Addressing Parenteral Manufacturing Challenges

Pharmaceutical Technology spoke with Miriam Beyer, European marketing manager, West Pharmaceutical Services, Inc, Germany about the company’s parenteral business.

PharmTech: The past few years have seen manufacturing issues as well as severe shortages of both small- and large-volume parenterals, including basic electrolytes and glucose. What are the reasons behind these problems? 
Beyer: The US Food and Drug Administration has recognized that drug shortages are a critical issue for the healthcare industry. Approximately 37% of shortages are due to manufacturing issues. Other major factors causing drug shortages are issues associated with raw materials (27%) as well as delays and capacity difficulties (27%). Drug shortages can result in problems ranging from the wrong expiration date on the package to particulates in the drug product or sterility issues with injectable drugs (see Table I). 

 Drug Type

 2011

 2012

 2013

2014

 All Forms

 251

 117

 44

 44

 Injectables

 183

 84

 35

 30

PharmTech: What are some best practices for maintaining sterility and avoiding non-compliance for each type of parenteral? 

Beyer: Maintaining sterility is vital to avoiding the main causes of drug shortages. Primary packaging plays a pivotal role in ensuring sterility, since it is in direct contact with the drug and poses risk of interaction if the packaging is not compatible with the drug product.

Manufacturing quality can be affected by several issues, including bacterial endotoxin, particulate matter, and bioburden. One example of the impact is well reflected in an FDA guidance recommending ‘the time between washing, drying (where appropriate), and sterilizing should be minimized because residual moisture on the stoppers can support microbial growth and the generation of endotoxins’ (1). This can cause a challenge if primary packaging components are not available already sterilized. 

Achieving lowest visible and subvisible particulate levels is currently a hot topic. While associated with cleanliness, it is a key factor today to meet product target profiles and ensure compliance.

Close collaboration between a pharmaceutical manufacturer and its drug packaging partner is key to ensuring that high quality standards are maintained throughout the manufacturing process. In terms of packaging, it is important that both parties agree upon the validation processes that will be used during manufacturing in order to establish--and adhere to--quality specifications for primary packaging components.

Validation processes can have significant benefits for drug manufacturing. For instance, a state-of-the-art validated washing process must reduce endotoxin content by at least 99.9% (a 3-log reduction).

Sterilization processes are generally also validated to meet sterility assurance levels. Furthermore, a sterilization process validation is maintained through appropriate change control and revalidation/periodic review programs, all of which comply with applicable cGMP requirements.

There are, however, additional variables that play a role in meeting best practices. Product configuration and formulation, for instance, may have an impact on quality, as do bioburden resistance and weight, along with bag material. It is also important to note that the packaging of the actual components in question should also be evaluated to determine whether a component/packaging format meets the necessary regulatory specifications.

PharmTech: What role can packaging play in preventing these problems?

Beyer: Packaging plays a significant role in maintaining the quality of a drug product and preventing impurities. To minimize interaction with the drug, it is essential that the packaging components’ design and formulation meet the containment requirements mandated by the physical and chemical attributes of the drug. Different drug products have different packaging needs, and what works for one product might not necessarily be the best choice for another. Selecting the right closure for a particular drug product is crucial to ensuring that the drug reaches the patient safely and with the intended therapeutic effect.

To ensure the perfect match between a drug and its packaging, it is important for pharmaceutical manufacturers to work closely with experienced packaging partners from the early stages of drug development through production. Having a reliable packaging partner allows pharmaceutical companies to focus on their core competencies: bringing valuable drug products to the marketplace. 

PharmTech: Can you please describe your company’s technology, its history, how it was developed, and how it is being applied?

Beyer: West was founded in 1923. Its early efforts pioneered the safe distribution of penicillin, insulin, and other life-saving drugs. Today, approximately 110 million West components and devices are used around the world every day. 

West has a long-standing partnership with Japan’s Daikyo Seiko, a manufacturer of high-quality pharmaceutical delivery system components. Daikyo has built a strong reputation for materials and manufacturing innovation. Our partnership with Daikyo has enabled us to develop products that help customers mitigate drug product development risks and enhance patient safety. These products include: FluroTec coated serum and lyophilization stoppers, syringe plungers, and tip caps, Daikyo Crystal Zenith vials and syringe barrels, and ready-to-sterilize (RSV) components. 

We recently launched Daikyo ready-to-use/validated (RUV) components. We believe these components meet the highest sterilization and quality standards, helping pharmaceutical manufacturers comply with rigorous aseptic processing requirements while reducing operational and capital resources.

PharmTech: Can you please elaborate on any innovative science/methods used and results achieved so far?

Beyer: Daikyo RSV and RUV components are manufactured using clean, high-quality elastomer formulations, and then washed and sterilized as needed to help reduce the manufacturing footprint, streamline processes, outsource risks around component preparation, and eliminate bioburden.

Both Daikyo RSV and RUV components are prepared to a tight particulate specification and fully visually-inspected. The new Daikyo RUV offering, which takes RSV components and steam-sterilizes them in a validated process, offers pharmaceutical manufacturers the opportunity to focus on the fill-finish with a high-quality, ready-to-use component.

Reference
1. FDA, Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing: Current Good Manufacturing Practice (Rockville, MD, September 2004).

Article DetailsPharmaceutical Technology
Vol. 39, No. 11
Page1: 21

Citation: 
When referring to this article, please cite it as A. Shanley, “Addressing Parenteral Manufacturing Challenges,” Pharmaceutical Technology 39 (11) 2015.