The challenges of biopharmaceutical manufacturing

A Roundtable with Creapharm, Laureate Pharma, Oystar, Nordvalls and Synomics Pharma

“The industry is slowly shifting to focus more on consumer needs rather than looking at individual requirements of process steps”
-Jens Torkel, Oystar Pharma Division

NGP. How has pharmaceutical manufacturing changed over the past few years? What are some of the current trends/developments and what impact are they having?
Robert J. Broeze. Biopharmaceutical manufacturing is a highly specialized and complex process because each protein molecule is unique in its characteristics and requires specific processes of production and purification. But now platform processes are becoming more of the norm in the Industry. One of the common platforms is to use recombinant CHO and other cells to produce monoclonal antibodies (mAb) in cell culture process. Major advances in cell line development has allowed protein expression levels to reach >10 Grams/Liter in bioreactors as large as 20,000 liters in size, the levels that did not exist several years ago. Standard platform purification schemes using the sequence starting with affinity capture on Protein A, followed by ion-exchange and other standard methods of chromatography, with concentration and diafiltration steps as needed, have become typical for purification of mAbs in the manufacturing plant.

John Pirro. Pharmaceutical companies have in-house manufacturing capabilities, but have decided to outsource these services and reduce their in-house manufacturing capabilities dramatically or completely. Delays in regulatory approvals have caused big swings in in-house manufacturing. Therefore, it is more cost effective to rely on outside manufacturing sources that can manage projects for a number of clients and have an understanding of regulatory issues. For example, holding up a production line while waiting for regulatory approval could cost pharmaceutical companies millions of dollars per day in their intended market.

Jens Torkel. The current trends and influences to the pharmaceutical manufacturing are significantly impacted by external influences such as governmental regulations due to changes in Health Systems with the target to control costs of the Health Systems. Additionally consolidation and with this a higher degree of competitiveness has influenced which manufacturing sites are surviving and still growing. Another significant trend is the shift from manufacturing capacities from one country to another. Again with the target of cost reduction due to lower labor costs. Slowly but steadily sustainability topics are being addressed as well as track and trace systems are being introduced. It seems the industry is slowly shifting to focus more on the consumer needs rather than looking at individual requirements of process steps. The product and the package design is more and more geared to present a much more holistic approach towards the end user.

Michel Pautrat. The former Big Pharma concept “one country / one plant” has gone in the last 10-15 years. This and the mergers have lead to numerous divestitures of plants to contract manufacturers. However, there were very few plant closures. The overcapacity remains in Western countries. I should say it is growing because demand in units volume starts to decrease, new therapies make traditional equipment inadapted and new capacities are added in the emerging markets. Standard forms manufacturing is likely to shrink. It has already started for non-sterile liquids.

Torbjörn Gunnarsson. Within the labelling and packaging area, increased demands for more information on packages and often also requests for multi-language versions, creates demands of extended patient product information.

A challenge in some situations are how to add and handle these requests to an already small package. The usage of a booklet label will here be a possible solution.

Problems with counterfeiting increases dramatically. Demands for track and trace within the logistic supply chain and securing the authentication of products need solutions. Technologies using 2D barcodes, RFID and other security features to creating smarter labels and packaging solutions will have an impact as well as Authorities globally looking for how to prevent the problems, by recommendations ,directives and even through legislation.

Braille marking is another issue as well as design for child resistant and safe solutions and at same time senior friendly packages and blisters.

NGP. Can you outline some of the most common challenges that arise in biopharmaceutical manufacturing especially regarding quality and compliance needs?
JP. Biopharmaceuticals by nature are made by biological systems. These biological systems are very difficult and complex from a scale-up manufacturing position. Some of the most common manufacturing processes are creating fermentation products using bacteria and yeast, creating synthetic proteins, and extracting from human sources. For these processes, regulating consistent yields, monitoring contamination, and validating efficacy of products are causes for concern. The challenges of selectivity, reproducibility and accurately quantitating these products, once they have been introduced into an in vivo system, have seriously handicapped biopharmaceuticals from being commercialized.

MP. I have little experience with bio manufacturing of API. This industry having developed after the chemical synthesis industry benefits from ground guidelines coming from the “old lady” in particular for the finishing steps. Bioproduction obviously has its specificities linked to the handling of live organisms, cells or bacteria, with the necessary precaution related to confinement on one side and viral contamination on the other.

Once the active is extracted and purified the formulation of the drug substance into drug product, even for clinical material, involves similar processes between small and large molecules (non live). Bio molecules tend to be in injectable form either liquid or lyophilized. QC at the pharmaceutical stage is also similar. Biomolecules may require bioanalytical methods (Elisa, PCR…)

TG. In relation to our business, label & packaging solutions, the challenges to the biopharmaceutical manufacturing would be same as outlined above, as we look at it.

RB. Challenges occur when trying to decide how to incorporate latest technology for testing process intermediates and final products. The sponsor (our client) has to work closely with the FDA to see what is acceptable with the agency and should have frequent meetings with the FDA prior to submitting their PLA. The FDA Quality and Compliance requirements are published in the "Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use". The current version of this document was published in February 28, 1997. This document lists testing requirements for cell banks, bioreactor harvests, purified bulk and final drug products.

NGP. What quality control procedures do you have in place to assess processes, end products etc?
JT. The Oystar Pharma Division has introduced and improved a project management system. The clear target is to have the whole order flow process clear and transparent at all times and by all means. This tool is already implemented during the quotation process in order to verify at an early stage all promises made to our clients are technically and commercially feasible and the anticipated timely horizon will achievable. To accomplish this, the process is broken down in several sub processes, mile stones and responsibilities are clearly defined in the beginning. All this is monitored, deviations will be recorded analyzed and corrective actions at least on a weekly base defined. Escalation procedures have been introduced during the course of 2008. A key tool bringing this to a mutual success was the recent introduction of quality gates that are key critical targets to be met in order to achieve the promised quality and timeline. All this is in addition to already existing quality procedures under ISO9001 and our own supplier audits that we are performing.

TG. All production for the pharmaceutical industry takes place in our special Pharma department. Only staff trained in GMP - Good Manufacturing Practice – work here. All production is done according to very strict routines for orders and manufacture. Each working operation is checked and signed in a special production protocol before the next step begins. Each printed product undergoes visual control, is paginated, reeled and marked according to the customer’s requirments. There is then a check to make sure that the inner and outer wrapping are correctly labelled. Finally, all previous controls are inspected and spot checks are made. When the products are finished and approved by us, printing samples and production certificates are sent to the customer.

The Swedish Medical Products Agency and its counterparts in different countries, along with the FDA and other authorities, regulary inspect pharmaceutical companies around the world. Since it is the duty of our customers to make certain that we satisfy the quality and safety requirements, the keep us under continual scrutiny and audit. This ensures that the applicable laws, ordinances and regulations are obeyed.

Our operation is of cause certified according to ISO 9001 and ISO 14001.

JP. Synomic’s analytical service for cGMP incorporates client complaints, event andclient complaint resolution, Out-Of-Spec’s, and Corrective Actions/Preventative Actions (CAPA) in our quality system. These processes, from an analytical manufacturing point of view, exceed the regulatory requirements for lot release. By incorporating client complaints and CAPA, as part of our event resolution process, we involve our clients more in the manufacturing analytical process.

RB. We have a quality policy to address all quality procedures. Our Quality Systems consist of cGMP Documentation System, Audit and Review System, Approval and Release System, Vendor Approval System and cGMP Compliance. Our Change Management System covers approved documents, facilities equipment & processes. The CAPA system assures that deviations and incidents are recorded and corrective/ preventive actions are implemented, investigations are conducted and remediation plans are set in place. Our analytical testing programs cover testing of Biopharmaceuticals, Pharmaceuticals and Radio-pharmaceuticals. QC Testing conducts tests on raw materials, In-process and intermediates and the final product. We also do environmental monitoring, tracking and trending data, and oversight of outside testing.

MP. As a contract manufacturer for clinical supply being often faced with new formulation processes which we have not developed, particularly for sterile formulation we first do a “paper review” to evaluate the critical points of the process. Then we usually perform a technical batch to verify the technical feasibility. Such batch can normally be used for preclinical, tox, stability studies. A key aspect is to assess the filtration performance. As GMP requires, depending on the specificity of the process, we perform media fill tests to verify the sterility aspects.

NGP. Pharmaceutical companies are under increasing pressure to reduce time to market. What methods can they use to help achieve this, while ensuring quality standards remain high?
TG. We offer a tool to our costumers called Webcenter. Webcenter – a web based online proof tool – allows a safe, structured and speedy process when developing new artwork to a new product. We facilitate an easy and correct version handling in the proofing process as well as filing and storage of your artwork. This implies substantial time saving in comparison to traditional proofing process. Security as well as openness and flexibility is provided as all files is in a server available to all parties given access.

Our digital technology allows us to supply you with dummies and trial labels of exactly the same quality as the final product. This makes it easy for you to test market reactions to your products as well as test a label’s mechanical properties before going into full production. For some products an alternative for short production runs and smaller batches. This enables you to save both time and money.

MP. There are no shortcuts in the pharmaceutical industry. From a time to market point of view it has been often demonstrated that it is preferable to add supporting studies rather than taking shortcuts. Therefore to gain development time, there are only two paths: to complete as much as possible studies in parallel rather than sequentially and to reduce “lost” time between sequential studies. This second point has a lot to do with communication and interfaces. A solution is to reduce the number of actors involved and to work with integrated multispecialists who can offer state of the art competence and seamless flow of the project.

JT. A good and proven way can be to include suppliers in early stages of such projects. Today’s new products are rarely having simple and standard demands in regards to supplies needed. The new products are complex and asking for creative solution later during manufacturing and packaging. A benefit of integrating key suppliers or integration partners into the earlier stages is that possible equipment can have from the beginning a high degree of standardization but modular customization at the same time. This route will lead to shorter lead times for pharmaceutical manufacturing equipment and simultaneously it does have a positive effect on the initial capital costs involved. Long term it also helps to drive the life cycle cost to a lower level and if done right the efficiency typically is optimized during the whole manufacturing process. Interfaces between process steps can easier be managed and optimized.

RB. Besides the platform approaches already described above, applying single-use, disposable systems can also streamline the process. These systems enable rapid turn-around time of equipment, as the product-contact materials are simply discarded and replaced for the next run. There is therefore no risk of any product carryover, and no need for the extensive cleaning typical of multi-use materials. Another route to reduce time to market would be to perform the aseptic filling in the same facility as the bulk production. This avoids the need to ship between locations with the attendant risks and potential for delay this brings. Laureate Pharma offers its clients all of these acceleration advantages.

JP. One of the major delays that pharmaceutical manufacturers have is transferring products from a GLP quality system to scale up cGMP for clinical trials and final market release. Gaps exist with regard to bioanalysis of products in a clinical setting, variations, delays going into the clinic, and gaps in submissions of NDAs and in moving products into the market place. One of the things pharmaceutical manufacturers can do to reduce delays is to address sensitivity, robustness and transferability of all assays under the GLP guidance. This would require some cGMP processes, such as managing event resolution and setting Out-Of-Spec criteria to be incorporated early in the GLP phase of product development.

NGP. Can you explain why it would be beneficial for a pharmaceutical company to employ the services of a contract manufacturing organization rather than doing things in-house?
MP. The key driver of outsourcing for Big Pharma companies is economical: to move fixed costs to variable costs, and to reduce the asset base to improve ROI (Return On Investment). The key drive of outsourcing for mid size pharma companies and startups is more technical: to find specialist competences absent or insufficient in house. This is particularly appropriate at the development stage more specifically for the supply of GMP API and drug product. This is a specialists job in many ways: small size clinical batches GMP manufacturing, randomised labelling and packaging of patient kits, controlled distribution to investigational centers requires specific know how, capabilities and authorizations. Less obvious but as important: the ability to rapidly interact with developers and to keep close to the typical stop and go of a project is key to reduce time to licence or time to market.

JP. While pharmaceutical companies have to wait for projects to come through their in-house manufacturing production line, CMOs efficiently have multiple clients in place to fill the manufacturing production line, allowing a reduction in overhead and cost.

This efficiency, combined with expertise, problem-solving skills and deadline management that comes with long-term exposure to difficult products within the pharmaceutical industry, helps reduce time to market for the pharmaceutical manufacturers. When pharmaceutical manufacturers are matched with reputable CMOs, they can greatly decrease the manufacturer’s time to market and increase profitability.

JT. Having agreements with contract manufacturing organizations are a standard tool to reduce fixed costs and make them directly variable. In case of sudden unexpected demand reductions your own manufacturing is not impacted at all. The risk of expensive unutilized capacities is mainly shifted to the contract manufacturer, who in return typically does have other clients which will enable the supplier to compensate with other jobs. On the contrary in a case of a sudden increase in demand it might be easier to fulfill this with the services provided through one or more contract manufacturers on hand. Certainly the initial transfer and validation topics need to be addressed and well executed. Another benefit might be that contract manufacturers often have a very variable manufacturing set up in order to react flexible to different manufacturing or packing demands.

TG. Possibility to achieve a closer access to certain markets geographical and of an environmental perspective advantages with shorter handling of the product from finished production out to the market and the end user.

Put own main efforts on development and introduce, release of further developed and new products, save costs of investments in production equipment, etc.

If possible, to slim, control and shorten the total supply chain will definitely have some positive impact of security issues.

RB. Biologics manufacturing is technologically complex and is highly regulated by the FDA. It requires significant experience and specialized skills to produce the large complex protein structures in large scale. Moreover, significant investment capital is needed to construct a manufacturing facility. It costs $10 million to construct, equip and launch a 100L traditional pilot plant facility. The cost goes up to $40 million for a 1000L pilot plant and for a 10,000 to 20,000L facility, the cost becomes prohibitive at several $100 millions. Outsourcing biomanufacturing also reduces time-to-market as constructing a new, fully validated facility takes several years. Finally, outsourcing manufacturing provides companies an opportunity to place greater focus on their own core competencies. By handing over the responsibility and complexity of daily production to CMOs, these companies can significantly minimize their risk and decrease their development timelines. Their time and resources can be better spent in drug discovery and lead optimization.

About the Contributors:

Michel Pautrat became the founder of Creapharm in 1998 after many years in executive positions with various Big Pharma groups, deciding to start his own pharmaceutical development and contract manufacturing organization. The industrial part was sold in 2005 and Creapharm group now focuses on pharmaceutical development and manufacturing, packaging, distribution of clinical materials.

Robert J. Broeze is the President of Laureate Pharma, holding over 20 years of experience in the biopharmaceutical industry. His technical expertise spans research, development, characterization, validation, testing and cGMP manufacture of biopharmaceutical products with a strong emphasis on monoclonal antibody products for therapeutic and diagnostic use. Dr. Broeze worked as a Postdoctoral Fellow at Yale University and earned his Ph.D. from Rensselaer Polytechnic Institute.

Torbjörn Gunnarsson is Business Area Manager Pharma of Nordvalls.

Jens Torkel was appointed in March 2008 as the Head of the Oystar Pharma Division. Since August 2007 he serves as CEO of Oystar IWK. The Oystar group is a leading supplier for Fluid Beds, Granulators from Oystar Hüttlin, Tablet Presses and Coaters from Oystar Manesty, Tube Fillers from Oystar IWK, Blister machines and cartoners from Oystar IWK and Oystar Fabrima.

John Pirro is the Vice President and COO of Synomics Pharma. Joining the company in 2007, he brings more than 20 years of experience in general management, business development and research. In addition to his recent position as Vice President and General Manager of MDS Pharma Services, Mr. Pirro has held executive positions with Charles River Laboratories. Prior to those positions he served in pharmaceutical research scientist roles with Bayer Corporation, Bristol-Myers-Squibb, and Columbia University. A co-holder of several patents, Mr. Pirro has published his research in numerous technical journals.