Stopper Preparation for Isolated Filling Units

When installing an isolator line in a pharmaceutical manufacturing facility, the presentation of stoppers must be considered.

A water-for-injection processing system is an essential part of stopper preparation (photo courtesy West Pharmaceutical Services).

Robert Nase, West Pharmaceutical Services; and Douglas Stockdale, Stockdale Associates Inc.

Pharmaceutical manufacturers must consider a number of factors when adding an isolated filling unit to an existing or new manufacturing facility. A full analysis of existing facilities and processes, as well as the effect new equipment may have on capital expense and schedule delays, must be taken into account.

Among the factors for consideration are the resources required to prepare and introduce stoppers into the isolator’s filling and finishing operation. Stopper preparation requires significant capital expense and could cause schedule delays. However, by working closely with a stopper manufacturer, the pharmaceutical company can expedite project completion times and enhance its process.

Sterilized stoppers, usually intended for use in isolated filling units, are designated as ready-to-use (RU) versus ready-to-sterilize (RS). RU stoppers must be final rinsed in USP water for injection (WFI) and must be terminally sterilized; they may also be siliconized at the pharmaceutical manufacturer’s request. The stoppers must be delivered to the isolator in a packaging system that allows direct introduction into the isolator, which is a sterile filling unit. One approach is to have the stopper manufacturer provide RU stoppers. In this scenario, the stopper manufacturer must control and validate the sterilization process, bacterial endotoxins, particle load, and silicone levels to comply with current U.S., Japanese, and European regulatory requirements.

Outsourcing Stopper Preparation: Arriving at the Decision

A decision to outsource any element of production must be based on financial and resource assumptions balanced against the operational risk. Valid reasons for outsourcing stopper preparation include improving the commercialization timeline; establishing an effective, dedicated supply chain; freeing up financial staff and facility resources; and limiting capital spending.

When changing in-house manufacturing processes, many pharmaceutical companies often add only those capabilities within their core competencies. Installation of an isolated filling unit could impose new stresses across multiple functions, many outside the core competencies. For instance, maintaining a supply of prepared stoppers often falls outside the core-competency realm. The existing technology for aseptic filling, with regard to the supply of sterile bottles to the filler and sterile fluids to the filling equipment, requires minimal modifications. However, processing and preparing the stoppers for an in-house isolator filling line requires capital investment and resolution of significant validation issues that can affect completion timelines.

Capital investments for stopper processing may include evaluating, purchasing, installing, and testing specialized equipment. Delays can result as operators and technicians are trained in the new processes. Further, ongoing laboratory and engineering expertise is needed for change control processing, development, qualifications, and validations.

As its evaluation process continues, the manufacturer should initiate discussions with its stopper supplier to determine the feasibility of buying RU stoppers delivered in packaging for introducing the stoppers into an isolated filling unit.

Building a Contingency Plan

When a new facility is being constructed or an existing facility is being renovated, decommissioning or removing old stopper processing equipment from the manufacturing floor to make room for new equipment may be necessary. If this is the case, the pharmaceutical manufacturer will need an alliance with a stopper supplier.

The stopper supplier and the drug manufacturer team should then consider the following questions: What is our contingency plan? Can we provide a needed safety net in order to maintain an uninterrupted supply of stoppers? These challenges should be discussed and documented into a formal contingency plan.

Gains

To understand the advantages of outsourcing stopper preparation and to define project requirements, a cross-functional team consisting of representatives from operations, quality assurance, regulatory, engineering, and purchasing must be established.

The team can mutually develop a full risk-assessment and validation master plan (VMP). They can establish commitments to minimize risk, including each company’s interpretation of best industry practices, sterility standards, regulatory requirements, and a clear understanding of change control requirements.

Collaboration between the two companies in the development stage is important. This includes setting up a pilot project with the implementation of isolation technology. Both parties must develop quality specifications based on existing stopper preparations. If the drug product is lyophilized, dryness is a consideration. Lubricity is a consideration for serum components. Stoppers and associated test methods need to be monitored regularly by both parties to ensure that stoppers meet the drug manufacturer’s quality standards.

Ready-to-sterilize stoppers are final-packed in a Class 100 cleanroom (photo courtesy West Pharmaceutical Services).

For the project to succeed, the stopper supplier must be capable of processing RU stoppers in quantity and must have validation and quality systems in place. Further, the RU stoppers must meet U.S., Japanese, and European regulatory requirements for primary pharmaceutical closures. Success will depend on the supplier’s ability to maintain an uninterrupted supply of stoppers.

Before that supply can be established, deciding whether to package the RU products for either a traditional cleanroom aseptic filling line or the new isolator filling line is among the final development tasks. Because the RU stoppers will be applied directly from ready-to-use packaging to a finished drug product, the quality attributes associated with the delivery of these components to the filling line (i.e., lubricity) and maintenance of the drug product integrity (i.e., stopper dryness in the case of lyophilized and some powder-filled product) must be considered. One proven packaging method employs a large, layered poly bag with one end designed to mate to a rapid transfer port (RTP) system. This system creates a total aseptic transfer into the isolator or aseptic filling system.

Ready-to-Sterilize Stoppers

For some pharmaceutical companies, an outsourcing program begins with the introduction of RS stoppers into their processing. Acceptance of RS stoppers and components, introduced to the pharmaceutical market in 1995, has steadily grown. An RS stopper is washed in a pharmaceutical washer with a clean-in-place system, rinsed in hot USP purified water, and further rinsed in WFI. Washed components are transferred to a Class 100 cleanroom for final packaging into a low-particulate, low-bioburden bag that is designed for direct entry into sterilization units. The process, testing, and validation program is detailed in a Type V Drug Master File with FDA and can be referenced at the request of a manufacturer in support of its respective regulatory application.

The water, washing, and packing facilities are fully validated and operate under applicable Current Good Manufacturing Practices (CGMPs). The extensive validation programs include installation, performance, and test method validation, as well as operations qualification and cleaning validation.

Outsourcing Stopper Preparation—Best Practices

The key to a good supplier relationship is establishing a cross-functional project team with representatives from engineering, quality assurance, regulatory, validation, and operations. Establishing a thorough understanding of each company’s process and product flow is important. Bottlenecks or constraints within each organization must be readily identified using process-mapping techniques. A detailed and well-constructed process map can be used to identify areas within the respective manufacturing operations that could result in a process or product failure. The process map can also assist quality and engineering with techniques such as failure mode effects analysis (FMEA) and can help identify potential areas of failure before the process is fully established.

Conclusion

Some pharmaceutical manufacturers may have a successful record of aseptic product processing with few defects and may not want to risk outsourcing any process, including stopper preparation.

However, by working together, the pharmaceutical manufacturer and the stopper supplier can establish a seamless program to transition the supply of sterile stoppers from the pharmaceutical manufacturer to the stopper supplier. This program will transfer the full responsibility of stopper preparation to the supplier, freeing up valuable resources and time for the pharmaceutical manufacturer. The shared knowledge and experience between the two companies will provide the highest quality closure system for direct introduction into the sterile fill operation. Constant follow-up and strong project management skills and techniques are critical to the success of such a program.

This article is based on a case study of an installation of an isolator filling line into an existing pharmaceutical manufacturing facility.

Robert Nase is Westar program director for West Pharmaceutical Services. He has held various positions in the quality assurance department at West in manufacturing and corporate levels. Prior to joining West Pharmaceutical Services, he was employed by the Johnson & Johnson family of companies for 11 years in the cardiovascular division, holding positions in quality assurance, microbiology, and sterilization technology. Nase holds a BS in biology and chemistry from Catawba College and is a member of the International Society of Pharmaceutical Engineers (ISPE) and the Association for the Advancement of Medical Instrumentation (AAMI). He has served on the AdvaMed Biological Support Committee for Microbiological Methods for Package Integrity. He can be reached at West Pharmaceutical Services, bob.nase@westpharma.com.

Douglas Stockdale is the president of Stockdale Associates Inc., which provides extensive aseptic filling and finishing and sterile packaging consulting services for the life sciences industry. Prior to founding Stockdale Associates, he had 20 years of operational experience with Baxter Healthcare. Stockdale is an internationally known consultant, speaker, and writer about the issues of aseptic fill/finish and sterile packaging. His company provides innovative strategic and implementation solutions for product development, manufacturing, compliance/auditing and validation. Stockdale is a member of PDA, AAPS, IOPP, and ISPE and is a member of the board of directors for the Greater Los Angeles chapter of ISPE. He has an MBA from the University of La Verne and a BS in engineering from Michigan State University. He can
be reached at 949/888-9488 or douglas@stockdale-inc.com.