State of the Union: Overview

Pharmaceutical manufacturing capacity is increasingly global and going biologic, but challenged to meet the realities of cGMP

By Steven Kuehn, Editor-in-Chief

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MORE DEMAND, BETTER PRODUCTION
Biologics manufacturers are also benefiting and reacting to expanding market opportunity. Biologics are expected to account for about 17 percent of total global spending on medicines by 2016, says IMS: “Seven of the top 10 global medicines by spending will be a biologic within five years.” The biopharma industry’s continued focus on process efficiency is being fueled by advances in biosimilars, smaller volume drugs, shorter drug lifecycles (faster trials, development cycles), and high-volume product manufacturing issues.

To evaluate the trends that are shaping the bioprocessing segment today, BioPlan Associates recently surveyed 450 global subject matter experts and senior participants on its Biotechnology Industry Council panel of bioprocessing professionals and asked them to identify the most critical factors and trends they expect will need to be addressed over the coming year. While “process efficiency” was a unifying thread, three clear sub-topics emerged: downstream processing; analytical methods development; and single-use system integration. This year, the industry will see an increase in multi-product
facilities, selective single-use adoption (both in clinical and commercial stage), a ramping up of continuous processing, and more advanced automation and monitoring. With downstream processing continuing to lag improvements in upstream, the industry will continue to look for better performing chromatography resins and consider alternatives to protein A.

Pharmaceutical manufacturers are responding to competition and change by decreasing manufacturing costs, primarily by increasing outsourcing to contract manufacturing organizations, onshore and off. Although they have closed many manufacturing plants, pharmaceutical manufacturers are building new capacity throughout the world, particularly biopharm plants, in high growth regions, using modular technology and disposable process equipment to reduce cost and risk.

In February, the FDA released “Guidance Agenda: New & Revised Draft Guidances CDER is planning to Publish during Calendar Year 2014.” Under the category, “Quality: Facility, Production and Process Control” FDA listed their agenda, which includes intended guidance on CMO Quality Agreements, GXP considerations for outsourced IT (cloud computing), and most notably for manufacturers “Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice.”

Since its inception 14 years ago, cGMP implementation has been executed by Pharma manufacturers with varying degrees of success. International regulators, especially the FDA, are pressing this agenda and remain committed to it, increasing their budgets and seeking revenues to help the entire global industry move toward its goals of drug quality and safety through manufacturing and process excellence.In her February 14 Blog, FDA director Margaret Hamburg noted after her visit to India, “In my talks with regulators and companies here in India, I have placed a great deal of emphasis on why quality matters. As I explained, quality is linked to product safety, and without a direct focus on quality, the potential for patient harm increases significantly. In recent years the FDA has identified significant lapses in quality by some companies operating in the U.S. and around the world. As a result, American consumers have had to endure greater risk of illnesses, recalls and warnings about the products many of them rely on each day. This is unacceptable. Consumers should be confident that the products they are using are safe and high quality, and when companies sacrifice quality — putting consumers at risk — they must be held accountable.”

In his recent blog post on pharmaevolution.com, Girish Malhotra, PE, president, EPCOT International, notes that despite ongoing product-quality issues, drug companies remain profitable. Malhotra explains that since profits are still being achieved with the current inefficient practices, leadership will remain resistant to improving its product development, business and manufacturing practices.

Malhotra predicts that over the next 5 to 15 years, that instead of becoming “process-centric,” as regulators hope, Pharma will stay “regulation-centric,” and “hedge in adopting many of the internal changes (manufacturing methods, technology and supply-chain improvements) that could improve profitability and move from the current quality by analysis/aggravation to a quality by design approach (QbD).”

Noting that this is due to regulatory constraints, Malhotra explains short patent lives for the ethical (brand) drugs are likely to impede innovation in manufacturing technologies. “Process-centricity, if adopted,” says Malhotra, “would allow companies to exceed regulatory requirements, which could also avoid many issues that have created public relations and financial headaches. Current regulatory guidelines and requirements discourage change. Since changing an existing process requires approval, it is still perceived to be a long and expensive step, and something to be avoided.”

Malhotra offers that because, in his view, not much is forthcoming from the industry to improve its manufacturing and business practices; regulatory bodies will pursue regulatory agendas that will force the industry to adopt better practices. “This tug of war will continue unless the industry takes the lead,” he says.

Although Malhotra is pointing a well-earned finger at generics manufacturers (one look at recent headlines concerning quality issues coming from India’s generics industry supports his assertion) not every generics producer is bereft when it comes to pursuing a regulatory approved quality agenda. Uri Hillel, head of R&D Quality and Corporate Quality & Compliance for Teva Pharmaceuticals, explained in an exchange with Pharmaceutical Manufacturing that Teva has worked on implementing guidelines defining Quality by Design (QbD) guidance and has adopted the QbD philosophy in its development of generic products. “For Teva, this means understanding the products, formulations and processes in depth, and submitting appropriate applications to the authorities using a more systematic development approach.”

Achieving appropriate quality outcomes is the generally understood goal of prevailing regulatory guidance, and those companies that adopt both QbD and (ICH Q10) Pharmaceutical Quality Systems will achieve the “desired state” of pharma manufacturing. And Hallel agrees: “By implementing QbD (ICH Q8, 9) together with ICH Q10 (which is an integrated part of QbD implementation), we can reach the ultimate goal: providing uninterrupted supply of affordable, high-quality medicines to our patient. This is the desired state for the customer and for the industry, while enhanced product and process understanding will facilitate substantial efficient tech transfers, higher rates of successful validation and timely introduction of new medicines to the patients.”

The manufacturing of pharmaceutical tablets is moving from its traditional batch process to continuous processing. While chemical and other industries have successfully implemented continuous manufacturing for many years, the drug industry has been slow to change due to the impact of FDA regulation.

Emerson’s Jim Lustri explains that for pharmaceutical the financial driver for the move to continuous manufacturing is a significant reduction in capital and operating costs. A batch process typically will have capacity utilization of 35%. This is caused by a significant amount of equipment usage lost to preparation, cleaning and scheduling.

“On the other hand,” says Lustri, “a continuous process can have a capacity utilization of over 80%.” Emerson says this means a continuous process can make the same amount of production in much smaller equipment. Additionally, continuous processes require less human activity to transport materials between units, so there is a savings in manpower as well.

TOWARDS A BETTER STATE
As demand for safe effective, high quality drugs at lower prices continues unabated, drug manufacturers and their financiers will respond because these are the market conditions in which the industry exists. Some companies will thrive and be profitable because they are adept at implementing change and instituting processes and procedures to improve the cost effectiveness and efficiency of their manufacturing operations. Others won’t be as successful and they are
already being shaken out of the Pharma universe. Regulators and politicians are adding their own pressures, but ultimately, pharmaceutical manufacturing will achieve a better state because so much is riding on the fact that they do.

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  • Steve:

    I have been a proponent of continuous msnufacturing for API and their formulations for a long time. We need to understand that API and their formulations are two different things. Technologies for continuous formulations have been existent for the last sixty plus years but Pharma has not made any move. In API for continuous manufacturing will not happen in existing model unless drastic changes are made. It could be possible but then the existing model will have to revised.

    Would Pharma companies get there? I doubt it.

    Reply

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