Large Molecule / Supply Chain / Packaging

On the Cusp of Change

Parenteral drug manufacturers are sharpening capabilities and coming into their own

By Karen Langhauser, Chief Content Director

The changing pharmaceutical landscape is a popular discussion point as of late. Armed with a fresh, non-blockbuster-reliant business model and treatment options that are expanding from small molecules to a range of new, more targeted therapies, the industry is at what PwC calls, “a critical juncture.”

Parenteral drug delivery is the second largest segment of this transformative pharmaceutical market — eclipsed only by the more mature oral solid dosage forms — accounting for nearly 30 percent of total pharma market share. According to Freedonia Group research, the market for parenteral drug delivery products is projected to rise over 10 percent annually to $86.5 billion in 2019.

Parenteral drugs — which enter the body via injection or infusion, rather than through the gastrointestinal tract — are taking a strong position alongside the more established oral solid dose forms and are quickly coming into their own.

As biologic drug approvals rise, the parenteral drug pipeline has followed suit by shifting from small molecules to complex biologics. A significant percentage of new drugs in the product pipeline are biologics. Of the Novel Drug Approvals for 2015, 32 were small molecules and 12 were biologics. All 12 approved biologics are delivered parenterally, as well as seven of the 32 new small molecules. Including Astella’s Cresemba (approved in both parenteral and capsule form), the 2015 parenteral drug approval total is 20.

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CURRENT CHALLENGES
No matter what the dosage form, pharmaceutical manufacturers are up against the same challenges: pressures to increase speed and reduce costs, expand product pipelines and meet more stringent regulatory requirements.

According to Hal Baseman, CEO, Valsource LLC and Immediate past Chair of the PDA (Parenteral Drug Association), several specific challenges are at the forefront of parenteral drug discussions, so much so that task forces and initiatives by trade organizations, such as PDA, have been formed to address these topics and help identify areas in which manufacturers can improve. Examples include:

Aging facilities: Aging facilities with ineffective process control systems may be a signifcant contributor to the drug shortage problem. Owners of aging facilities are often choosing between continuing to use old, perhaps outdated technologies previously validated, or modernizing the facility with new, more effective technology closer to the industry standard.

Offshore manufacturing: The need to reduce costs has increased the number of pharmaceuticals and APIs manufactured and sourced from abroad, especially from India and China. While more mature markets have spent decades defining quality culture, companies in emerging markets may lack the experience level necessary for effective contamination control, especially when it comes to the complexity of sterile injectables.

Harmonization of global requirements/regulations: While the FDA used to be what Baseman calls the “gold standard” for regulatory guidance, advancements made in Europe and Asia have created multiple levels of regulatory expectations. Differing requirements often create redundant efforts and drug approval challenges.

“Oftentimes it does not appear that regulatory expectations from different countries are aligned. But this is often a misconception stemming from differing terminology and nuances,” explains Baseman. “But on a positive note, there is an increase in awareness and discussion between regulators, and they are working to better harmonize expectations.”

Quality management: The number of industry drug shortages that have impacted parenteral medications is significant. Many of these drug shortages, according to Martin VanTrieste, senior vice president, Quality at Amgen Inc., could be avoided by developing a robust quality system, designing in product quality and establishing a culture of quality.

“I believe that there are three essential elements for product quality in parenteral medications. First, a modern quality system that is robust, simple and sustainable that provides knowledge to individuals and the organization. Second, strong support from R&D to develop and characterize robust raw materials, manufacturing processes and products using a Quality by Design approach. Third, a culture of quality that instills flawless execution and continuous improvement at all levels of the organization. By having developed these three elements, an organization can achieve quality beyond compliance,” says VanTrieste.


PICKING UP THE PACE

While the injectable drug sector faces some of the same practical difficulties in adopting change that inhibit conventional pharma, change is on the horizon. According to Baseman, “The industry has faced challenges bringing new technologies into practice. However, those in the industry are starting to realize how the use of new technology can truly reduce risk.” There are several areas in particular where parenterals are seeing improvement:

Isolators/barrier systems: The need for process improvement has led to the introduction of encouraging innovations and ideas, including the use of advanced aseptic filling/packaging systems such as barrier systems and isolators. These technologies are designed to reduce the impact of personnel and the environment on product quality.

“More and more the industry is adopting these technologies to reduce risk. We are seeing better designs that lead to better assurance of sterility and productivity,” says Baseman.

Real-time detection: For years there has been a gradual increase in the use of rapid microbiological methods within the injectable drug industry, but still there has not been the mass migration to rapid micro. As regulators continue to push for real-time quality assurance, the industry is slowly modernizing its means of environmental monitoring and in-process product testing.

“Most companies are still using traditional methods for monitoring the environment for microbial growth and these can take days to produce results,” notes Baseman.

But as the industry builds a business case, establishing a tangible ROI for rapid microbiology, forward-thinking companies are opting for faster results, with increased accuracy and consistency.

Advanced analytics: McKinsey & Co. explains advanced analytics as the application of elaborate statistics and mathematical tools to business data in order to assess and improve business practices. While success in pharma has historically depended heavily on research and product innovation, manufacturers are starting to realize that in order to achieve true operational excellence, they must further develop capabilities in advanced analytics.

“With the advancement in computing power, the use of advanced analytics has enabled continuous improvement to happen at a much faster rate and higher quality levels,” says VanTrieste.

Amgen has used advanced analytics to work with raw materials suppliers to identify, track and control variability, which has reduced the variability of Amgen’s manufacturing process. Amgen works with its suppliers to collect the supplier’s raw material manufacturing process and performance data. Then Amgen combines the supplier’s raw material data with Amgen’s manufacturing and performance data. Using multivariate statistical process control, it can turn years’ worth of data into knowledge for both Amgen and the supplier.

This knowledge can then be used to prevent batches from failing specifications and subsequently being rejected, to improve Amgen’s manufacturing process capabilities and even to improve yields.

PACKAGING CONSIDERATIONS 
Recent trends toward complex proteins — mainly offered in liquid form and administered parenterally — has increased the demand for flexible, safe and economical production possibilities.

Jeffrey Reid, Global Market Manager for WHEATON Industries, recently spoke at Interphex 2016 about key considerations for packaging parenteral products. In his presentation, Reid outlined the essential processes that a primary packaging component must undergo when utilized for parenterals.

To review, the process starts off with the pre-sterilization process known as particulate cleaning. The process consists of four major steps: 1. Sterile air blowing; 2. Three USP purified water rinses; 3. One final rinse with water for injection; and 4. Final sterile air blowing (test limits are outlined in USP 788).

This is followed by depyrogenation, meant to reduce the amount of bacterial endotoxins that can be found in a packaging component (test methods outlined in USP 85). Lastly is a sterilization process. There are three main methods for sterilization including high temperature and pressure sterilization, chemical sterilization or radiation sterilization (test methods outlined in USP 71) and, according the Reid, “the method of choice is strictly dependent on the chemical characteristics that make up the packaging component.”

Packaging components need to meet or exceed these three standards in order to be utilized for injectables. Smart suppliers such as WHEATON and Bosch (see: Meeting New Biopharma Filling Challenges in this issue) are stepping in and providing assistance to manufacturers in the form of pre-sterilized containers. Since the preparatory steps for pre-sterilized containers have already been carried out by the supplier, the drugmaker then does not have to purchase or operate machines for sterilization and depyrogenation.

PRIVILEGE & RESPONSIBILITIES
“Producing medications is a complex and difficult endeavor, and it is critical to get it right for patients. Serving patients is a privilege and this privilege comes with significant responsibilities,” emphasizes VanTrieste.

Delivering quality medications in a robust and reliable supply chain is a huge responsibility. The standards for drugs directly injected into patients must be nothing short of uncompromising.

As parenteral manufacturers gain proficiency, they are utilizing new technologies and practices to better assess quality. “Manufacturers are using risk and science to make better informed decisions, and this is quite encouraging for the future,” concludes Baseman.