Sterile Products Manufacturing- Prepared For The Future?

Introduction
Traditionally aseptic processing has been a niche area in the pharmaceutical industry. The big majority of pharmaceutical products were manufactured as tablets or capsules and the standard formulation would be as a dry or wet powder mix, granulation etc. under pragmatic room classification conditions and quite effective for large product volumes. From a volume perspective this is still the case today and will remain so in the future.
But from a value perspective this picture started changing with the so-called “patent cliff” 2011-15 where a large number of high-value OSD products lost their patent protection within very few years. Looking back from today, this “patent cliff” was the first disruption in pharma manufacturing for many years, as the traditional “blockbusters” of large volume patented products approached its end. These products are still needed on the market, but many of them have become generics and are no longer among the top value generators of the pharmaceutical industry.
For generic companies this has been an opportunity to enhance the product range within a number of diseases where the former blockbusters have made a big difference for patients and consumers. For patients and payers it has enabled significant savings. In any case, it was the end of the blockbuster era and the beginning of a new: The era of speciality medicines.
From a manufacturing perspective this new era of specialty medicines and orphan drugs means new challenges that can only be overcome by thinking different from the blockbuster era. The speciality medicines and orphan drugs are much smaller in production volumes and much larger in value. This is probably why investors and mainstream media saw the end of the blockbuster era as a “patent cliff” with a high associated business risk. Looking back from today it has become clear that speciality medicines became the next blockbusters. However they cannot continue to be manufactured in the traditional “blockbuster era” facilities, because most of them are no longer tablets or capsules – they are injectables. And the volumes of production is significantly smaller.
In other words: Sterile, injectable products have become hot and is no longer an insignificant niche. Indications such as rheumatoid arthritis, cancer, multiple sclerosis, Crohn’s syndrome and many more chronic and rare diseases are mainly treated with injectables and some of these have significantly higher impact on the disease, either as treatment or even cure, than the previous small molecule drugs. So aseptic processing has become a mainstream pharmaceutical manufacturing technology.

Traditional aseptic processing is a challenge
But aseptic processing technology is not well prepared for the new pharma reality in the specialty medicine era. In fact, these technologies have only evolved slowly over the last 20 years compared to other areas of pharmaceutical manufacturing. A few significant breakthroughs opened for barrier technology and the first ready-to-use pre-sterilised components for pre-filled syringes a couple of decades ago but until recently there has been limited innovations. Most aseptic facilities are designed for high volume production of traditional injectable products such as vaccines, insulin, infusions and other traditional product. These facilities were designed for high volumes and high speed production and are difficult to change. Production changeover, batch shift and glass breakage are frequent events that makes effective manufacturing difficult.
The challenges of aseptic processing has become visible for the public because of significant drug shortages of important injectable medications. The number of warning letters, recalls or drug shortages of sterile products has become significant and has been reported for several years. Many traditional aseptic facilities are very old and most of them are not designed to be agile or effective. They were designed to be effective at large product volumes with traditional cleanrooms filled with operators that operate often quite old equipment. Although many of these facilities have been upgraded, they still suffer from the old manufacturing paradigm and they will never become as safe, flexible and agile as their modern counterparts. But since many of them manufacturers very old products and holds the necessary production approval certificates, they will continue to operate for many of the legacy injectable products.
The main challenge is, however, that most of the new speciality medicines does not fit well with these old facilities. They are simply not dynamic enough. They are hard to operate with small or mid-sized batch volumes and they have high cost of operation. So they are becoming increasingly difficult for next generations of sterile products and will only stay in operation as long as their legacy products are meeting a market demand. They will gradually be phased out, as modern aseptic processing begins to evolve.
This may however take a long time before we see real breakthrough facilities for aseptic processing. There are many enablers for a new sterile product manufacturing paradigm, but there are not many facilities that really breaks away from the mainstream traditional aseptic facilities. Some companies have fully acknowledged the benefits of RABS or isolator technology and are changing their manufacturing concept towards closed systems and elimination of direct operator contact with the manufacturing process. So though there are many enablers for a new aseptic processing paradigm there are only few full-scale facility examples and it will be interesting to watch how pharmaceutical companies, equipment suppliers, engineering companies and regulators will facilitate a real breakthrough towards next generation of aseptic processing in the same way as it is happening in other parts of pharmaceutical manufacturing – and in other industries.

Inspiration from other manufacturing technologies
Traditionally aseptic processing technology development was mainly driven by large volume biotech products within diabetes, vaccines, infusion parenterals, and lately by monoclonal antibodies and proteins. Compared to the large chemical API plants and traditional tableting plants for OSD products, the aseptic facilities are very different both from a process perspective, a technology perspective and a regulatory perspective.
Within small molecule API and OSD facilities there are signs of a number of technology breakthroughs that points towards the next generation facilities. There are already several examples of continuous manufacturing facilities within API and tableting that are manufacturing at commercial scale and the regulators, especially the US FDA, has endorsed and even promoted some of these new manufacturing approaches as part of the new regulatory paradigm, based on the new quality paradigm of science and risk management that is strong in USA, Japan and Europe. It is too early to consider the new continuous facilities a breakthrough, but at least they are getting much attention and interest throughout the global pharmaceutical manufacturing sector and there are more examples every month of next generation facilities that are being made public.
The same is happening for aseptic production outside the pharmaceutical industry, for example in food processing. Aseptic processing of food products have been commonplace for 25 years and products such as juice, milk and many others are manufactured at so high aseptic standards that they can be stored at room temperature or warmer for weeks and months without being affected. These other industries are much more dynamic and innovative than the pharmaceutical industry, although their business volume is much higher and margins much lower. Of course the requirements for a sterile injectable pharmaceutical product is higher than a carton of juice or a can of fast food, but the theories and basics of aseptic processing is exactly the same and the mutual learning between food and pharmaceuticals could be much better than it is. In fact many of the significant suppliers of technology for aseptic processing of pharmaceuticals are also significant suppliers in the food industry and they can easily compare the mindset and willingness to learn and change between the two industries. These suppliers are witnessing a conservative pharma business that could become much more agile and flexible if it was more willing to learn, adapt and improve what can be learned from others.
Another parallel technology to learn from is semiconductors and other electronics industries. These factories uses the same cleanroom standards as pharma, but they use significantly cleaner room classifications than traditional pharma. Not because it is required but because the business risk of failure in case of particles in the manufacturing process is far too high. These facilities learned the hard way that the biggest risk to product quality in the manufacturing process is the human interventions. So for many years these facilities have been highly automated and heavily manned with robots that keeps emissions and risk of particles at a minimum that the pharmaceutical industry can only dream of.
Neither the technologies from sterile food processing or particle-free semiconductor facilities can be directly transferred to pharmaceutical facilities, but they serve as inspiration to show that it can be done. But since the pharmaceutical industry in general is not under cost pressure and since many of the regulators prefers the conservative approach to new technology, the adoption of new technology in aseptic processing is only evolving very slowly. At least until now.

Technology enablers of a new paradigm
Times are changing and there is a growing awareness in the industry of sterile pharmaceutical products that a change is possible and necessary. The next generation of sterile pharmaceuticals does not require large production volumes because the majority of them are specialty medicines. Besides, there is a strong growth in orphan drugs for rare diseases that are being manufactured in even smaller volumes and batches than most other specialty medicines, adding to the challenge of agile and flexible manufacturing for the future. Both specialty medicines and orphan drugs are generally quite expensive and therefore they are really hard to predict from a manufacturing volume perspective. For many innovative pharmaceutical companies investment planning has probably never been as complex as it is today, because the cost, the future prices and the reimbursement decisions makes the uncertainty on manufacturing volume much more important than it was before. The high values involved in modern products has much bigger impact of the potential value generation if a product becomes a true breakthrough commercial success and therefore investment volume assumptions are increasingly difficult.
Some of the new technologies are more flexible than the old, but it depends on some very important core decisions. For example the new single-use biopharmaceutical process technology is a breakthrough that enables smaller investments, shorter implementation time and higher flexibility, at least at small to medium scale production. But in case of a blockbuster success, the small scale single-use technology (currently limited to 2000 liter bioreactors) may not be the most feasible solution from the operational cost perspective. Besides there is a long and complicated way from an approved product to the commercial success. In all countries the payers are becoming an increasingly important factor. With the ongoing trend in innovative drug pricing and the public concern about the coverage, the investment case for a new facility is difficult to calculate. A number of pharmaceutical companies have started sharing such concerns about the future capacity needs for products in their pipeline, because market uptake speed will have significant impact on the needed capacity.
An important alternative to these investments is the use of contract manufacturing, possibly based on a co-investment scheme. For companies that have established a strategic partnership with a competent CMO or CDMO organisation, there are win-win agreements that takes the worst peaks out of the decision uncertainty. More and more companies are planning for the combination of own commercial production and CDMO sourcing. In fact, recent reports show that an increasing number of companies are planning for CDMO supply as their primary source as a response to this increased uncertainty of future capacity needs. So contract manufacturers with some research capability will be a very important part of the next generation of aseptic processing.

Injectables are becoming “the new oral”
The main challenge may be that the next generation sterile products are very different from the products that aseptic manufacturing has been used to for the past 50 years. In fact, this part of the pharma industry has never tried anything similar to what is coming. Mainly because there is a strong correlation between price and volume, even at very small volumes. Many of the very innovative new sterile drug products are meeting previously unmet medical needs with treatments that patients had almost given up their hope to ever see. Disease areas where patients thought they were living with a death sentence or at least a very difficult future. There had never been a treatment for many of these diseases that are now becoming treatable and many of them come at high prices. But the important thing is that these treatments are coming and that there has to be cost-efficient and safe ways of manufacturing them, even at very small scale.
So there is a need for a new aseptic manufacturing paradigm that meets the future needs as aseptic products are gaining the popularity that oral products have had in the past. We will take a look at some of the enablers of this new paradigm:

Improved RABS and isolators
The isolators and other Restricted Area Barrier System (RABS) technologies was one of the first breakthroughs towards next generation of aseptic processing in truly closed systems. Most of these are closed systems, but can be opened and can typically be assisted through glove systems that enables operators to correct minor production problems within the isolator or RABS system. Both RABS and isolators are normally associated with use of VHP to ensure the sterility within the inner filling area of the machine and together with the barrier itself it has improved the product protection and mitigated many of the risks from manual handling within aseptic processing. For several years these technologies have also been endorsed or even recommended by the regulators worldwide as preferable to traditional cleanrooms with operator manning. But these can be even more improved from a manufacturing perspective, because the necessity to open the system for cleaning, change of format parts, repairs etc. costs significant production time due to the decontamination cycle associated with these interventions.
Next generation of isolators and RABS are truly closed without any gloves or need for opening, but there are still very few of these on the market. The main enablers of this next generation of truly closed systems, are mentioned below but realistically it may take a few years before the broad scale commercial breakthrough of this next generation of technology, including the filling machine, lyophilizer, capping etc. can be considered a truly closed systems operating for long periods of time without any manual intervention,

The challenge of truly closed systems
Perhaps the most important enabler of next generation aseptic processing is the rapid development within pre-sterilised, ready-to-use vials, syringes, cartridges or potential other primary packaging materials. The fact that these are kept in close containers and mainly handled within the container is a primary driver towards truly closed systems throughout the manufacturing process. Most of the suppliers of glass products for aseptic processing now offer one or more other formats and although they are proprietary, there is a de-facto standardisation in the horizon. Besides, many of the aseptic filling equipment suppliers are bringing a new generation of machines to the market, that can handle multiple formats of these trays and operate them in a flexible manner that even avoids format parts on the machine. For some primary containers, especially pre-filled syringes, the ready-to-use components have been available for many years, but for most of them the ready-to-use option is fairly new.
However, ready-to-use glass components only solves part of the challenge as there are other components such as stoppers or plungers that have to be introduced into the filling machine too. There are new solutions to this challenge, also based on ready-to-use concepts, but these are very early in the development and not widely commercially available yet. These technologies are undergoing a fast development and this is expected to increase in the near future as the drive towards truly closed systems continues. With truly closed systems comes other manufacturing concept opportunities since the risk of cross contamination and other contaminations becomes almost non-existing, thus opening opportunities for some very flexible manufacturing concepts that might lead towards ‘farms’ of isolator filling lines within ‘ballrooms’ of lower classified large cleanrooms, each operating as totally closed systems in which product and containers are never exposed to human interaction or other sources of contamination.

Robot technology in aseptic processing
Another main enabler for next generation of aseptic processing is the robot technology. Robots have been popular in most other areas of industrial manufacturing for decades and they have been a major driver for today’s agility and flexibility in major industries such as car manufacturing. Due to many specialised types of robots the car manufacturing is seeing changeover times of seconds instead of hours or even days in the old manufacturing paradigm, but this change has not yet affected the pharmaceutical industry on a broad scale. It may come now, since a new generation of robots are really well suited for aseptic processing. Some of the newest robots can be decontaminated by VHP or even terminally sterilised and they can be used for highly flexible solutions that breaks away from the traditional aseptic filling lines of the past. In combination with tray-based glass handling they enable a very robust and flexible solution, but at significantly lower manufacturing capacity than high-speed filling lines. However, they fit nicely with small or mid-scale manufacturing volumes of some of the speciality drugs and many of the orphan drugs, so with the change in the portfolio of future products the focus on changeover time will increase over the focus on production volumes, except in the areas of traditional large-volume sterile products.

Single-use technology
The strong development of single-use plastic component technology is another driver for next generation aseptic processing. As this technology has grown out of traditional biotech production and become a viable alternative to stainless steel solutions for many product types, it is becoming increasingly popular within aseptic processing for the same reasons that made it popular in bioprocessing: It reduces complexity by removing the need for cleaning, sterilisation and other measures to eliminate contamination. In aseptic processing also eliminates stainless steel solutions such as vessels, piping, tubing, pumps etc. and thus simplifying the manufacturing solutions, especially for small and mid-sized product volumes. Several suppliers of single-use solutions are providing ready-to-use, pre-sterilised kits that are dedicated to for example a filling machine and thus enabling a faster and safer changeover between products or batches in production campaigns.

Sterilisation technology
Traditionally the main technologies for sterilisation has been based on dry heat, clean steam or VHP. For certain purposes there are several other technologies available and there may be a drive towards some of these alternatives as the traditional solutions all have certain limitations. Especially in combination with ready-to-use solutions, there is a growth within e-beam sterilisation which is both faster and easier to control than the traditional technologies and it may be expected that such alternatives becomes part of next generation aseptic processing as the technologies evolves. Also here a main driver is the flexibility and the ability to do rapid change-over in a safe and efficient manner.

Rapid microbiology methods
Most of the enablers of next generation aseptic processing relates to the manufacturing process and associated technologies. One of the associated technologies is the environmental monitoring. These monitoring systems has undergone significant development over the last decade and this will continue to evolve, strongly supported by the evolution in rapid microbiology technology that speeds up the detection of viable particles as part of the environmental monitoring. As these technologies evolve the quality monitoring of the manufacturing process will improve and may be used for faster product release after manufacturing which in itself is part of a more agile operation. So far there has been only limited application of PAT technology (Process Analytical Technology) in aseptic processing, except for the use of TOC (Total Organic Carbon) detection within WFI utility technology. However, there may be technology breakthroughs in the future that enables much better detection of microbiological issues or closure integrity detection in the future, as has been seen with e.g. the headspace measurement technology that is becoming increasingly popular for closure integrity testing.

Next generation pharmaceutical manufacturing: the time-to-market challenge
The next generation of aseptic processing is only a small part of the next generation of pharmaceutical manufacturing that may be about to evolve. But unlike the disruptive changes in other industries, it may not be cost drivers that are the most important drivers for the pharmaceutical industry. In fact very few pharmaceutical companies have a track record of being able to drive cost down significantly year after year, compared to what is seen in many other industries. Several consulting companies have demonstrated this in several reports comparing pharma to many of the leading manufacturing sectors across industries.
So if cost will not be the most significant driver, what might drive the industry towards a new manufacturing paradigm with the endorsement of the regulators of the pharmaceutical industry? Innovation and time-to-market may become this driver. In fact, there seems to be a trend towards faster approvals of new, innovative medicines and medical technology products. Every year lost in time to market for a new and innovative product, especially products meeting unmet needs in diseases or diagnostics are candidates here. Time-to-market may become the mantra for pharmaceutical production as well as suppliers, partners and regulators. Other parts of the pharmaceutical industry has seen this coming long before the sterile injectable products sector did. In fact Oral Solid Dosage Form drugs manufacturing has started to prepare for next generation pharmaceutical manufacturing a decade ago.
In fact continuous manufacturing could be changing the pharmaceutical manufacturing sector long-term but the technology has progressed less within biotech and fill-finish than within chemical synthesis and OSD manufacturing. The technology makes progress partly due to a strong regulatory support, especially from FDA’s CDER (Center of Drug Evaluation and Research) and a handful of key suppliers that are making the technology available. Some of them have many installations worldwide, although only a few of them are yet in approved commercial manufacturing scale, but almost all big pharma companies have small or large scale facilities under construction for either pilot or commercial purpose.
Biotech and fill-finish is only starting to look into continuous manufacturing and especially fill-finish has not had any significant facility announcements based on aseptic processing. Some argues that this is due to that it makes less sense within fill-finish, but if one looks closely at the manufacturing processes within aseptic processing, inspection, packaging etc. it becomes clear that almost all of these processes are by nature continuous, so actually continuous manufacturing within fill-finish makes a lot of sense and may become a key element of aseptic facilities of the future.
In order to compare to next generation aseptic processing, the breakthrough facilities within OSD has been driven by flexibility and scalability. Not cost, not the size of the facility, not the investment size, but because it is scalable and may bring products to the market fast. Some of the big pharma companies have even developed modular concepts that allows very cost-effective global deployment of small-size continuous manufacturing plants (or “pods”) that uses continuous manufacturing technology to keep size, investments and timelines attractive, even in remote or challenging markets. Because continuous manufacturing is extremely scalable and with its reliance on PAT and advanced control strategies, it is almost independent on size of equipment, vessels, pipes etc. that are the constant bottleneck for traditional batch-based manufacturing.
This lack of scalability is not as big in fill-finish and especially within aseptic manufacturing. The compounding equipment all the way into the filling tank before the filling machine is a limiting factor, but after these initial processes, the batching of manufacturing is ‘only’ an operational and quality-related issue. A filling machine can produce almost as long as desired, including traditional lines with washing, depyrogenation tunnel and filling stations as well as the new generation of ready-to-fill lines with tray-based supply of the primary packaging material. The same applies for the processes after filling, such as inspection, assembly (for steriles drug delivery systems) and all the packaging steps.
In other words a change towards continuous manufacturing requires mainly a mindset change in fill-finish manufacturing – not huge investments as in biotech, chemical synthesis or OSD manufacturing. Most of the needed technology is already there.
Still there is a lack of solutions for the ultimate holy grail of aseptic manufacturing: the PAT technology for sterility testing. A test that can do in-line, at-line or at least on-line measurement of the sterility of a vial, cartridge or pre-filled syringe. There are PAT solutions commercially available for headspace detection and a significant development within rapid microbiology measurement technologies that looks very promising and are being used in many modern aseptic processing plants, but there is no breakthrough on the ultimate detection of sterility, at least yet. Could it come? Why not? With the significant breakthroughs in detection technologies, industrial artificial intelligence and next generation sequencing it is hard to predict what is possible and what not. But one thing is for sure: the first companies that comes up with reliable and regulatory recognised solutions to detect sterility in a closed container such as a vial have a very promising future ahead of them.
This has already been demonstrated in the significant growth of TOC measurements (Total Organic Carbon) related to many industrial applications, including the production of WFI (Water for Injection). The ability to determine the presence of organic carbon from microorganisms or endotoxins has revolutionised the monitoring programs for pharmaceutical water systems and other applications. So what comes next?

Conclusion
The manufacturing capabilities within aseptic processing are lagging behind the rest of the pharmaceutical industry. There are enablers that may be used to change the paradigm of next generation aseptic processing but the speed of adaption in the industry is not very high. Some examples from new and innovative facilities are showing the direction towards more agility and flexibility that enables cost savings as well as shorter time-to-market, but still the rate of adoption is very low.
But there is a need for a new generation of aseptic processing that utilised many of the enablers mentioned in this article. The big question will be: who is first? Who will demonstrate the first example of the aseptic facility of the future, enabling fast time to market as well as the agility and flexibility that the regulators wants to see. Eliminating the risk of human interaction and yet enabling a safe and efficient manufacturing environment to the benefits of the patients waiting for the next generation of drugs that meets the unmet needs of the future. There are many suggestions for “moonshots” in the pharmaceutical treatments of the future, but very few of them reflects the manufacturing aspect. The reality is that pharmaceutical manufacturing, especially within aseptic processing, may not be ready to provide the thrust that it takes to deliver a moonshot…

Author Biography
Gert Moelgaard
 has more than 30 years experience in the pharmaceutical and biotech industry, including Novo Nordisk and NNE Pharmaplan, an international engineering and consulting company with focus on the pharma and biotech industry. He has been engaged in several projects and assignments within pharmaceutical manufacturing as well as validation and quality management. He has been engaged in international guidelines, conferences and courses on pharmaceutical manufacturing, compliance, technology and validation and is now working as independant consulting at Moelgaard Consulting.
He can be reached at gtm@moelgaardconsulting.com

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