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Continuous manufacturing: Upgrading the supply chain to meet rising demand

Published on 10/08/17 at 12:34pm

Pharmaceutical production has long been the object of scrutiny to ensure the highest levels of quality and safety are maintained. However, a new functional model is gaining momentum, promising greater speed and efficiency. But is it a one-size-fits-all solution? Matt Fellows investigates

Pharmaceutical production has traditionally relied upon a process known as batch manufacturing – a staple which has served the industry well for over 50 years. The process is characterised by a number of discrete steps in which the five stages – synthesis, crystalisation, blending, granulation and sizing, and tablet press and coating – are clearly distinct. Not only this, but between each production stage, the product is rigorously tested to ensure it complies with industry standards. During this testing period, the product may be stored or shipped to other facilities. This entire process can take a number of months, and while it has been a cornerstone of production in the industry, it is increasingly showing its age and limitations. For instance, the model is very difficult to upscale in the event that global necessity for a particular drug or active pharmaceutical ingredient suddenly takes an upsurge. As the needs of patients and worldwide healthcare evolve, so too does the demand to meet these needs.

These demands now call for an evolution in delivery model. The number of drug recalls in recent years has grown sharply as regulators demand more exacting standards of product quality and contamination in the manufacturing process; mistakes occur due to the flawed and antiquated batch system, which is inherently subjective and variable thanks to its reliance on human operators. The last three years have seen as many recalls as the last nine years combined. Putting this into perspective, the industry has made a loss of $50 billion a year due to inefficient processes, and the FDA estimates that as many as 300 drugs are currently in short supply worldwide.

The answer, say many voices from within the industry, is the continuous manufacturing model. This system eschews the large-scale equipment and does away with the segmented, discrete methodology of the traditional model in favour of a faster, more efficient process. Within this model, distinct steps with ‘hold times’ in between are scrapped, so drug products are constantly moved through the five major steps within the same facility, achieving in a matter of days what takes the batch system months.

Besides speed, this system also reduces reliance on human intervention and therefore lowers the risk of error, while response to market changes can be enacted quickly, requiring less money to upscale. While the benefits seem clear, the industry, as with the adoption of many other innovative models and technology, has been apprehensive in making the leap to continuous manufacturing. Why is this? The FDA itself has noted that it encourages the move; Dr Sau Lee, Deputy Director of the Office of Testing and Research, and Chair of the Emerging Technology Team, Office of Pharmaceutical Quality at the Center for Drug Evaluation and Research notes that the US regulator is “urging manufacturers to shift to continuous processing for its numerous advantages, including flexibility, reliability and scalability. But above all, the pharmaceutical manufacturing industry faces a dire need to reduce its burden and shift its focus onto quality manufacturing (quality by design via well-established risk and product quality). True continuous processing not only addresses the most fundamental concerns relating to regulatory requirements and quality, but also provides manufacturers with a significant reduction in capital and operating costs, manufacturing footprint, wastage and downtime, while significantly increasing the speed to market.”

Lee’s assertion that the more modern model, “addresses the most fundamental concerns relating to regulatory requirements and quality” is of particular interest. Think tank MForesight states: “While pharmaceutical leaders like Johnson & Johnson, Eli Lilly, GlaxoSmithKline, Vertex, and Pfizer have initiated efforts and confirmed strong interest in conversion to continuous manufacturing in the years ahead, no individual firm can take the leap alone. Beyond the considerable upfront costs of developing and implementing the new technology, the industry must also overcome regulatory risks and uncertainties in seeking to make such a major technological leap. For America’s small and medium sized manufacturers especially, the upfront technological costs required to incorporate this new technology into standard operations are too great.”

While industries such as the chemical and petrochemical sectors have already adopted continuous models of manufacturing, the pharmaceutical industry remains hesitant, and here we see why – there are a host of considerations to be taken into account which could make the considerable upgrade a risky move, not least because the system is still in its relative infancy within this space.

Lee continues: “For the pharmaceutical industry, the transition to continuous manufacturing is still in its early stages for several reasons. First, start-up costs for such a transition can be high. Retiring old batch equipment, purchasing new technology and training staff on how to use it, and revamping industry infrastructure is expensive, requiring a serious commitment from a drug maker. Still, economic analyses have shown potential significant long-term savings. In addition, some technologies still need to mature before being commercially viable. For certain types of drugs, such as biological products, the technology for producing them by continuous manufacturing may not yet exist. Research is underway to address these and other challenges. Furthermore, drug makers still perceive of regulatory uncertainty that may delay product approval when a new manufacturing technology is used.”

Again, amongst a string of concerns, we see the fear of regulatory risk taking a foremost position in the minds of pharmaceutical manufacturing decision makers. The concern is a sizeable one in the context of a business which demands consistent sales performance, particularly as you reach the upper echelons of the industry where some of the biggest companies reside. A break in production caused by failure to comply to necessary guidelines could result in product shortages or all-out delays to market, which could mean the difference between successful and impactful penetration and being bested by a rival product.

Image credit: Sau Lee. J. Pharm Innov (2015) 10:191-199., 23/06/2017, https://www.fda.gov/Drugs/NewsEvents/ucm557448.htm

Batch production features breakpoints which provide the ‘hold times’ during which tests can be performed to confirm whether adequate compliance is being achieved – an element which continuous manufacturing is lacking. The Continuous progress in continuous manufacturing report confronts this problem, stating:A large question is how to ensure quality and regulatory compliance when there are no breakpoints as batch production features. The answer is to monitor critical process parameters and critical quality attributes at a frequency that allows for sufficient monitoring of the process and product quality. In addition, the real-time application of Process Analytical Technology for continuous processes is essential to quality control and must be integrated into the process control strategies.”

In order to encourage the industry to take full advantage of the benefits offered by the new system, the FDA is offering its full support to expedite greater adoption, as Lee explains: “As the industry considers how to make the switch, the FDA is providing resources and information to help facilitate the transition. For example, the agency is partnering with the Biomedical Advanced Research and Development Authority, a programme within the US Department of Health and Human Services, to help fund and support research in this area.”

What about generics?

While the adoption of continuous manufacturing is a major topic in the production of branded drugs, [Pharmafocus] spoke to Paul Fleming, Technical Director at the British Generic Manufacturer’s Association (BGMA), to see whether this extends into the generic space. He was quick to point out that while compliance is a very key issue in the generic space today, the way it manifests is quite different to how it does in branded production. To meet these specific needs, the BGMA takes a specialised approach:

I would say that it’s a continuous activity for us,” Fleming began. “How we work in the area of manufacturing compliance is that we have a standing working group which is called the BGMA Quality Forum. We have three full-scale meetings a year with the Medicines and Healthcare products Regulatory Agency (MHRA) inspectorate. We get all our members together – we have around 35 – to reflect on the whole manufacturing supply chain. We also get together with the regulator’s inspectorate group to discuss the current issues at the time, share experience, and try to identify areas of best practice.

“We use it as a forum to share experiences, and we try to do that in a continuous way,” he continues. “What we’ve tried to do with that is reflect changes which tend not to be shifting dramatically; continuously, there are new things coming into focus, particularly if they’re driven by new legislation or particular events around the interpretation of things. We are not reactive to changes; we’ve got more of a monitoring and raising awareness-type of approach to changes and implementation. What we’ve learned through that is, at the starting point, people do look at changes in requirements differently, and it’s only through bringing people together and sharing their different interpretations and bouncing them off the regulators that a consensus emerges. We find that that helps the members in many ways to implement things proportionately within their business with a degree of planning so that things are implemented more smoothly.”

Specifically, Fleming put forward two key compliance issues which face the generic manufacturing today, the first of which is elemental impurities.

“Elemental impurities is about looking holistically at whether there is any chance of very small amounts of metal ions getting into the product,” he explains. “That can be down to things like raw materials; how it’s packaged; how it’s handled; whether the machinery utilised is coated or uncoated; what sort of solvents have been used in the process as they could potentially wash off some of the surface ions into the medicine. How do you translate that into a potential level of risk of contamination? You would combine raw data with toxicological evaluation and exposure levels, and that’s a slightly different way of working to methods that have been used in the industry before. Trying to combine all of the elements of the supply chain that go into the finished product, and the manufacturing machinery associated with that, together with a toxicological evaluation to decide if the level of the elements present could possibly pose a risk, and then relating that to the dose of the medicine that’s actually consumed, is quite a different approach to what has been done traditionally.

“Combining the traditional method with a toxicological evaluation and looking at the whole supply chain of the components as they come in, and then linking it to the dose that’s taken by the patient – that’s adding a much more end-to-end and holistic approach to the whole thing. That was successfully brought through by discussing it collectively as a group and also discussing it with the regulator in a forum that was outside of the particular manufacturing site. It’s helped to nurture a more uniform implementation of the legislation.” 

The second issue raised by Fleming was the risk of cross-contamination within the large-scale equipment used to manufacture the generic drugs – a risk area that affects this specific sector in a much more pronounced way than it would branded production, which relies on dedicated machinery to manufacture single drugs.

“With the manufacture of generic medicines, one of the key features is multipurpose equipment. Companies will look to have sets of equipment that they use for different products, so it’s quite rare in the generic medicine sector to have dedicated full sets of machinery – you might have particular components that you keep dedicated for individual products, but a lot of your equipment parts will be multipurpose,” Fleming told us. “The whole process around changeover, cleaning, setting up for new products, and interchangeability are very key components of manufacturing generic medicines. The cleaning and changeover can be done scrupulously well, but also the changeover times can be minimised in order to get greater manufacturing efficiency, so machinery utilisation fractions are increased.

“The companies have got large portfolios - they’re not continuously making the same products all the time. They may combine batches or run campaigns of several strengths of the same products to reduce changeover times. What is the specific characteristic of a generic manufacturing plant? Making lots of different products on broadly the same sets of equipment, and how they manage that changes from one product to another, including the cleaning, the validation of the cleaning, setting up the new products, reconfiguring equipment and starting production – those are the key efficiency components of generic manufacturing.”  

In which case, how does continuous manufacturing fit into the generic sector? We asked Fleming whether the process featured on the BGMA’s radar for adoption in the near or far future: “We’re aware of it, and it is a live topic of discussion within pharmaceutical manufacturing,” he replied, “but for the reasons I have just described, it doesn’t fit so well with continuous manufacture where you’re making a lot of the same product over an extended period of time.”

The reason why adoption would be difficult is not down to regulatory concerns, instead it is because, in the predominance of cases, it is perhaps downright inapplicable to the nature of generic manufacturing. Though this may be the case, the system has definitely piqued the interest of generic manufacturers, and particularly those members of the BGMA – the topic could find itself on the Quality Forum’s agenda in the future.

“I think it’s truthful to say that it’s something that the generic industry is very interested in monitoring, but it’s got less applicability because of this large portfolio with multiple products being made in the same factories,” Fleming remarks. “There’s nothing that is specific to our business that’s different to any other part of the pharmaceutical sector – we’re inspected in exactly the same way by the regulator, and working to the same regime. The primary difference is that the companies are making lots of products. Several of our member companies will have up to 600 products in their portfolio, whereas if you’re an originator, you may have 15.”

Are we looking at a game changer?

The benefits offered through adoption of continuous manufacturing are clear to see for a significant portion of the industry: greater cost effectiveness, considerably faster production times, and more flexibility in market response, to name a few. Though it may simply be too early for the generic sector, which currently faces its own compliance hurdles and will be keeping its eye on developments as time goes on, the consensus from wider pharma appears to be that the industry is standing on the ridge of change, and that the main obstacle for many is making the first leap. While this may seem unfeasible to many smaller business, the support and encouragement of the FDA will surely help galvanise a wider movement towards this more efficient method. There is a sense of imperativeness at this particular moment, and, as Lee notes, there is much that can be done between various parties within and beyond life sciences to ease and encourage this transition:

Right now, there’s an opportunity for different stakeholders from government, industry, and academia to come together and consolidate United States leadership in this game changer,” he states. “The idea is to standardise the technology and product development pathways so that diverse producers can adopt continuous manufacturing techniques at lower cost and decreased regulatory risk. There are existing models for how to succeed in these kinds of efforts — like the National Science Foundation’s Engineering Research Centers or the National Manufacturing Innovation Institutes, both of which provide help to industry and academic partners with coordination of technology development and support in seeking modified regulations to facilitate product development.”

As MForesight noted, “no individual firm can take the leap” – we must see a more collaborative effort to push for adoption.

Matt Fellows

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