The market for biopharmaceuticals continues to expand worldwide, and they have been the primary growth driver for the pharmaceutical industry. Biopharmaceuticals will continue to provide significant growth for the pharmaceutical market over the next five years. Biopharmaceutical contract fill-and-finish has expanded in recent years as more biopharmaceuticals enter the market. Pharmaceutical and biotechnology companies look to contract manufacturing organizations (CMOs) as a way to meet their fill-and-finish needs and reduce risk. This article reviews selected market trends, the use of multi-molecule agreements, and underserved market segments.

Background
The information presented in this article draws from HighTech Business Decisions’ latest report, “Biopharmaceutical Contract Fill-and-Finish: Best Practices Study 2018.” The findings in this report come from primary research through interviews and written surveys from senior-level executives and scientists at pharmaceutical and biotechnology companies and fill-and-finish contract manufacturing organizations. For purposes of our article, we define biopharmaceuticals as complex molecules created through the genetic manipulation of living cells or organisms used for therapeutics or vaccines. We define fill-and-finish CMOs as contract manufacturing organizations that provide drug product manufacturing services under a fee-for-service contract. Manufacturing services include formulation, fill, packaging and labeling, lyophilization, and other services for the final production of the drug product. 

Fill-and-finish services outsourced
Contract fill-and-finish services remain one of the most outsourced services today. Almost all pharmaceutical and biotechnology companies outsource at least a portion of their fill-and-finish needs. A virtual start-up company uses a CMO because it lacks both capacity and the means to build capacity. Large companies with in-house fill-and-finish capacity outsource at least some of its fill-and-finish needs to lower supply chain risks. The reasons to use a CMO’s capacity include unexpected demand, second source policies, or better matching scale with need. Companies with in-house capacity will also use a CMO when it lacks the ability to produce novel products or formats. Specialized capabilities such as lyophilization, filling prefilled syringes and cartridges, or novel therapeutics may require specialized manufacturing that may be more cost-effective to outsource. For those companies with in-house aseptic fill-and-finish capacity, they outsource on average 39% of their fill-and-finish needs. 

Most companies outsource some portion of aseptic filling (96% of respondents), and analytical testing (92%), see Figure A. On the other hand, regulatory related services and IND consultancy mostly remain in-house. This may be because many companies a) have internal regulatory departments, b) use consultants who specialize in this area, or c) use CMOs that do not offer this service. Over the next three years, all companies will outsource some portion of their fill needs. One service area that will significantly increase is lyophilization. From our study, we see the share of companies that outsource lyophilization increase from 44% to 72%. Conversely, regulatory assistance share increases modestly from 36% to 44%. Most companies will continue to keep regulatory work in-house. From our analysis, the two largest fill-and-finish market segments are filling, which accounts for 59% of total market, and lyophilization, which accounts for 24% of the total market.




Price change for fill-and-finish services in last two years
Given the continued strong outsourcing trend in fill-and-finish services, it is worthwhile to explore how prices have changed from both user and CMOs’ view. In general, our study finds that more user respondents saw higher prices than CMO respondents (see Figure B). Most respondents report price increases between 3% and 10%, but some have reported increases greater than 10%, especially in the area of viral products. Some users credit the price increase to new rules aimed to improve sterility. This resulted in CMOs overhauling their fill areas and creating aseptic environment by installing isolators and RABS systems. CMOs on the other hand reported more stable pricing. A few CMOs commented that their pricing is supply and demand driven where a unique capability and lack of competition in certain segment commands slightly higher prices.




Below are selected comments from our study’s respondents regarding their observations of price changes in the last two years:

• “We have had a 30% increase in the past five to six years. We’ve seen prices go up a lot. There are new regulations. Most CMOs had to revamp their filling area, installing grade A clean spaces between the filling machine and lyophilizer.”  —Pharma/Biotechnology Respondent

• “For viral products, we have experienced an increase of 40% to 50%.”  —Pharma/Biotechnology Respondent

• “Price increases have been more than 10% for certain capabilities, e.g., prefilled syringes, in part because there are fewer suppliers. Price increases have also been higher in certain regions where there are fewer options and where government regulations say products to be sold there must be manufactured there. It’s a matter of supply and demand.” —CMO Respondent

Effect of multi-molecule agreement on pricing
To stabilize prices, companies with multiple products have multi-molecule agreements with their CMOs. The most significant value-add of a multi-molecule or master service agreement according to the CMO respondents is price discounts. With multi-molecule agreements, CMOs can plan for larger quantity purchases and share those savings with their clients.

Besides lower prices, clients with multi-molecule agreements also benefit from flexibility of reserving capacity across the CMO’s network. Thus, reserved capacity is not tied to a specific molecule; when forecasts change, the client can rebalance their needs based on their overall portfolio demand. This reduces costs and cancellation fees.

An intangible but valuable advantage of a multi-molecule agreement is the seamless management of multiple projects by the CMO. CMOs use the same project manager who oversees the client’s entire outsourced portfolio. This continuity leads to faster contract facilitation from additional work orders. It also promotes good communication—always a challenge in client management.

Although each CMO agreement differs, these agreements offer benefits to both parties and help keep long-term relationships. However, not all CMOs offer these agreements; about half the CMOs (55%) offer multi-molecule or master service agreements. 

The following are selected comments from CMOs on their offering of the multi-molecule or master service agreements and the benefits they provide:

• “For multi-molecule agreements, we give our customers a price break. They are also assigned to the same project manager for continuity and more seamless management of multiple projects. Ordering vials and syringes in larger quantities can also provide the price break.” —CMO Respondent

• “Our pricing structure has three variables: price, number of units, and terms. The fourth variable would be the number of molecules. Our project management costs won’t change but for larger volumes and long-term relationships there is an advantage for us. We are open to master agreements with the terms that are favorable for both parties. However, sometimes this leads to more misunderstandings and demands which can be more difficult.”  —CMO Respondent

• “It’s an important part of our growing business. We can support companies with multiple products in development across multiple sites. We have an enterprise capacity model. Rather than just pricing per unit or straight fee-for-service, customers can reserve capacity, e.g., 50 batches/years across our entire network. It’s meant to give more flexibility to our customers.” —CMO Respondent

Underserved market segments
Eighty-nine percent of the companies in our study have difficulty outsourcing all their production needs. Services and production for ADCs, live viruses, cytotoxics with slow-release formulations, and small-batch runs are all areas with limited choices. Technologies like ADCs and cell therapies need specialized manufacturing. The respondents report a limited number of CMOs and a scarcity of good-quality capacity with state-of-the-art equipment to support their production needs. In particular, companies working with live virus report supply shortages and significant price increases. These are potential growth opportunities for fill-and-finish CMOs.

The respondents also note shortages of ancillary services such as analytical testing, release and stability testing. Often, third-party CROs perform these services because fill-and-finish CMOs do not provide the service. CMOs that provide analytical services help simplify their clients’ supply chain and differentiate themselves from their competitors.

Finally, while not technically a market segment, CMOs who have continued to invest in equipment and process technologies are at a competitive advantage. A few respondents told us about their concerns over CMOs with outdated filling equipment or semi-automated systems. Newer technology equipment streamlines the manufacturing process and increases efficiency while reducing risks. Fully automated systems and disposable setup provide flexibility and reduce cross-contamination. This allows more CMOs to take on novel therapeutics such as live virus products and helps with capacity planning.

Below are selected comments from biopharmaceutical respondents regarding their view of underserved areas by the fill-and-finish CMOs:

• “ADC manufacturing is underserved. We would like to see more CMOs that can offer this specialized manufacturing. ADC manufacturing is challenging. ADCs require extra monitoring, cleaning and validation. Changeover for ADC products is not simple, compared to mAbs. Disposable facilities are attractive for this reason. They save time and money on cleaning and validation.” 
—Pharma/Biotechnology Respondent

• “The viral space is underserved, starting from drug substance and going forward. There are not many CMOs willing to work with viruses so they can charge whatever price they want. Even when they are willing to work with viruses, most specialize in adenovirus and they don’t want to add another virus to the mix. With a small number of suppliers, the price goes up. The virus space is overheated.”  —Pharma/Biotechnology Respondent

• “Live products are difficult to get done. Because the product is unstable, we prefer to do the fermentation, fill and lyophilization at the same site. The knowledge supporting lyophilization activities was surprisingly weak. Another unfilled need is that no one offers large lyophilization capacity.”  —Pharma/Biotechnology Respondent

• “Personalized medicine is underserved. There is a big trend for drug candidates designed specifically for one person, which will mean there are a large number of small batches. From a timing perspective, manufacturing will be unpredictable, and the cost and scale of very small batches will be difficult. The current CMO model of manufacturing is not compatible with this type of manufacturing.”  —Pharma/Biotechnology Respondent

• “Fill-and-finish CMOs have development capabilities but often no analytical support. We generally have to find another CMO for analytical testing. If fill-and-finish CMOs offered these services it would add flexibility and would be a big advantage to us.” —Pharma/Biotechnology Respondent

• “In addition to drug product manufacturing, we also outsource formulation development, analytical development, analytical testing and analytical qualification. It would be nice to have a CMO that provides multiple services but I would choose go to the CMO that provides the best match for formulation or the best match for analytical activities.”  —Pharma/Biotechnology Respondent

• “They’re slow to move to newer technologies. Some don’t have the capital to make the investments, but it’s not just a money issue because it’s a problem with both small and large companies. Fill-and-finish CMOs are way behind on filling equipment. They need to streamline to make more product faster and with less risk. The higher throughput would benefit them and me.” 
—Pharma/Biotechnology Respondent

• “For clinical projects, I know of very few adaptive, fully flexible CMOs—where the set-up is all disposable and the CMO can easily move from viral projects to non-viral then back again. I know new requirements for sterility and isolators limit flexibility. Few [CMOs] have this flexibility. They are all product and dosage form specialists.”  —Pharma/Biotechnology Respondent

• “There are not that many top tier fill-and-finish CMOs in the U.S., so there isn’t enough high-quality capacity. We need existing high quality CMOs to expand their capacity and for new ones to come online. But no one wants to spend the money. Some existing high quality CMOs only do early phase. It would help if they invested in commercial as well. That’s more likely to happen than investments to bring new fill-and-finish CMOs online.”  —Pharma/Biotechnology Respondent

Closing
The pharmaceutical and biotechnology companies’ production strategy drives the market for contract fill-and-finish capacity and capability. Filling and lyophilization services continue to be significant market segments. Overall prices have increased modestly, and this trend will continue with expanded regulations and greater CMO investments in capabilities. Multi-molecule agreement provides benefits for both clients and CMOs. New technologies and capacity to meet the needs for novel drug products are underserved segments that will fuel industry growth. 

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Cindy LIu is managing director and William Downey is president of HighTech Business Decisions, a market research and consulting company that has been publishing reports on the biopharmaceutical contract manufacturing market since 1997. For more information, visit www.hightechdecisions.com or call (408) 978-1035.