Parenterals, Particulates, and Quality by Design

Particulate matter in parenteral drugs has been recognized as a risk to patients for nearly two centuries. Contaminants can come from the environment, packaging materials, formulation ingredients, interactions between the formulation and the product packaging, or be generated during processing (1). Therefore, with an in-depth understanding of the raw material, product, packaging properties, and manufacturing processes, it should be possible to establish systems to reduce particulate matter contamination of parenteral formulations. An apparent increase in the number of recalls due to particulate contamination has drawn the attention of the industry and led to a greater focus on improving quality systems across the supply chain. One aspect of those efforts is the implementation of quality by design (QbD) to ensure consistent and robust quality.

Consequences of particulate matter
In a 2013 article, Stephen E. Langille, a senior microbiology reviewer in the Office of Pharmaceutical Science at FDA’s Center for Drug Evaluation and Research (CDER), estimated that approximately 190 million liters of intravenous fluids are administered to patients each year in the United States (1). Several different clinical effects ranging from minor problems to serious complications and death have occurred as a result of the injection of particulate matter (1). Therefore, particulate matter contamination is a real concern for the pharmaceutical industry.

The consequences depend significantly on the size, shape, quantity, and composition of the particulate matter, as well as the method of administration and level of risk presented by the patient (1). Large, hard non-spherical particles can block blood flow and cause emboli, while large, softer, spherical particles may collect in organs and cause damage over time. Premature infants and patients suffering from severe tissue damage may be at greater risk from harm due to particulate matter contamination; similarly, vascular injection appears to present higher risk. In addition, critically ill patients tend to receive large quantities of parenteral therapies and, often, larger doses of particulate matter (1).

Recent recalls
Particulate contaminants are generally classified as extrinsic, intrinsic, or inherent, according to Tony Perry, director of regional quality for pharmaceutical packaging with SCHOTT North America. Extrinsic particulates originate from outside the process and include, for example, garment fibers and plastic particles. Intrinsic particulates are generated from within the glass vial such as glass flakes that delaminate from the vial wall. Inherent particulates are derived from the formulation itself, such as when a portion of it aggregates or crystallizes.

There have been recent recalls attributed to all three types of particulates. In August 2014, Baxter voluntarily recalled in the US two lots of Dianeal Low Calcium Peritoneal Dialysis Solution due to the presence of oxidized stainless steel, garment fiber, and polyvinyl chloride particulate matter identified during the manufacturing process (2). Cephalon’s January 2012 voluntary recall of Treanda (bendamustine HCL) for Injection was based on the identification of glass fragments in a single vial (3). In December 2012, Hospira issued a voluntary recall in the US of three lots of carboplatin injection due to presence of visible particulates identified as Carboplatin crystals (4).

In fact, particulate contamination in parenteral drugs packaged in glass vials has created significant drug shortages recently, according to Perry. He notes that according to the FDA Office of Manufacturing and Product Quality, from 2008-2012 the presence of visible particles accounted for 22% of all drug recalls (5).

Many contributing factors
Various industry players point to many different reasons for the increase in recalls due to particulates. “Today, quality has never been higher, but the manufacturing process is more versatile and complex than ever before,” states Wolfgang Weikmann, senior vice-president of quality for Vetter Pharma-Fertigung. “As a result, there are numerous individual process steps and a multitude of single components (e.g., the glass barrel, stoppers, caps) that serve as potential sources for particulate contamination during production,” says Weikmann. The growing use of prefilled syringes is another contributor to the increased incidence of problems with visible particulate matter, according to an industry expert. The expert adds that the continuing predominance of protein therapeutic agents has also resulted in more numerous mechanisms by which particulates can develop, because proteins are known to interact with components of the primary packaging system under certain conditions.

As demand from customers and regulatory authorities for ever-higher quality continues to grow, there is also a greater awareness of the possibility of particulate contamination, according to Weikmann. “There is definitely a heightened sensitivity in the industry to particulates given the greater understanding of their potential safety implications, and that led to a greater number of reports,” says Fran L. DeGrazio, vice-president of global R&D, strategic program management, and technical customer support for West Pharmaceutical Services. In particular, according to an industry expert, there is a growing awareness of the importance of subvisible particles with diameters in the range from 2-10 microns, which are currently below the “radar” of compendial testing.  “The number of particles in that range is enormous compared to the number of particles with diameters above 10 microns, and these colloidal particles can aggregate over time, producing visible particles,” the expert explains.

Industry understanding of the physical and chemical mechanisms of particulate formation is also improving. For instance, shear denaturation can produce visible particles, according to an industry expert. “There are instances where the type of filling pump (piston vs. peristaltic) makes an observable difference in the development of particulate matter in a drug product,” the expert says.

Investigations of glass delamination mechanisms are also providing insights that are leading to new glass manufacturing methods. Glass delamination is normally the result of chemical reactions between the drug and the interior surface of the glass container. “The occurrence of these reactions is the result of a complex interplay of different variables, such as the type of glass container, glass type (composition), pH range, drug type, and/or drug formulation (chemistry of the formulation). Importantly, a change in a single variable can make the difference between success and failure,” observes Dan Haines, scientific advisor, Pharma Services with SCHOTT North America. Additional risk factors have the potential to influence the possibility of delamination, including the storage time and temperature, the container manufacturing conditions, and the sterilization process.

Taking action
The industry as a whole has tried to bring more visability to the particulates issue, according to DeGrazio. “Parenteral manufacturers have taken a number of actions to address the issue, including optimization of comprehensive quality management systems starting with supplier audits through to final visual inspections, as well as implementing permanent process monitoring approaches that are designed to detect potential hazards,” Weikmann says.

One biopharmaceutical company, for example, is focusing on understanding shear effects on particulate formation, particularly from filling pumps, through measurement of changes in conformation that could eventually lead to aggregation, and thus particulate formation, according to an industry expert. His company is also using instruments such as the FlowCAM (Fluid Imaging Technologies) and Micro–flow Imaging (ProteinSimple) to investigate subvisible particles.

Other activities at biopharmaceutical companies include making adjustments to fill and finish processes and the development of new material and system innovations, such as polymers and special biotech delivery systems, to reduce possible particulate contamination. Glass manufacturers are also responding by adjusting manufacturing processes and developing alternate methods that minimize the types of issues that have been seen in the marketplace, according to DeGrazio.

Importantly, there is greater sharing of knowledge between all of the involved parties. “Closer cooperation with suppliers, logistic partners, and technical engineering supports the implementation of corrective and preventive actions along the supply chain,” notes Weikmann. Collaborations with critical external partners, such as container producers that have shifted the focus to quality instead of treating glass vials as a commodity, are helping drug companies understand products and processes and improve overall quality, according to Perry. “By incorporating supplier expertise up front and engaging in information exchange from the beginning to the end of the drug development process, manufacturers can ensure that the material is used in the correct way,” he says.  Perry also notes that new guidance covering inspections is also providing manufacturers with further support to ensure quality.

Benefits of a QbD approach
Another approach that many companies are taking to improve quality, reduce the risk of particulate contamination, and avoid recalls involves the implementation of programs such as Six Sigma, risk management, right first time, and QbD, according to Perry. “The focus is now on minimizing the risk and doing it right the first time. These tools ensure that processes are well managed by understanding the key process parameters and risks associated with those parameters,” he explains.

“The very heart of the QbD concept is that quality is built into a product based on an in-depth understanding of the compound and the process by which it is developed and manufactured. Critical steps in the fill and finish process of parenteral manufacturing that affect quality are identified and their influence evaluated. Matching the appropriate processes to the actual needs of the product may help to identify potential risks in the process including possible sources for particulate contamination,” says Weikmann. For a CDMO like Vetter, he adds that the QbD approach is an important concept, primarily because of the many advantages it offers to industry stakeholders. “This approach enables consistent and robust production of high quality products and, therefore, the reduction of batch failures and stock-outs. It also offers the potential for greater confidence in drug quality and may reduce the need for intensive oversight by regulatory authorities,” Weikmann asserts.

For glass manufacturers, a QbD approach ensures a good understanding of which material and process inputs have an impact on glass particulates, as well as the ways in which the process and material interactions could lead to certain glass characteristics that predispose the glass to particulate formation, according to DeGrazio.

The implementation and success of QbD is also a way to help build long-lasting relationships with customers and key partners, according to Perry. “By taking a global view of our processes and products, we have been able to shift our focus from price-based discussions to total cost of ownership and quality. With QbD, we have adopted more of a risk-based approach to production and in the end have been able to look further down the value chain to make sure we are doing what is right for patients,” he comments.

A variety of challenges
These numerous benefits of QbD aren’t realized without significant effort, however. QbD is essentially a holistic, proactive, science-and-risk-based approach to the development and manufacturing of drugs, and proper implementation presents a variety of challenges for the manufacturer. According to an industry expert, the biggest issue is the lack of a clear translation from the broad principles of QbD to specific implementation actions. “It is definitely necessary to have the right level of technical ability within the organization to understand and implement QbD effectively,” Perry states. In addition, the organizational mindset must be aligned and willing to take on such programs and to live by the relevant principles and disciplines. “QbD cannot be seen as the next fad and is most successful when driven from the top of the organization,” adds Perry.

Time and cost are also issues. “Incorporating QbD into a process takes more time, and due to the need for improved understanding and greater testing, costs more money,” DeGrazio says. She goes on to say, however, that in the long run, use of a QbD approach should reduce many of the downstream issues that can occur, and for those that do occur, allow for better knowledge as to why. As a result, QbD should ultimately help the industry reduce costs.

Additional challenges can also include finding the right business partners that share the same quality understanding and meeting increasing regulatory requirements, such as the FDA’s process validation guidance, according to Weikmann.

References

1. S.E. Langille, PDA J. Pharm. Sci. and Tech. 67 (3) 186-200 (2013).

1. Baxter, “Baxter Voluntarily Initiates U.S. Recall of Two Lots of Peritoneal Dialysis Solution Due to Presence of Particulate Matter,” Press Release, Aug. 13, 2014.
2. Cephalon, “Cephalon, Inc. issues a voluntary nationwide recall of Treanda (bendamustine HCL) for Injection 25mg/Vial Due to Particulate Matter,” Press Release, Jan. 27, 2012.
3. Hospira, “Hospira Issues Voluntary Nationwide Recall of Three Lots of Carboplatin Injection Due to Visible Particulate Matter,” Press Release, Dec.14, 2012, accessed Oct. 7, 2014.
4. John G. Shabushnig, Insight Pharma Consulting, LLC, “Detection and Control of Visible Particles in Injectable Products,” accessed Sep. 30, 2014.