Aseptic Fill/Finish Roundtable

The last step of the injectable drug manufacturing process, fill/finish, is often characterized as the most critical step in drug manufacturing due to its highly specialized nature, which makes it difficult getting products to market or clinical trials. In addition to being extremely costly, fill/finish operations are subject to extreme scrutiny by regulatory agencies.

For this panel discussion, Contract Pharma talked to some of the leading players in the fill/finish space, including Catalent, LSNE, Piramal, Symbiosis and PCI, to discuss market and technology trends, and get an overall feel for where the market is headed.

Contract Pharma: How would you describe the current state of the aseptic fill/finish outsourcing market?
Carole Delauney, account director, drug delivery solutions, Catalent: It appears to us that the aseptic fill/finish outsourcing market is, and looks to remain, very healthy. The growth of generic injectables appears to be outpacing that of innovator products. Biotech firms, unless very well funded, will always seek to outsource fill/finish. Even if successful developments will eventually be out-licensed to large pharma, who may have spare capacity, securing the supply chain with an experienced partner will likely have a positive impact on the value of the deal. Indeed, the scale-up phases of some processes or drug substance handling are so complex, that the choice of the right fill/finish partner for phase III trials and commercial supply may be an asset and add value to the program.

The outsourcing strategies of large pharma companies vary from one company to another and sometimes corporate strategy, for example, toward facility utilization, may take precedence over the specific needs of an individual program. Large pharma tends to outsource fill/finish of established products, which are perhaps nearing the end of their lifespan or that are of lower strategic importance, whilst keeping more strategically important product manufacturing in-house. However, pharma companies still have an interest in outsourcing where specific expertise is not available in-house, or when they want to secure their supply chain network with a second source. Also, in-house investments can be at higher risk compared to a CDMO’s business model, because excess capacity is more likely to remain underutilized within pharma’s own network.

Joanne Anderson, business development director, Symbiosis Pharmaceutical Services: The last few years have seen some major changes to the aseptic fill/finish landscape. The market will continue to change and evolve, but as ever, customers are faced with the choice of engaging a big one-stop-shop service provider or electing to go with a smaller, more specialist, flexible and time-conscious partners. Ultimately for clients, it’s about getting to clinical trials in the safest and quickest route they possibly can. We believe there is significant market demand for aseptic manufacturing capabilities for biologics, highly potent APIs and small molecules, due to the increased number of oncology products requiring containment capabilities.

The level of growth within the biotech sector is driving a surge in demand for aseptically processed parenteral drug products. There is a positive investment climate in the biotech space, which is facilitating the development of new biological drugs, increasing the depth of an industry-wide drug pipeline and fueling demand for outsourced manufacturing services to bring products to clinical trial stage. With biotech companies, we are seeing more and more coming to us at the late preclinical drug development stage so they can start planning production in line with clinical milestones.

Lonny White, chief operating officer, Piramal Pharma Solutions: Aseptic fill/finish outsourcing continues to be a growing market, particularly for hi-tech service offerings—lyophilization, potent compound manufacturing and complex formulations. Growth will continue in the generics market, mainly fueled by a 13% growth in China, 6% growth in the U.S., and 12% among remaining emerging markets. Moving forward, emerging markets will pose a greater threat to CDMOs as they mature and stabilize, and growth in developing markets continues in general. However, concerns with quality and reliability of supply persist in these emerging markets.

Justin Schroeder, executive diretor marketing, business development, PCI Pharma Services: The market is certainly strong by virtue of growth in biologics and biosimilars. Drug companies are increasingly reliant on CMOs to support the trend towards complexity and customization in delivery forms. The infrastructure needed to support these products is considerable. CMOs play a vital role in defraying capital costs and providing expertise in bringing new products to market quickly and effectively, for development stages, clinical trials, as well as commercial supply.

Christine Palus, vice president, sales and marketing, Lyophilization Services of New England (LSNE): Fill/finish is historically one of the most outsourced activities due to the high cost of equipment, quality and facility requirements. Many CMOs have experienced a surge in the market due to several factors, including the decrease in the amount of high-quality CMO capacity available for aseptic fill/finish. There have been a number of CMOs that have had compliance issues and experienced lengthy shut-downs or have gone out of business altogether, so currently there are fewer established and reliable CMOs available for fill/finish. Additionally, we have seen many small and mid-sized companies get acquired by global pharma companies or merged with other CMOs to expand their upstream or downstream services, as many are moving towards the one-stop-shop model. Some large pharmaceutical companies have also decided to build their own fill sites, which has reduced or eliminated their need for a filling CMO.

CP: What pharma/biopharma macro trends are you seeing and how are they trickling down to impact aseptic fill/finish operations?
Delauney, Catalent: Our experience is of continued strong interest in injectables, despite constant innovation to bring more non-invasive dose forms to market, and outsourcing of vaccines, biologics and biosimilars appears to be keeping the injectables pipeline buoyant. It has been estimated that the market has shifted from just one of the top ten marketed pharmaceuticals being delivered by injection ten years ago, to seven out of the 10 today.

With the complexity of biosimilar regulatory approval, biologically-derived drugs have a longer lifespan on the market compared to small molecule drugs. When a biosimilar does reach market, its impact on the market share of the originator’s product is less than what was typical for small molecule blockbusters in the past, and market prices for biosimilars remain high compared with those for small molecule generics. Both situations are beneficial for CMOs and CDMOs involved in such fill/finish projects.

Finally, patient compliance is being improved with the use of drug delivery devices or new formulation technologies, with the advantages of fewer dosing errors, lower dose frequency, or reduced side effects. This innovation may confer a second life to generic drugs and extended patent life and retained market share. Therefore, I believe that the trend for injectables is still very strong and promising.

Anderson, Symbiosis: There is increased emphasis on the development of treatments for small patient populations in the case of orphan indications and novel tailored personalized medicines. Such products require specific capabilities and experience in GMP manufacturing for small-scale sterile batches for clinical evaluations, hence trickling down to what we do at Symbiosis. Furthermore, having specific experience in handling biologic drug substances is a significant advantage for a specialist CMO as many of these new entities require aseptic fill finish.

White, Piramal: Lyophilization capacity for potent products is expected to become tight unless there is significant expansion of capacity. Demand for aseptic manufacturing has outstripped supply in the market place, particularly for cytotoxic products. Demand for potent generic products for the U.S. should plateau as products restore supply through new ANDAs. For example, U.S. demand will likely continue to grow as underserved markets try to catch up. Various acquisitions have changed the competitive landscape of aseptic manufacturing capacity. Large players in the pharmaceutical industry, particularly generic players, have taken to buying capacity to ensure their future. In addition, quality and regulatory issues at CDMOs persist for both U.S. and ex-U.S. manufacturing sites, while expansion of active drug substance manufacturers into contract manufacturing space offering end-to-end service is growing.

Schroeder, PCI: There is significant growth in both biologics generally, as well as biosimilar development activity. A recent IMS study identified over 50 distinct biosimilars in development. Likewise, IMS reports that over 37% of all drugs in pipeline development are biologics. From a packaging perspective, this has led to considerable need for solutions for vials, and increasingly prefilled syringes that require some level of assembly at our sites such as plunger rod, finger flange, labeling, etc. Demand is also increasing for prefilled syringes that require additional assembly for safety devices and ancillary add-on technologies to improve the patient experience. Downstream we are often placing these vials and syringes into complex kits with multiple components such as various gauge needles, transfer devices and safety caps, instructions for use, regulatory literature, alcohol pads, and other inclusions specific to the drug. We use sophisticated vision systems to ensure the presence and correctness of each component throughout the process as accuracy is paramount. This growth in parenteral delivery forms also requires considerable capacity and knowledge of best practices for supporting these high value, cold chain medicines, and in some instances actually requires packaging in a cold chain environment if the product has no allowable excursion time. It takes a depth of expertise to ensure a safe and effective supply chain.

Palus, LSNE: The pharma/biopharma industry is an ever-evolving industry and these changes inevitably affect aseptic fill/finish CMOs. Overall, we have experienced a rise in the volume of incoming business over the last couple of years due in part to an increase in the amount of R&D spending and NDA submissions, which has affected both LSNE’s development services as well as our GMP filling services. One specific factor contributing to the rise in business is the greater number of biosimilars in development, which require fill/finish capabilities. The number of Orphan Designated Drugs (ODD) has also increased significantly so there is less focus on capacity and more focus on technologies, timelines and quality. There are not as many blockbuster drugs being developed and the need for small to mid-size batches is increasing. 

We have also seen more stringent requirements from the regulatory bodies, and aseptic fill/finish has been one of the main areas of focus. This additional scrutiny has caused many CMOs to either exit the business or invest in their facilities and employees in order to remain compliant. With tighter requirements at CMOs, the cost associated with outsourcing has continued to grow. This is causing some large and medium-sized companies to make the investment to bring on in-house manufacturing capabilities. 

Other changes in the industry have been the increase in the number of combination products being developed. These types of products require a QA staff that is well versed in a range of regulatory requirements from both the drug/biologic product and the medical device guidances, which can be a challenge. We also foresee an increase in the number of products for animal use needing higher quality cGMP aseptic fill/finish. The level of scrutiny for veterinarian drugs is ever increasing so companies are outsourcing their drugs to CMOs with robust quality systems that can meet CVM guidance.  

CP: What are the most important trends in aseptic fill/finish outsourcing today?
Delauney, Catalent: Demands differ from one market to another. For instance, ampoules are not a U.S. preference but they are manufactured by the millions in Europe. Vial filling—liquid and lyophilization—remains the largest portion of the fill/finish market at both the development and commercial stages. With some macromolecule products reaching later development phases, I have noticed increasing demands from biotech/pharma companies planning to secure their supply chain network through qualification of a second manufacturing site. Also, with the development of technologies enabling self-injections and the need to decrease the number of preparation steps for injectables, the trend for pre-filled syringes is still on the rise.

Time and flexibility often have a very high influence on the selection of a fill/finish CDMO partner, and after the often lengthy and expensive process of securing drug substance manufacturing, clients can sometimes underestimate the complexity of setting up fill/finish operations that are suitable and scalable. This also means they may have unreasonable expectations of the cost and time required to find an optimal solution. We are however seeing more experienced innovators engaging external support earlier in development, and some are seeking more strategic relationships that begin at an early stage of development but take into account the needs of later stage supply. With the increasing proportion of orphan drug development going on, the need for flexibility when market demands or forecasts change, for example when follow-on indications are launched, CDMOs often prove their experience by adapting to their client’s needs.

With the shift from the historical blockbuster model towards the more frequent focus on smaller batch sizes and personalized medicines, flexibility in the manufacturing environment is again necessary. To name a few examples, the use of a restricted access barrier system (RABS), as a viable alternative to isolators in reducing human intervention in a controlled environment, is better suited to multiple product filling lines and may simplify primary container format changes. In addition, single-use equipment, as opposed to traditional multi-use stainless steel tanks, has also had a positive impact on overall project timing.

Anderson, Symbiosis: Success in outsourcing is underpinned by technical capabilities and effective communication on both sides of the supply contract. In addition, the relationship between the client and service provider is fundamental. We are seeing more and more clients moving away from tactical outsourcing initiatives in favor of a relationship-oriented strategic partnership with CMO partners across a collaborative supply chain. Due to the nature and complexity of sterile fill finish, most drug developers need a long-term vendor that will invest time, energy and resource into achieving a productive outcome. The long-term benefit for a CMO like Symbiosis is we grow and scale-up as clients’ products move through phases. It also gives us a strong understanding of each client’s product and process, which we may have developed, adding huge value when it comes to increased batch outputs and meeting clinical deadlines. 

White, Piramal: Demand for hi-tech capabilities should grow as ADCs and other high value products predominate the potent development space. Approximately 119 traditional cytotoxic compounds are being developed, nearly all represent new formulations of older known cytotoxic APIs. Many are liposomal and nanoparticle delivery systems thus supporting the need for hi-tech capabilities. In addition, continued generic demand is being driven by the drugs in shortage in the U.S.; 77% of the drugs in shortage are injectable drugs. Also, there will be greater price pressures as CDMOs in emerging markets become a greater threat to U.S. and EU competitors.

Schroeder, PCI: We see increasingly that new drugs are being developed for very specialized disease states and unmet needs. This translates to much smaller batch sizes and smaller patient populations, which has a significant impact on operations and the technologies that are the best fit for the application. We have focused on flexible equipment friendly to frequent changeover and redeployment.

There is also a shift from clinical administration to in-home administration by the patient, which drives the push towards patient convenience in delivery form, namely prefilled syringes, pens and autoinjectors, as well as metered deliveries such as infusions and wearable devices. Packaging operations are certainly becoming more complex and specialized, with a need for real precision and automated quality inspection. Having a deep experience supporting various parenteral delivery forms allows us to support our clients with best practices and solutions to ensure success.

Palus, LSNE: The demand for highly potent/cytotoxic processing has continued to grow, along with the increase in the ADC market. A number of CMOs have added this capability over the last couple of years but there still does seem to be some shortage in available capacity. 

The number of biologic INDs is increasing faster than the number of small molecule INDs. Specifically, the field of oligonucleotides is rapidly expanding with the number of companies developing antisense, siRNA, and RNAi technologies. Many products within this class of therapeutics lack of stability in an aqueous solution and many companies are turning to lyophilization to increase shelf life. These high value APIs should also benefit from reliable equipment with redundant systems. Many of these new APIs are extremely expensive. It is important to minimize the risk of loss both through the implementation of an efficient production process and having redundant equipment to support the manufacture of such products.

As new solubilization technologies become available, many low solubility APIs have been able to enter the market. A CMO needs to stay abreast of these technologies to support liposomal formulations, emulsions, suspensions, etc. Many companies have developed platform technologies, which are used for many products within the company’s pipeline. CMOs working collaboratively with the developer on complex/aseptically processed projects are driving the business towards long term partnerships rather than one-off fills. 

CP: What are the key new technology innovations making an impact?
Delauney, Catalent: Blow-fill-seal (BFS) technology offers an alternative to filling into traditional glass vials and can demonstrate advantages over the use of glass itself, and in reducing the risk of particulate contamination, because with BFS the container is formed, filled and sealed very quickly within a highly controllable space.
Catalent has demonstrated that BFS is suitable for biologics, and has completed compatibility assessments of a model monoclonal antibody formulation in a BFS plastic vial, compared and a glass vial, with good results.

Anderson, Symbiosis: Single-use, disposable technologies form the foundation of all that we do at Symbiosis and help us to achieve absolute compliance by eliminating potential for cross-contamination.

Schroeder, PCI: There is a real focus on patient safety and convenience for injectable products, which will support more personal administration and allow patients to not feel tied to the home or clinic due to their medication regimen.  The developments in safety syringes and pen/autoinjector technologies make it much more convenient for patients to live a normal lifestyle, which is a tremendous development for everyone. Likewise, the inherent fragility of parenteral delivery forms is being addressed through advanced materials, further benefitting the patient. Similarly, needle technologies are rapidly advancing to provide patients a more enjoyable experience in taking their medication without discomfort.

Palus, LSNE: The industry is continuing to evolve and there have been many new technology innovations that have impacted the CMO industry. Since we are a multi-use facility, we use disposable and single-use equipment whenever possible. These disposable materials reduce the risk of cross contamination and protect both our facility and our operators. There has also been a focus on producing pharmaceutically elegant products at an earlier stage than was expected in the past, so LSNE’s development team continues to add new technologies to better serve our clients. Additionally, LSNE has brought on UPLC capabilities which provide more sensitive analysis in a much shorter time compared to traditional HPLC.