Testing for Container Closure Integrity Using Helium Leak Testing

Container closure integrity is defined as the ability and quality of a container closure system to provide protection and maintain efficacy and sterility during the shelf life of a sterile drug product. The ability of rubber components to prevent microbial ingress of parenteral containers can be measured by seal integrity.

In practice, there are numerous types of container closure integrity methods that are available with varying sensitivities. West Analytical Services offers as part of our standard capabilities a validated Helium Leak Test Method that is state of the art in addition to other traditional methods that have been used by the industry for many years.

Helium Leak Testing

The most sensitive seal integrity testing technique is the use of helium leak detection. This technique offers advantages over other conventional seal integrity test methods. West uses a Seal Integrity Monitoring System (SIMS™) for helium leak detection. The system is based on a helium mass spectrometer leak detector equipped with custom fixtures for the particular vial or parenteral container to be tested. The instrument is calibrated against a NIST-traceable standard leak and measures the rate of helium leak from the vial/container as well as the actual percent of helium that is filled within the vial/container. Various types of containers including vials, syringe systems, cartridges and blister packs can be evaluated.

By using the tracer helium gas technique, the leakages could be determined quantitatively. Published research [see Kirsch, et. al., PDA J. Pharm. Sci. & Tech., Vol. 51, pp. 195-207 (1997)] has demonstrated that a helium leak rate greater than 10^-6 cc/sec can be considered a failure for closure integrity. Helium leak rates lower than 10^-6 cc/sec have been associated with acceptable microbial challenge results. For sensitivity comparison, conventional seal integrity methods (i.e. dye leakage) have leak rates of 10^-3 cc/sec.

Recommended Applications:

•    General container closure integrity testing
•    Seal integrity monitoring during stability studies
•    Closure formulation/configuration selection
•    Sealing machinery optimization/validation
•    Prediction of shelf life seal integrity through use of proprietary software
•    Identifying the source of leaks using the “sniffer mode”

Traditional Methods

West Analytical Services provide other traditional seal integrity test methods that are widely accepted by the industry and are routinely used by clients for research and development studies, problem solving and to generate baseline data. Options available for client testing include:

•     Vacuum Decay by PTI Micro Leak Detection
•     Determination of the amount of vacuum within a sealed vial – Lighthouse Capability
•     Determination of sealability of rubber closures – Methylene Blue Dye
•     Residual Seal Force

For more information about testing, contact the author.

Doug Hostetler
Senior Technical Account Manager
610-594-3066
Doug.Hostetler@westpharma.com

SIMS™ is a trademark of MEA Group.

The Effect of a Barrier Film on Elastomeric Extractables in a Parenteral Packaging System

Amy Miller and Jennifer Riter

Extractables from elastomeric components become an issue even before a pharmaceutical drug makes contact with the elastomeric component. The suitability of the elastomer and the drug product needs to be taken into consideration at the development stage of the packaging and delivery system for the drug product. The potential for an extractable to leach into the drug product and the impact that leachable will have on the drug’s stability, efficacy and toxicity needs to be scientifically evaluated. A way to reduce the amount of extractables that could potentially leach into a drug product from an elastomeric closure is to utilize a fluoropolymer film on the closure. The fluoropolymer film reduces the closure-drug interaction there-by reducing the amount of leachables in the drug product. To demonstrate the effectiveness of the fluoropolymer film, multiple closures, some laminated with fluoropolymer film and some without, were sealed onto vials containing various solvents representing typical drug product solvent vehicles. To stimulate a worst-case scenario the vials were inverted and stored at 40°C/75% RH (± 2°C/5% RH). Each set of vials/solvents was tested at time 0, 3 months and 6 months. The analytical techniques used to identify any leachables included Ion Chromatography (IC), Inductively Coupled Plasma Spectroscopy (ICP), and High Performance Liquid Chromatography utilizing Photodiode Array and Mass Spectrometry (LC/PDA/MS) and Gas Chromatography with Mass Spectrometry (GC/MS). The results from this study confirmed that inclusion of a fluoropolymer film reduced leachables from the elastomeric closures.

The results of this study show that the potential for extractables leaching into drug product solvent vehicles from closures is a reality. The LC and GC results show that antioxidants and other formulation-related compounds leached from the closures without fluoropolymer film into 50% ethanol/water and 50% propylene glycol/water solutions. These antioxidants and other formula-related compounds were either not detected or were only seen at reduced levels with the closures coated with fluoropolymer film.

The ICP analysis showed quantifiable levels of calcium leached into the pH 3 and 0.03% Polysorbate 80 solutions from the closures without fluoropolymer film, while over the same period of time, no quantifiable level of calcium leached from the closures with the fluoropolymer film. The IC results show that chloride was detected from closures without the fluoropolymer film but not from the closures with fluoropolymer film after 3 and 6 month of storage at accelerated conditions.

The study revealed that even over a period of 6 months, leachables can be detected and there is a potential for those leachables to increase over time. It is important to not only look at what can leach from the closure but how much of that leachable can be detected and its effect on the drug product.

The methods used in this study are screening methods. Now that extractables have been identified, the next step is to develop and validate test methods in drug product. The leachables can then be quantified over the shelf life of the drug product. Three key points to take from this study are that the use of a fluoropolymer film can greatly reduce the risk of leachables in a drug product, leachables can increase over even a short time period at accelerated conditions, and choosing the correct methods for analysis of leachables is critical.

To read the full scientific poster, visit http://www.westpharma.com/en/support/Scientific%20Posters/The%20Effect%20of%20a%20Barrier%20Film%20on%20Elastomeric%20Extractables%20in%20a%20Parenteral%20Packaging%20System.pdf

West and Tech Group to Present at MD&M West, Feb. 13-16

West and The Tech Group will present at the Medical Design & Manufacturing (MD&M) West conference on February 13-16, 2012, in Anaheim, California. MD&M West is a comprehensive resource for medical device development. Medtech professionals and leading medical OEM suppliers come together at the conference to offer hands-on access to the tools and information companies need to bring a new device to market.

West’s Scott Young, Sr. Director, will present at Session 204, “New Materials Processing Technologies for Medical Devices,” on February 14.  In “Qualification of Components for Use in Medical Devices,” Scott will discuss:

• Requirements of pharmaceutical delivery systems
• Current issues with traditional glass packaging
• Testing and performance of syringe systems
• Design flexibility of plastics

The Tech Group’s Mark McElfresh, Plant Manager at the Rockford facility, will present at Session 102, “Adapting to a New Era of Supplier Controls” on February 13.  He will speak about “What This Means to Suppliers: a Contract Manufacturers Perspective.”

Be sure to look for The Tech Group at booth 3019.  See you there!

For more information or to register to attend, visit http://bit.ly/ahysqH.

Pharmapack Europe 2012: What are you looking forward to?

Date: February 15-16
Location: Grande Halle De La Villette – Paris, France
Website: http://www.pharmapack.fr/

Join West and The Tech Group at Booths 560 and 570!

As one of the largest annual platforms dedicated to packaging innovation and drug delivery systems for the pharmaceutical industry, Pharmapack Europe 2012 looks to be an exciting event this year. West will be there to help customers learn more about products such as Envision^TM and Westar^® RU components, LyoSeal^® plastic caps and Daikyo Crystal Zenith^® products.

More than 260 leading international companies specializing in design, manufacturing and supply of products and services for the pharmaceutical packaging industry will attend, and we’re excited to see their new products.  We’re also looking forward to the multitude of first-class speakers and presentations focused on innovation.

Innovation is key for West. We pride ourselves on providing our customers with innovative solutions to packaging issues.  And 2012 will be no exception.  Watch for a new product line introduction focused on high-quality components manufactured with Quality by Design principals, coming in April.

The Tech Group will be welcoming customers at stand #570 at Pharmapack. We will present our expanded capabilities both in device development and device manufacture. We look forward to welcoming visitors and having the opportunity to discuss all aspects of device requirements.

So what are you looking forward to discovering at Pharmapack this year?

West Authors Contribute Chapters to New Leachables and Extractables Handbook

West authors Diane Paskiet, Kim Miller, Laura Stubbs and Diego Zurbriggen contributed to several chapters in the new “Leachables and Extractables Handbook: Safety Evaluation, Qualification, and Best Practices Applied to Inhalation Drug Products” available from Wiley Scientific.

The Handbook offers a practical and science-based approach for addressing toxicological concerns related to leachables and extractables associated with inhalation drug products, including metered dose inhalers, dry powder inhalers and nasal spray.  Such products pose potential safety risks from leachables and extractables, chemicals that can be released or migrate from these components into the drug product.  The Handbook offers a practical approach to familiarize readers with the recent recommendations for safety and risk assessment established through a joint effort of scientists from the FDA, academia, and industry.

Chapters where West authors contributed include:

• Chapter 11. Chemical and Physical Attributes of Plastics and Elastomers: Impact on the Extractables Profile of Container Closure Systems (Michael A Ruberto, Diane Paskiet and Kim Miller)
• Chapter 16: Extractables – Case Study of a Polypropylene (Diane Paskiet, Laura Stubbs, and Alan D. Hendricker)
• Chapter 20: Inorganic Leachables (Diane Paskiet, Ernest L. Lippert, Brian D. Mitchell, and Diego Zurbriggen)

For more information or to purchase a copy of the Handbook, visit: http://www.wiley.com/WileyCDA/WileyTitle/productCd-0470173653.html

Young to Present at MD&M West – February 14-16

West’s Scott Young will present “Qualification of Components for Use in a Medical Device: Daikyo Crystal Zenith^® – A Unique Plastic Container System,” at MD&M West in Anaheim, California, on February 14-16, 2012.

The presentation will center on ultra high-quality plastic syringe systems, which provide a compelling alternative to glass syringe systems. Through simplified usage, support for new classes of biopharmaceutical products, reduced waste, break-resistance, dosage precision and the virtual elimination of extractables and leachables, plastic prefillable syringes present attractive benefits that are gaining increased attention from manufacturers seeking new answers to today’s and tomorrow’s drug-delivery and administration challenges.

Additionally, rapid growth of injection systems has become increasingly prevalent in pharmaceutical drug delivery. There is an emerging need to minimize or eliminate protein aggregation due to silicone oil interaction, reduce contamination due to extractables and minimize drug loss due to adsorption. Choosing the right injection system can mitigate these protein aggregation and instability issues. The session will discuss key attributes of a silicone-free prefillable syringe system, including syringe functional performance attributes, ideal for biopharmaceutical drug delivery applications.

For more information or to register to attend, visit: http://bit.ly/ahysqH 

Scott Young
Sr. Director, Crystal Zenith
610-594-3135
Scott.Young@westpharma.com

Daikyo Crystal Zenith^® is a registered trademark of Daikyo Seiko, Ltd.
Daikyo Crystal Zenith technology is licensed from Daikyo Seiko, Ltd.

Quality Control – Vision Inspection Systems | Automated Vision Inspection for Parenteral Closures

West’s Peg Frandolig and Lynn Lundy share how vision inspection systems can help drug product manufacturers and packaging suppliers work together to regulate foreign and particulate matter in finished drug products in the December/January issue of Pharmaceutical Formulation & Quality.

Manufacturers of sterile drug products are confronted with increasing quality standards to produce defect-free products, reduce process/product variation, and minimize product rejects. Parenteral drug products intended for injection must meet requirements set forth in the United States Pharmacopeia (USP) Chapter <1> Injections, including the following specifications regarding foreign and particulate matter:

“Each final container of all parenteral preparations shall be inspected to the extent possible for the presence of observable foreign and particulate matter … in its contents. The inspection process shall be designed and qualified to ensure that every lot of all parenteral preparations is essentially free from visible particulates.”¹

Particulate matter in finished pharmaceuticals can come from multiple sources, such as the ingredients in the drug product, processing equipment, or the container closure system. Manufacturers of sterile drug products should consider a means to reduce or exclude particulate matter and container closure defects in products.²

Read the full article here: http://bit.ly/z1scmY 

 

1.     U.S. Pharmacopeia. USP 34–NF 29 General chapter <1> Injections, labeling of ferrules and cap overseals section. Aug. 4, 2010. USP website. Available at: www.usp.org/USPNF/notices/ferrulesCapOverseals.html. Accessed Nov. 22, 2011.

2.     U.S. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research. Center for Biologics Evaluation and Research. Office of Regulatory Affairs. Guidance for industry: Sterile drug products produced by aseptic processing – current good manufacturing practice. September 2004. Available at: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070342.pdf. Accessed Nov. 22, 2011.

 

Screening Analysis Can Assure Proper Packaging Selection

According to the Code of Federal Regulations Title 21 Food and Drugs Part 211.94(a) Subpart E Control of Components and Drug Product Containers and Closures, drug containers must not react or add to a drug product in a way that alters the drug’s safety or quality. Concerns related to the packaging system can include:

- Poor chemical durability
- Use of silicone lubricants and impact to product quality
- Compatibility concerns related to biopharmaceuticals
- Potential for leaching and interaction with drug products
- Drug product shifts in pH due to glass dissolution
- Reduced potency from adsorption of drug product onto glass surface
- Breakage, scratches or particles resulting from packing, transport and filling

To help assure proper package selection and avoid potential incompatibilities between product and closure systems, a screening comparison study can be completed.  This typically includes an 8-week investigational study that will help manufacturers determine the best elastomer selection for their drug product.

First, a study questionnaire is completed by the manufacturer to help the selected lab gain knowledge of the drug product. From this information, a list of potentially suitable elastomeric formulations is chosen for the study.

A gross compatibility study is designed to accelerate any incompatibilities that may exist between the drug product and the potential packaging. To accomplish this, the customer must supply bulk product or placebo for testing. Processing of components is then simulated and sample vials are inverted to maximize contact between the elastomer and the drug product.  Accelerated conditions are used to help speed the analysis.

A thorough analysis may include the following screening techniques:

• Inductively Coupled Plasma Screening
• pH Shift
• Turbidity
• Ultraviolet Spectrum
• Visual Inspection in High Intensity Light
• Ion Chromatography Screening
• NonVolatile Residue / Infrared Spectroscopy 
• High Performance Liquid Chromatography / Mass Spectroscopy Screening*
• Gas Chromatography/Mass Spectroscopy Screening*

Appropriate sample preparations for these analyses will also need to be established as part of the study.  

*These screenings involve the use of a general method, which may qualitatively uncover extractables that are present. West recommends a more thorough leachable analysis be performed on the chosen closure candidate during later evaluations. 

For more information about screening analyses, contact: 

Doug Hostetler
Senior Technical Account Manager
610-594-3066
Doug.Hostetler@westpharma.com

Reynolds to Speak at Drug Delivery Partnerships Conference

West’s Graham Reynolds will present “An Integrated Approach to Biologic Drug Delivery Systems: Meeting the needs of the patient, and optimizing drug product performance,” at the Drug Delivery Partnerships meeting in Las Vegas, on January 25, 2012.

Graham will speak at a session entitled “Maximize the potential of your drug delivery system through drug device combination products,” chaired by Phil Green, Senior Director Drug Delivery Devices at Merck.

The presentation will focus on the importance of considering four key elements of an integrated drug delivery system and the critical interfaces between them. These four elements are:

• The patient: All aspects of the system are designed to bring benefit to the patient
• The drug: The drug molecule remains critical; however, the presentation will highlight the value of ensuring that the drug containment system and the delivery device provide the appropriate therapy or treatment
• The container: While the container is critical to ensuring drug stability and integrity, considering interface options with the device may help to optimize the overall system
• The device: As the use of devices grows, drug companies are considering device selection at an earlier phase, recognizing that it can impact market position and treatment effectiveness

West is uniquely positioned to understand and support this need, combining leadership in drug containment systems with device development and manufacturing expertise, and a network of industry partnerships aimed at ensuring optimum packaging and delivery systems for today’s sophisticated drug products. Examples of solutions will be briefly discussed, including Daikyo Crystal Zenith^® containment systems and the SmartDose^® electronic patch injector, which is an ideal example of an integrated packaging and delivery system that meets a growing market need.

Graham Reynolds
Vice President, Marketing and Innovation
610 594 2935
Graham.Reynolds@westpharma.com 

West markets SmartDose® as a multi-component system only. Final assembly of the prefilled component is completed by the pharmaceutical company. SmartDose® is a registered trademark of Medimop Medical Projects Ltd., a subsidiary of West Pharmaceutical Services, Inc.

Daikyo Crystal Zenith® is a registered trademark of Daikyo Seiko, Ltd. Daikyo Crystal Zenith technology is licensed from Daikyo Seiko, Ltd.

West without Borders 2011 Charity Efforts See Success

The West without Borders charity fundraising initiative had a terrific year in 2011.  West employees around the globe contributed more than $210,000 to aid local charities.  To date, the charity campaign has raised more than $1 million since its inception in 2004.  The 2011 campaign focused on local charities selected by the employees in West’s global facilities.

“Our 2011 efforts truly made a difference in the communities where we live and work,” said West’s Chairman and CEO Donald E. Morel, Jr. Ph.D.  “We’re looking forward to another exciting local campaign in 2012 to once again support children in need.”

Many of West’s locations are involved in multi-year programs, including Colombia, where West employees support the Mahavir K-Mina Foundation, which manufactures and installs lower-limb prosthesis.  Last year, a seven-year old girl received her first prosthesis.  As she continues to grow each year, she will require a larger limb, and in February 2011, she received her second limb thanks to West’s generous donations.

In China, the West Love Library, a three-year program to provide books and materials to a small village school, received more than 1,000 books and additional materials to aid children with their reading. More than 70 employees participated in the efforts to collect and purchase the supplies.

Overall, the 2011 campaign aided 27 local charities in a variety of locations. 

A History of Giving

West without Borders kicked off in late 2004 with fundraising programs to aid those affected by the Asian tsunami and then hurricane Katrina in the fall of 2005. Targeted, company-wide projects have included:

• Local Charities: In 2010, West designed its campaign to reach charities focused on aiding children with special needs in the communities where our employees live and work. More than $200,000 was raised for a variety of charities located around the globe.
• Africa Health Placements: In 2009, West employees raised more than $140,000 for this not-for-profit organization that recruits doctors from around the world to provide critical care for patients in rural Africa.
• Braille without Borders: In 2008, West employees raised more than $200,000 to support this international program to educate blind children in developing areas such as Tibet and India.
• Camp Victory Treehouse: In 2007, West employees donated $240,000 along with hundreds of hours in manpower to build a wheelchair-accessible treehouse for children with chronic illnesses at Camp Victory in Millville, Pa.
• Hope Lodge: In 2006, West employees raised more than $192,000 to help build the AstraZeneca Hope Lodge of the American Cancer Society in Philadelphia, a 30,000 square-foot facility that provides free temporary housing to approximately 1,300 cancer patients annually.

Looking Forward to 2012

Thanks to the success of our 2011 campaign, West is once again encouraging each individual facility to select a local charity as the recipient of its efforts for 2012.

“Our employees have always given generously, and I’m certain 2012 will be no different,” said Morel.  “I look forward to seeing just how much good we can do for those in need in our communities and thank everyone for their generous participation during these difficult financial times.”

Watch for more news regarding West’s charity 2012 efforts – including a look at the life of service-dog-in-training, Dookie, who joined west as part of the Canine Partners for Life puppy training program.  In the meantime, you can read about the H.O. West Foundation here.

West without Borders is not affiliated with Doctors Without Borders®, which is a registered service mark of Bureau International de Medecins San Frontieres.