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.
 
Contract Pharma talked to Carole Delauney, account director, drug delivery solutions at Catalent Pharma Solutions about market and technology trends, to 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: 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 for 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, while 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.
 
CP: What trends are driving aseptic fill-finish operations?
 
Delauney: 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.
 
CP: How do you see the aseptic fill-finish market evolving in the years ahead?
 
Delauney: Demands differ from one market to another. For instance, ampoules are not a U.S. preference but they are manufactured by the million 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.