BioProcess Theater: Clinical and Commercial Manufacturing

When it comes to clinical and commercial manufacturing of therapeutic products, outsourcing is an integral part of the biopharmaceutical industry. In the 21st century, product sponsors are increasingly relying on expert contract assistance in process development and production of clinical and commercial materials. Many companies are reaching beyond their local and national borders to extend networks of partnerships into emerging markets, particularly in Asia (1, 2).

Most biologics are proteins, with monoclonal antibodies (MAbs) dominating the scene over a number of other classes such as cytokines, blood factors, enzymes, and hormones. Vaccines and immunotherapies form a healthy segment as well. New product categories are growing fast: especially biosimilars, antibody–drug conjugates (ADCs), and cell therapies. And many experts project a growing need for outsourcing services in all these areas.

Contract manufacturing is not simply a cost-cutting measure (3). In many cases, it provides a means for product sponsors to access specific expertise and/or proprietary process technologies that are otherwise unavailable to them (4). Either way, a formal quality agreement forms the basis of the relationship, which when successful is more like a partnership than a simple client–service contract (5). That can be especially important in overseas outsourcing, with time zones and cultural differences complicating matters of science and technology and business, all of which are complex enough to begin with.

Information technology (IT) is a vital component of biomanufacturing, both within and among the companies involved (6). A surprising number of organizations have yet to progress beyond the use of paper and CDs to exchange final executed documents. More effective collaboration is possible, but for many it remains a goal rather than a reality. Often, uncertainties over regulatory requirements can get in the way. Both US and European regulatory authorities have strict mandates on managing electronic systems and records. But interconnected IT systems can help partners and colleagues respond to opportunities and challenges as they arise.

Scale-Up and Technology Transfer: Whether operations are outsourced or not, risk-based technology transfer strategies are fundamental to biopharmaceutical manufacturing. Not only are they part of outsourcing, but they also enable scaling up processes in-house. As a product must be manufactured in larger quantities — from milligrams needed for preclinical testing and produced by laboratory bench-scale equipment through grams made for pilot-scale early clinical trials to kilograms for commercial sale — the systems used to manufacture it must be demonstrated to function equivalently. That is, they must make the same product.

No matter what technology is transferred — and no matter its origin or destination — the project begins with a process-flow diagram (7). Raw materials and consumables must be ordered from reputable suppliers, with testing factored into their schedules. Process and analytical methods are transferred along with standard operating procedures (SOPs), and personnel must be trained on them. Results must be reproducible, with appropriate accuracy and precision. Defining and meeting acceptance criteria take time. New equipment may need to be purchased, or existing units adapted, with some perhaps physically transferred to the new site. Scientific know-how is important, as are face-to-face meetings and discussions. Early and late-stage transfers differ. At earlier stages, bioprocesses and analytical methods are not yet fully defined and specifications may not be worked out, so acceptance criteria might be less precise. Later-stage transfers usually include process and analytical definitions, but for GMP manufacturing regulatory compliance becomes essential. Finally, a technology transfer report, comparability test report, and batch-release records will document the success of a transfer.

Quality By Design

Risk management is at the heart of the 21st-century regulatory approach to the drug industry (9–13). It is the main means by which companies can achieve quality by design (QbD). No longer is biologic quality determined merely by lot-release testing after each batch is manufactured. Instead, regulatory authorities in Europe, North America, and parts of Asia want biopharmaceutical companies to characterize and understand their bioprocesses well enough to control them, thus ensuring robust and reproducible results. For biologics, products will always be inextricably tied to their processes; modern process knowledge makes it possible to predict and manage a product quality based on a well-characterized process (9, 10).

Many strategic “tools” are available to help companies use the ever-wider array of analytical test results available for characterizing both products and bioprocesses to achieve the QbD goal. These include failure modes and effects analysis (FMEA); fishbone, cause-and-effect, or Ishikawa diagramming; contradiction matrices; and the “five-whys” approach. No matter what method is chosen, what’s most important is that project managers take a rational approach to identifying, prioritizing, and managing risks (11). That includes an intimate understanding of process variation and its sources (12): raw materials, equipment, and consumables; operational inputs; environmental factors; and the inevitable variations inherent to biological systems.

Process validation is also essential to quality by design (as well as to scale-up and technology transfer). In early 2011, the US FDA introduced a guidance document describing a new approach to this concept, which was reinforced about a year later by a draft guidance in the European Union (14). Both drew heavily on harmonized tripartite guidelines on quality from the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Old concepts like “three to five lots run at the center point of proposed ranges for operating parameters” and old systems like installation, operational, performance, and design qualification of equipment (“4 Qs”) have been deemphasized:

New approaches leverage product design and process development information. They facilitate adapting the QbD paradigm to allow for a science- and risk-based selection of critical process parameters, key process indicators, and appropriate specification criteria. The number of runs for process performance qualification must be determined using a risk-based understanding and control of process variability. (14)

This new risk-management approach helps companies make the best use of their reams of data to strengthen their process understanding. Process performance is qualified, then continued process verification goes on indefinitely. This ensures a sufficient control strategy and demonstrates that the manufacturing process remains in a state of control. Process verification    ultimately should be reduced to a standard, continuous process monitoring system for ensuring process robustness and stability.

Supply Chain Management

With the costs of doing business rising, and with the trend toward more outsourcing and licensing, supply chain management has become more important than ever before. Flexible manufacturing plants that make consistent high-quality products on demand can alleviate the need for huge capital investments in new facilities. Operational inefficiencies can limit capacity use and cost money that otherwise might be put to better use.

There are two sides to the supply chain: raw materials on one side and finished products on the other. You might even consider in-house and outsourced transfer of technologies and materials to be a third aspect. Here, too, risk assessment is key (15).

Contingency planning isn’t only about natural disasters and the potential for political unrest; sometimes it’s about something as simple as the interface between shipping schedules and the weather. It’s important to be realistic. No amount of planning will protect a company’s reputation if something goes wrong. But when a problem does arise, a speedy and efficient solution can save the day.

Ancillary business operations such as logistics and supply chain management are often relegated far down on the priority list that begins with producing safe and effective therapeutics. But optimizing a clinical-trial supply chain can provide a strategic advantage and accelerate drug development in a business for which time really is money (16, 17).

Strong supply chain management also ensures continued operation with uncompromised product quality if changes in raw materials and/or vendors have to occur (18). Companies should have investigational procedures in place for evaluating the possible effects of a raw-material change on a process or product (19).

New Product Types, New Business Models

As next-generation biologics such as cell/tissue therapies, ADCs, gene therapies, and even biosimilars step out of the realm of the theoretical into the reality of the market, companies involved in their development have to face regulatory hurdles to their production, clinical testing, and ultimate commercialization (20–29). Each type of product presents its own challenges. For example, biosimilars must prove themselves to be adequate replacements for innovator drugs already on the market. ADCs combine the concerns of highly potent small-molecule active pharmaceutical ingredients (APIs) with the sensitivities of biomolecules for a double-whammy of difficulty. And cell therapies face technological hurdles in scaling up/out as well as reimbursement issues that have already sent one early adopter into bankruptcy. The latter trouble complicates matters for biotech vaccines as well.

Many of those problems will require whole new ways of looking at bioprocessing, product development, and biotech business to solve. Innovation will be necessary across the board. And many of the companies who are working to solve them can be found at BIO 2015.

References

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2 Langer ES. Sponsors Look to Asia for Potential Contract Partners: China Tops the List of Destinations. BioProcess Int. 11(1) 2013: 18–23.

3 Langer ES. Manufacturers Open Their Wallets for Outsourcing: Accessing Technical Expertise and Cutting Costs. BioProcess Int. 12(6) 2014: S12–S17.

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5 Calcott PH. Managing Contract Relationships with Quality Agreements: Keeping in Mind the New FDA Guidance. BioProcess Int. 12(6) 2014: S4–S10, S17.

6 Quilligan A. Managing Collaboration Across the Extended Organization. BioProcess Int. 12(6) 2014: S18–S23.

7 Dennett R. Modern Technology Transfer Strategies for Biopharmaceutical Companies. BioProcess Int. 13(3) 2015: 10–17.

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9 Little TA. Essentials in Quality By Design. BioProcess Int. 12(3) 2014: 18–24.

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14 Mire-Sluis A, et al. New Paradigms for Process Validation: A Practical Approach. BioProcess Int. 11(9) 2013: 28–39.

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19 Bowman D. A Quick Guide for Sourcing Biopharmaceutical Raw Materials. BioProcess Int. 13(3) 2015: 51–52.

20 Rader RA. An Analysis of the US Biosimilars Development Pipeline and Likely Market Evolution. BioProcess Int. 11(6) 2013: S16–S23.

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22 Moore WA, Bermel J. Cell Therapy Manufacturing: Addressing Regulatory and CGMP Challenges for Late-Stage Products. BioProcess Int. 12(3) 2014: S22–S25.

23 Ruffin M. Advocating for Advanced Therapies: Another Significant Year Ahead for the Regenerative Medicine Sector. BioProcess Int. 12(3) 2014: S12–S13.

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25 Pritchett T, Little L. “Hard Cell”: Potency Testing for Cellular Therapy Products. BioProcess Int. 10(3) 2012: S36–S48.

26 Brindley DA, Bure K. Automation of Cell Therapy Biomanufacturing. BioProcess Int. 11(3) 2013: S18–S25.

27 Gottschalk U. Antibody Drug Conjugates: The State of the Art. BioProcess Int. 12(9) 2014: S4–S5.

28 Wooge C. Process Challenges of Antibody–Drug Conjugates. BioProcess Int. 12(6) 2014: S28–S31.

29 Rader RA. Bioprocessing Challenges of Antibody–Drug Conjugates. BioProcess Int. 12(9) 2014: S6–S9. c

Cheryl Scott is cofounder and senior technical editor, and Maribel Rios is managing editor of BioProcess International.