1. What, in your opinion, is currently the single largest trend with respect to biologics manufacturing?
SW: One area where we see continued change in the industry is in the use of single-use (disposable) materials for processing. These materials include bioreactors, solution storage containers, filters and other items that are used for one or a few batches of production and then are replaced with new materials. The increase in the use of these materials is driven by the reduced capital cost associated with their use and the improved quality and cost/benefit of these materials, which enable their use to reduce the number of failed batches or in other ways to reduce the cost of production.
PS: From our perspective, the most important single trend in the pharmaceutical and biotech industry is the strengthening of the overall injectable market. A recent Datamonitor forecast projects a growth of $33bn in this sector by the year 2016, with biologics predicted to be a major contributor to this growth.
Thus, all indications point to a number of significant opportunities in this area. A few of particular interest include the field of complex biologics, e.g. therapeutic vaccines and other high-value compounds.
And while manufacturers will enjoy opportunities in this area, these opportunities will also present challenges as well. Due to their biochemical composition, the requirements for their manufacturing and their administration are wholly different.
Such opportunities and challenges have led to a growing need for production sites that allow for efficient manufacturing of complex and sensitive biologics e.g. in syringes. These facilities need to be able to scale up rapidly. At the same time, they must also be flexible, allowing for a quick switch of products being manufactured.
As the blockbuster model runs its course, monoplants will no longer be viable in this area. Biologic properties mean production facilities will need to enable high quality and safety standards even with rapidly changing products. Given these requirements and conditions, as a CDMO we see an important growth area in this field of biologics. That is the main reason why we have proactively invested in an innovative high-performance production line in one of our European facilities which can fill up to one million pre-sterilized syringes per day.
MJ: The continued transition to and acceptance of single-use technologies is currently the largest trend.
CG: There are quite a few processing trends that are at varying stages of evolution in fill/finish: the move away from stainless steel to single-use systems, the evaluation of plastic components as an alternative to glass components, the lure of micro-needle or needlefree dosage forms vs. vials and current PFS delivery technologies, etc. However, the single largest trend may be related to scale of operations. The movement toward personalized or targeted medicines, evidenced by the rise of orphan drug designations/approvals and the growing companion diagnostics market, means that existing large scale manufacturers must be able to scale down efficiently and effectively to be competitive.
LT: The industry trends we are seeing ask for flexible and cost-effective manufacturing facilities and processes. DSM’s answers to these challenges are technology solutions offered through the CMO services of our Biologics business, which significantly drive down the costs of biologics manufacturing including operating costs, capital requirements and scale-up risks.
Speed to market for clinical trials and security of supply at the commercial production level of finished dosages is also critical. Our broad capabilities include aseptic filling of liquid and freeze-dried cytotoxic and non-cytotoxic compounds, manufacture of tablets and capsules, pharmaceutical development services, and clinical trial materials manufacturing for solid and injectable forms at our 1.5M square foot facility in Greenville, North Carolina.
To meet supply demand we offer aseptic liquid filling using a proprietary, flexible, state-of-the-art distributed control system, and lyophilizers that range in size from 8 to 640 square feet. Within our cytotoxic capabilities for filling and lyophilization, we hold Potent Compound Safety Certification from SafeBridge Consultants, Inc.
2. What are the challenges of working in biologics manufacturing?
SW: The biggest challenge in working in biologics manufacturing is the inherent instability of the proteins and related materials we produce. This natural tendency to degrade leads to variations in product uniformity, in increased related substances and to changes in activity and toxicity. Even as the material is processed, chemical reactions take place that alter the composition and behavior of the product. The challenge is to stabilize the materials as they move through production and as they are stored at the end of manufacturing. Improvements in stabilizing intermediates and products would increase the shelf life and decrease the lot to lot variation in manufacturing.
PS: Biologics manufacturing demands experience and substantial process expertise. Active ingredients based on biotechnological processes are extremely complex compounds with large molecules. Substances like this react with far greater sensitivity to environmental influences such as light and heat than do other substances. This requires high standards in manufacturing as it pertains to quality and safety. In addition, a manufacturer will need to master apposite production processes, such as the use of certain pumps in the filling of active ingredients. Furthermore, a manufacturer will need extensive knowledge of packing materials and components. For example, biologics will react more strongly to the silicon film required inside a glass syringe or to the chemical composition of a stopper. Therefore, safe manufacturing of biologics requires more extensive development work than was necessary in the past. As a CDMO, we believe it makes best sense to begin adjusting packing materials, components and ingredients in the earliest clinical stages. And because more and more products are also used in homecare, greater attention should be given to life cycle management as well. In this way, drugs might be migrated to syringes following their launch in vials. Another step would be the use of autoinjectors to make their administration easier for users. Such devices, however, must be aligned with the active ingredients. The earlier pharmaceutical and biotech companies come to understand this complex technology, the more rapid and smooth the implementation of lifecycle steps can occur.
MJ: 1. Managing capacity constraints
2. Project cancellations
3. Project funding
4. Surprises during scale-up/ development stages
CG: The high dollar value of APIs puts a lot of pressure on manufacturing to maximize yields and minimize rejected material at the fill/finish stage. And the importance of the drugs in the marketplace puts a lot of pressure on manufacturing and quality to deliver on time and in full. Whether these operations are performed in house or outsourced, manufacturing is the key to achieving/ maintaining margins and market share that allows companies to be successful.
LT: One of the most significant challenges is that because each product is different in upstream and downstream process conditions, you need expertise and experience in your manufacturing team so that each batch can be executed successfully. It requires a flexible facility and one capable of handling different operating conditions. DSM has this expertise in our Groningen, The Netherlands and new Brisbane, Australia facilities and along with our technology solutions we feel we are uniquely positioned to deal with these challenges. In the area of filling biologic drug products, injectables sterility is a huge factor and critically important. Our track record with regulatory agencies for our Greenville facility is very strong.
3. Is there a country or region of the world that is currently increasing their expertise and market share in biologics manufacturing?
SW: If we look at the fraction of total prescription drugs sold in the US and worldwide that is composed of biologics, we see that about 20% of all sales come from biologics. However, in China this fraction is only about 2%. There is nothing particular to the China market that suggests that biologics should have less utility than in other markets. Therefore, the reason why biologics represent a lower proportion of sales in China is probably due to the availability and affordability of these products in China. The Chinese market for pharmaceuticals is expanding at over 20% per year. It is reasonable that sales of biologicals may increase even more rapidly than this in the next decade.
PS: As a CDMO, our clients include some world leading pharma and biotech companies. We do not see any dramatic changes in positions on the international market. In biologics, the established markets are still setting the tone even though pharmerging markets such as South America and Asia are catching up. In research and development, the U.S. still has a lead since - with approximately two-thirds - the majority of new drugs, particularly the biologics, are developed there. Because we see no huge change here we decided to set up a facility for early development of drugs in the U.S.
Following North America are Europe and Japan. We believe these regions are poised for moderate growth in the years to come. However, major growth surges in biologics can be expected from a lower base, especially in pharmerging markets. And while some experts foresee yearly rates of about 20 percent, we believe that emerging regions will gain only incremental market share in manufacturing due to the high demands of biologics manufacturing and the vast experience of established markets in the field.
KP: Asia: Korea, China, India and Singapore in particular are increasing expertise and market share.
4. Where do you see biologics manufacturing in 5 -10 years?
SW: Over the last several years the industry has witnessed an increase in the use of platforms for production of biologics, with multiple products within a company using similar production processes. By using platform processes, companies are able to use the same facility for multiple products and reduce the cost of manufacturing, through shorter product changeovers, less custom equipment and better training. If this trend continues, we should expect to see continued improvement in cost of goods.
PS: Given long-term developments and trends influencing the industry, we think the current evolution will continue. We project that economics will lead to a higher proportion of biologics manufacturing being outsourced. However, more and more specialized service providers will be needed as regulators raise their requirements. This means CDMOs will need to continue investing and expanding their expertise in order to retain their capability with regards to future complex substances.
Polymer syringes can be one solution in biologics manufacturing because they are well suited to a wide spectrum of active ingredients. By then the industry will have made further progress in orphan drugs and in personalized medicine. We also predict that over the next five to ten years we will see secure profitable models and processes emerging in these segments. This will be coupled with demographic change and scientific progress which will lead to a growing demand and more offerings, especially in biologics.
MJ: Over the next several years, there will be a continuation of the trend away from 10,000-20,000 liter batch production, to smaller more flexible scales for new products. Personalized medicines will help drive this trend. Look for more efficient purification systems and innovation to be driven by the need for low cost of goods and biosimilar competition. Expect large- and medium-sized Pharma to partner with CMOs for pre-commercial production and transfer projects “in house” as they are commercialized.
KP: Government requirements for local manufacturing will drive added capacity into emerging markets. Additionally, the high cost of manufacturing will incent innovation to reduce costs as well as movement of manufacturing into lower cost geographies with concomitant enhancements in technical expertise and regulatory sophistication in those geographies.
CG: Over the next 10 years, as biosimilars and personalized branded biologic drugs drive manufacturing into smaller, more frequent batch production, we could see an increase in the number of providers of manufacturing services. CMOs must be able to prove that they have superior expertise, reliability, cost effectiveness and trust to hold off these potential new entrants. If unsuccessful, smaller biotech companies may decide to build appropriate-sized facilities with the latest technologies to keep greater control of products. As a group, CMOs must perform very well over the next 5 years to make such investments in new facilities unattractive/unnecessary for other organizations.
LT: For the delivery of drug substance during this period, we see a greater adoption of fast and flexible manufacturing options that will begin to dominate the industry. These new facilities will be largely dependent on disposable technology that require a smaller footprint, are more sustainable by using less water and energy, and most importantly require less capital investment.
In this environment, DSM’s proprietary upstream and downstream technologies, XD process technology and RHOBUST direct capture technology, result in much lower cost of goods, faster production times and better sustainability by significantly reducing water and energy usage per unit of material produced. In combination with developing cutting-edge technologies we are able to offer custom manufacturing services with full flexibility and secure, on time supply from our facilities in Europe and Australia.
5. What role does strategic partnering play in relation to biologics manufacturing?
SW: Strategic partnering is a means by which a product development company can reduce the risk of manufacturing by offering future income in a product sales stream to a manufacturing partner in exchange for reduced costs during product development and clinical testing. Thus some of the costs of manufacturing are borne by the strategic partner, who benefits from potential future revenue streams. This is of particular benefit to smaller firms without their own manufacturing capability, but is not basically different from the partnering of development programs that goes on among all of the big pharmaceutical companies around the world. Many companies partner their programs in order to mitigate the risk associated with large clinical trials. Strategic partnering with manufacturers is new in that within the last few years we have seen CMOs willing to accept future returns in exchange for discounts in current production.
PS: In our view, several trends will increase the importance of strategic partnerships, particularly in the area of biologics manufacturing. For business reasons, pharmaceutical and biotech companies will focus greater attention on their core competences such as research and development as well as marketing. This will strengthen the trend towards outsourcing. At the same time, complexity will grow further in active ingredients and production processes.
Ensuring the demand for safe and high-quality production will warrant extensive expertise. This will require drug manufacturers to share their know-how with service providers, and vice versa. In our view, involving a service provider early in the process allows for the establishment of end-to- end safe processes. Such strategic partnerships support better business. Also, this early involvement allows service providers to contribute their expertise as early as the development stage, crucially raising the potential for success of new drugs. Even today, leading manufacturers have come to rely on strategic cooperation with experienced CDMOs who support their drug products from early development all the way through to long-term supply to the market. This allows pharma and biotech companies to benefit from commercial manufacturing know-how in early development onward, enabling companies to create seamless transfer from drug development to commercial manufacturing.
MJ: Companies with excess capacity will continue to try to find ways to offer their capacity on either a fee for service basis or in conjunction with product partnerships. Contract manufacturers will also be driven to consider additional partnership approaches that involve more financial risk…and more reward.
Innovation and new products will continue to be developed at small fragile companies and large Biotech/Pharma will need to find the best ways to nurture access and transfer these to commercial products. These discussions need to go all the way down to the University levels and focus on both products and business models.
CG: There is a definite ease in the learning curve and an increase in organization efficiency when you reach the partner level. And once trust is established and the communication channels are opened, issues/challenges are typically resolved more quickly. Ultimately, if the partnership survives and thrives, the new business cycle (i.e. time from feasibility discussions to first batch production) can be drastically reduced. From a CMO business perspective, the downside may be that sponsors exert significant margin pressure in exchange for increase in volume commitments. Some CROs are struggling with this now as a result of such partnerships, and it is possible that CMOs will begin to feel this effect more as vendor consolidation picks up steam in the manufacturing services space.
6. Any additional or closing thoughts on this topic?
PS: In previous years, pharmaceutical companies would not have called on the contribution of CMOs before the end of phase II or during phase III of development. But complexity in biologics development and manufacturing is leading to a major change in outsourcing. Therefore CMO support often begins much earlier. This has led some CMOs to expand their development capacity and expertise, turning them into contract development and manufacturing organizations (CDMOs). Vetter, for example, has been supporting early development work for many years through Vetter Development Service. As a CDMO we have taken the next step with e.g. a new facility in Chicago that allowed us to expand our capacity in the development area. This facility supports preclinical through phase II projects, featuring equipment optimized for small-batch manufacturing. We have also significantly expanded our project management capacity in the past few years, offering specialized expertise and tools for large and small companies in all phases of drug development. In addition, we have refocused the supply chain management on processes and requirements that are becoming increasingly complex, allowing close collaboration with all parties concerned including individual customer divisions and suppliers.
LT: As a contract manufacturer and technology provider, we make a commitment to employ expertise across our organization to achieve success for our customers; to this end DSM offers an integrated approach to sustainable manufacturing using biotechnology, chemistry, and process technology. With capabilities in mammalian-based biologics such as monoclonal antibodies and proteins; microbial-based fermentation derived APIs including small molecules, therapeutic proteins and enzymes; substantial small molecule API capabilities based on complex chemistries as well as solid and sterile dosage finished dosage manufacturing, we strive to bring the most economic and sustainable solutions to customers.
This article was printed in the September/October 2012 issue of Pharmaceutical Outsourcing, Volume 13, Issue 5. Copyright rests with the publisher. For more information about Pharmaceutical Outsourcing and to read similar articles, visit www.pharmoutsourcing.com and subscribe for free.