may be necessary to validate the manufacturing process for the singleuse components and the quality assurance systems applied by the supplier. Finally, the actual supply chain process of the singleuse system and the stability of the supply chain must be evaluated. The validation approaches will also very much depend on whether the system is standard or customised. Suppliers are now developing a range of standard packages for both components and control systems and, in such instances, validation packages can be obtained from the supplier, which offer significant cost and time savings.

Key points to consider

The key consideration for the validation of single-use systems is the recognition that much of the ownership of the quality systems will lie with the selected system's vendor. Additionally, as stated above, if the systems are part of standard packages then this also needs to be factored into the validation approach. Companies are developing increasingly detailed packages on leachables and extractables based on USP Class VI and European Pharmacopoeia requirements, as well as recommendations by user groups, such as the BioProcess Systems Alliance. A casebycase assessment is required to determine, for example, if the proposed process fits within the range of process fluids and operational conditions previously assessed by the vendor.

It should also be recognised that the use of the systems places much greater emphasis on the operators responsible for conducting system assembly procedures. In most cases, there will be a reduced capacity to verify systems ahead of manufacturing operations. Under these circumstances, IQ is required every time a system is used and the validation approach needs to take this into consideration. Assessment of OP and staff training is also required to accommodate the change in process risk.

The risks lie not only in the formation of secure connections between items, such as sterile welds and connectors, but also in connecting the various components correctly to form the intended assemblies. The impact of this is that in the initial design phases, thorough URS generation and DQ emphasis needs to be placed on how the system is to be used and how operations personnel will interface with the system, rather than assessing purely functional aspects. This, in turn, means that the process will require a high level of input from the operational team throughout the design and validation process.

Over and above validating the fixed plant and the process, the programme will involve reviewing operational procedures — many of which will be performed at a remote, third-party site. As such, the validation process will need to be more extensive with respect to vendor audits where the entire operational and QA systems of the selected supplier will be appraised. A much closer relationship between the supplier and end users will need to be established. One approach is to identify a limited number of preferred suppliers — based as much on quality systems and supply chain stability as price — and then to look at the procurement of new systems solely from pre-selected vendors. In addition, detailed assessments of operational procedures, including system assembly and the training of associated procedures will be required. This is where the highest risks are likely to lie in terms of operational errors and failed batches.

Vendor selection

The vendor is now being assessed not just on price and quality, but on its whole business process — and on an ongoing basis. As a part of the vendor selection process, suppliers will need to demonstrate that they can establish long-term working relationships with customers. Additionally, the vendor audit process needs to become continuous rather than relying on singular assessments at set time intervals. The expectation of customers and the resulting vendor response to these requirements will have a significant impact on vendor selection, and QA groups will play a greater role in the approval and preselection of vendors. The capability of the vendor to be able to maintain long-term supplies of components will also be critical. Business stability, therefore, becomes even more important, as does the vendors' policies towards product and process change.

With respect to changes in component manufacturing procedures, this is a critical area — particularly in a field where rapid advances in manufacturing procedures are being made. This will also be an issue where designs of equipment are continually changing. In response, suppliers will need to develop agreed redundancy/obsolescence policies for older components.

Case study

At the 2nd Annual Disposable Solutions for Biomanufacturing conference held earlier this year, a case study was presented relating to the production of a monoseptic whole cell bacterial vaccine for Advaxis Inc. (NJ, USA). The requirement was to grow and then purify the cells by washing them with ultrafiltration membranes, and then formulating the product into a selected buffer. The aim was to achieve this as a closed process using singleuse technologies, and the process incorporated the use of Wave reactors, hollow fiber systems and a number of bag manifold systems.

The challenge was firstly in developing the technical platform to perform this operation and to maintain high levels of product viability, as well as achieving the required levels of purity and then to be able to validate the process to demonstrate the retention of monosepsis throughout. As the product was being produced under the EU clinical trials directive, there was the need for full validation of the process with regards to monosepsis, even though the product was only being used for earlystage clinical trials.

To achieve this, standard validation (DQ/IQ and OQ) was performed around the individual components and then three full broth simulations were performed within the facility followed by shipping studies to the site of drug product manufacturing, which was actually within the US. The process also included a significant amount of operator training and water simulation because it was essential to fully train the operators in all the key process steps ahead of these validation studies.

The take-home message was the need to retain and build upon existing validation approaches, and also to involve operators and QA staff in all stages of the development and design processes.

Tony Hitchcock is Head of Manufacturing Technologies at RecipharmCobra Bio.

George Saunders is Validation Manager at RecipharmCobra Bio.