The Challenges of Implementing Single Use Technology in a Commercial Space

Ken Wong, Deputy Director, Sanofi Pasteur joins Pharma IQ to discuss some of the key difficulties to implementing single use technology in a commercial space. Wong also covers the advantages and limitations of single use systems and shares his top tip for developing an extractables and leachables compliance remediation strategy.

Pharma IQ: In your opinion, what is the strategic outlook for Biopharma?

K Wong: Almost all biopharmaceutical manufacturers are starting to embrace single use technology. The challenge is that there are still some difficulties implementing in the commercial space. This is stemmed from the uncertainty of regulatory expectation. The requirements for commercial applications are completely more stringent than from clinical manufacturing, as it should be. From that perspective, extractables and leachables are now more scrutinised in the commercial setting.

From an extractable and leachable standpoint, the grey area is that some suppliers will have a very strong data package available for the end user, some have almost none. In a submission, if the process that is using fifty or to a hundred single use components in oner process, the progress is as good as the weakest link of the process – the component with the less information which allow one to move forward to final process validation.

It can slow down in terms of how fast one can get this implementation qualification complete, then proceed to process validate and final submission. 

The challenge right now is the questionable reliability of the result that we are getting back, and the amount of work we need to do just to make sure that we get the right level of data that we need for submission is quite strenuous. The duration it takes to fill all the gaps in qualification and subsequent validation leading to longer implementation period than most people are hoping to benefit from the single use systems.

Pharma IQ: What are some of the advantages and limitations of single use systems? 

K Wong: In this space one can easily see, the biggest advantage of single use is the quick turn around time, lean production process and scheduling flexibility provided to the production floor, and also the start up cost is much lower. Implementation time should be faster once it’s qualified and validated. At the same time, many biopharmaceutical companies who are doing business in emerging markets realise that all these countries actually are requiring them to have some sort of presence, may that be manufacturing, packaging and so on, to do business in those countries. 

One cannot simply invest stainless steel facility in every single country. So the idea is to make use of the single use technology to provide some sort of tailor batch size manufacturing capability in that specific location without high up-front capital investment. The limitation there for the single use, is now that one is expecting the supplier to provide what one call flexible production facility on demand, so the supply chain of those materials is extremely critical, as well as how one actually maintain quality using these materials - the single use system. Equally important is the how does one manipulate and handle them, especially for bag system. One can image leak is the key concern during production. Freezing is also a key concern which can lead to leakage. so when one are trying to implement this across multiple sites, training on how to handle all these material becomes an integral part of the manufacturing process as well, and how one can remain in control their qualify.

The other limitation there is quite certain is when one have all these components necessary for production, one need to have them ready to go in most cases, so the warehouse space will increase as well to house all the production components. 

The last part would be the concern in the environment. For example, there is an area where we may be able to eliminate or maybe lighten packaging material.

Pharma IQ: What is the biggest challenge with respect to extractable and leachables?

K Wong: This is a really hot topic. Basically two fold. So first one is the manufacturability, if they cannot grow the cells they can’t even make the material. If they do make the material, there is potentially a lower yield, and the costs higher. Even then, the big unknown is how the large protein has changed because of the leachable in the system. Would that pose any risk to patient?

It is very challenging to detect changes on a protein structure standpoint, especially conformational changes. The analytical technology has not caught up just yet to provide that detectability for us. Such changes can lead to mutagenicity risk.

The other one has to do with basic protein stability in the SUS, such as bag for example. If one do store the proteins at certain duration, a leachable stability is likely to be required. 

Other than the bags, the other smaller SUS components which are not well publicised just yet at this point are tubing, aseptic connectors, sensors and etc. Those are generally considered lower risk, but it’s not well studied at this point like the bag.

The biggest challenge is the amount of extractable and leachable qualification and validation of the SUS train in the process. The amount of individual SUS component in highly disposable manufacturing facility can add up to hundreds.

Pharma IQ: How much of a priority is extractable and leachable testing for one currently? 

K Wong: It has reached a critical point where multiple organisations are trying to propose a standard/recommended extractable protocol, just so that we have a uniform extractable approach. The most impactful organization is the end-users consortium, known as BioPhorum Operation Group (BPOG). There are over 20 biopharmaceutical companies with BPOG. Also there is suppliers and users consortium called BioProcess System Alliance (BPSA). So they also have some published documentations (white papers).

Then there are other standard bodies such as ASME-BPE, which is the Bio Process Equipment Standardisation Subcommittee, they also are providing some recommendation. ASTM is also drafting an Extractable and Leachable standards on disposables. Last but not less is the USP; they will kick off their USP Chapter <661.3> expert panel in December 2013 to start developing the manufacturing equipment requirement. So we can see that everybody is trying to provide some sort of guidance to the industry, but the fear we all have as end user is, if they are not aligned, it’s worse than having no standard at all.

Recognizing the potential misalignment and the need to collaborate, in parallel to their own standard development, all the organizations are also seeking inputs from BPOG in their process of standard/guidance drafting journey. The challenge now is can they all hash out the differences? This is going to be a long, challenging process to go through. 

BPOG have finalised the revision of their initial proposal, and they are in discussion with BPSA to agree on the standard extractable protocol. Once the joint protocol (BPSA and BPOG) is finalized, it will then share with ASTM, ASME, and USP for their consideration.

Pharma IQ: What time frame does one think we have for this? 

K Wong: It’s a big unknown at this point. From the end user standpoint, we would certainly like to see a solid proposal being accepted and implemented as soon as possible. BPOG and BPSA are working to finalize a joint version of the standard extractable protocol by 1Q2014. They do understand that no one can simply just complete all the testing with respect of the proposed extractable protocol. So they will probably propose a reasonable time frame for implementation to bridge the existing gaps for those materials that are already in the marketplace. But going forward, anything that’s new and introduced to the market will follow the jointly approved protocol from BPOG and BPSA.

Pharma IQ: What would be one top tip for developing an extractables and leachables compliance remediation strategy?

K Wong: I think first and foremost, each company will have to develop their own risk assessment model that is very comprehensive in evaluating the risk associate with the use of single use in their processes. Then, they will need to determine the right amount of data to develop and demonstrate the compatibility and safety with their use of the disposable systems associate with each risk category. Extractables and leachables is certainly one of many other requirements in that risk mitigation strategy.

Pharma IQ: What are the key challenges with respect to qualification?

K Wong: At this point, most suppliers now have some sort of validation package available for the end users; especially for the more complex single use systems. The weaker one will be those with maybe a simple commodity type of single use system. In general, again, this is probably all over the place as well, and the challenge right now is to get the same sort of baseline information that one can easily look across the process say with five different or six different components and make their assessments. Based on their own risk assessment, they can qualify the component with an increase in qualification and even validation study as they move up the risk categories of components.

Some of the basic requirements such as Class VI, physico-chemical properties, irradiation compatibility, pH, leak (seal integrity), extractable, TOC and other key information/attributes for their specific functionalities should be required at minimum from suppliers. But some of the other attributes that are not quite available from most suppliers such as sorption loss of the material information. Unfortunately there’s no clear regulatory guidance out there right now to spell out exactly what information are necessary to qualify disposable components.

Pharma IQ: Please could you give us a brief overview of your presentation? 

K Wong: I will be giving an update on what the BPOG (Biophorum Operation Group) are working on in terms of proposing/considering best practices in the way to standardise extractable protocol. This protocol is intended to be for the suppliers, so they can apply it for their extractable studies. This information should be available for the end user, and all of us will be getting the same set of package from them, as part of our evaluation of the single use systems, and qualification. Most importantly, we envision the outcome will provide high level of confidence in the results from the suppliers. Such confidence is derived from the consistency on how they execute their extractable studies and how they report the information to the end users. I will also highlight what are the agreed elements of the protocol among BPOG and BPSA.

Interview conducted by Andrea Charles

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