Focus on packaging and sterilization

Bischof + Klein GmbH & Co. KG

Fittings, valves, and connectors can be assembled with packaging fabricated from polyethylene, Tyvek, or laminates by a company that is certified to ISO 9001:2000 and complies with US FDA CGMP guidelines. Bischof + Klein GmbH & Co. KG (Lengerich, Germany; www.bk-packaging.com) operates on-site laboratory and testing de­partments, and extrusion, printing, and con­verting services are carried out by the firm in cleanroom conditions.

The company offers an extensive range of flexible packaging products to meet the changing needs of its customers. Products currently available include bottle-shaped bags, multiple-ply bags, single-wound and tubular films, open-mouth and side-gusseted mitred sealed bags, and laminated aluminium bags with sealing seams. The firm also can develop custom packaging.

Sonolite Plastics Corp.

Thermoformed plastic trays for medical and surgical devices can be specified in a range of environ­mentally friendly materials. Available from Sonolite Plastics Corp. (Gloucester, MA, USA; www.sonoliteplastics.com), the open-face trays are available in various sizes and can incorporate features such as symbols and engraved lettering or part numbers, undercuts, and locating detents for nesting and stacking. The trays also can be used with various types of snap lids and other customer-specified features.

Ranging in size from 1 in. sq to 48 × 72 in., the trays are made from materials such as styrene, polyethylene, polycarbonate, ABS, and PETG in 0.010 to 0.375 in. gauge. They are priced according to configuration; quotations are available after receipt of blueprints or parts.

Steris Isomedix Services

Capable of accommodating custom processing requirements, Steris Isomedix Services (Mentor, OH, USA; www.isomedix.com) has 35 years of experience providing contract sterilization and microbial reduction services. The company performs gamma, EtO, and E-beam sterilization at 21 facilities throughout North America.

By performing preconditioning, sterilization, and aeration within a single vessel, the firm can sterilize and release products to market in one day. In addition to EOExpress, as the technique is called, the firm offers GammaExpress, which uses dosimetric release to allow products to be shipped immediately after processing.

The company’s SteriLink online service is de­signed to shorten time between manufacturing and distribution by allowing customers to monitor inventory, send and receive alerts, review processing documents, check performance metrics, generate reports, and more quickly make critical supply-chain decisions.

The firm’s facilities are registered with US FDA and are certified to ISO 13485, ISO 11135, ISO 11137, and EN 552. Technical support is provided in all phases of sterilization design including product development, materials testing, protocol generation, and sterility validation.

Leoni Studer AG

A company offers contract sterilization services suited for medical devices, pharmaceutical packaging, raw materials, and lab instruments. Leoni Studer AG (Däniken, Switzerland, www.leoni-studer.ch) also provides assistance to medical device OEMs with materials testing, validation, and documentation for regulatory purposes.

E-beam and gamma sterilization services are available; the company operates seven E-beam accelerators for cross-linking and materials modification, as well as for sterilization purposes. Handling systems are designed to ensure efficient and homogenous treatment of products. The company complies with various international standards and guidelines, including ISO 9001:2000, ISO 13485, and US FDA CGMP.

Multivac

A supplier of thermoform-fill-seal rollstock packaging machinery, chamber vacuum pouch sealers, tray sealers, and cross-web and in-line labelers has introduced a complete validation package in accordance with ISO 11607. Developed in concert with medical device manufacturers, the package includes documentation of all functions and potential risks along with proof of process suitability and software validation. Especially noteworthy, according to Multivac (Wolfertschwenden, Germany; www. multivac.com), is adoption of failure modes and effects analysis (FMEA) to ascertain risk.

Prior to each validation, Multivac conducts an FMEA-based risk analysis in accordance with customer specifications, explains Jürgen Steinbauer, who is responsible for validation at Multivac. “This lets us focus on those areas that are essential for process safety.” If desirable, measurement of the temperature, pressure/vacuum, and time values can be calibrated.

Multivac operates more than 30 subsidiaries and 40 agencies worldwide. It has manufactured and installed more than 50,000 packaging machines internationally.

S-Y-M Products Co.

Cohesive tapes that secure devices within their packaging without leaving a sticky residue on the product are now available in a latex-free formulation. Available from S-Y-M Products Co. (Litchfield, CT, USA; www.symproducts.com), the tapes reportedly have a longer shelf life than conventional products.

Cohesive tapes are available in a range of sizes and widths and can be custom printed. They maintain full integrity following sterilization. Custom product development services are also available.

In addition to tapes, the company offers tube coiling equipment and cohesive tape machines for medical device packaging applications.

Vetter Pharma-Fertigung GmbH & Co. KG

A closure system for prefilled syringes features mechanisms that prevent tampering and counter­feiting. Available from Vetter Pharma-Fertigung GmbH & Co. KG (Ravensburg, Germany; www.vetter-pharma.com), the V-OVS NS closure system is designed for use with 1-ml glass-barrel syringes. It consists of a sealing ring and a protective cap of solid plastic with a needle-protection component made of soft rubber. Removing the cap breaks the seal, indicating that the syringe has been used or manipulated.

The company offers a variety of other prefilled systems. It routinely takes on projects encompassing everything from product development to launch for customers involved in the international pharmaceutical and biotechnology industries.

Huhtamaki

A manufacturer provides medical device firms with flexible packaging for a range of applications including pharmaceutical products and medical devices. Offering both primary and secondary packaging, Huhtamaki (Ronsberg, Germany; www.huhtamaki.com) has expertise in extrusion, lamination, and processing technology. Medical applications of the company’s products include packaging for wound dressings, transdermal patches, and a range of pharmaceutical products.

Versed in EtO and gamma sterilization, the company is certified to ISO 9001:2000 and ISO 14001. It has extensive experience designing and manufacturing easy-open packages and high-barrier films, which it offers in transparent and aluminium-based versions.

Reducing Risk through Packaging, Part 1: Understanding the Nuances of ISO 11607

The Sterilization Packaging Manufacturers Council (SPMC) is addressing a number of questions presented to them during their February 2008 Webcast, “Understanding the Nuances of ISO 11607.” You may also find a complete list of questions and answers at the SPMC Web site at www.sterilizationpackaging.org, and at www.pmpnews.com.

And if you think of another question, please feel free to submit it to PMP News through Editor Daphne Allen at daphne.allen@cancom.com.

If you have a sterile fluid pathway, is this considered your sterile barrier system (SBS)? What would you suggest for validation of this SBS? Is outer packaging considered protective?

The following response was provided by Mike Scholla, Senior Consultant for DuPont, PMP News Editorial Advisory Board member, and convener of ISO TC198 WG7 group, which wrote and maintains responsibility for revising ISO 11607.

A sterile fluid path is a special case when it comes to a sterile barrier system, which is why there is a specific definition in ISO 11607. In a sterile fluid path system, fluids flow through a lumen; the critical characteristic is that the inside of the tube is sterile. This is in contrast to a typical medical device, where is it critical that the outside of the instrument is sterile. The sterility of the sterile fluid path system is maintained by the closure system of the fluid path, and it must be demonstrated that the closure system maintains sterility until point of use. Sterilization validation is usually conducted by exposure to an aerosol of spores followed by sterility testing of the lumen.

As many sterile fluid path systems are packaged in pouches, a common sterile barrier system, it is important to determine in each case what is providing the sterile barrier and to make sure that the package is labeled accordingly. Without such labeling, a user may assume that the pouch is providing the sterile barrier. If the sterile fluid pathway is labeled as such, then the pouch enclosing it may be considered protective packaging and validated as part of the packaging system.

When doing a test method validation, how do you know what the acceptable results are?

The acceptable results are relative to your test method and your specifications. For variable data, the results would be gauge repeatability and reproducibility (R&R) percentages per testing equipment. For attribute data, this could be based on confidence limits set by your company’s risk policy.

Percent R&R are common statistical references with the following ranges:

• 0–10% of tolerance—typically acceptable.
• 10–30% of tolerance—can be acceptable with rationale or justification.
• >30% of tolerance—typically unacceptable.

Other acceptance criteria should be based on your company’s risk policy and the relationship to specifications, if not already defined in a standard test method.

If a test method is validated (accuracy, precision, repeatability defined), does it need to be verified every time the test is run? For example, for the dye-penetration test, I validated it for a 0.002-in. channel leak. Do I need to prove it again every time I run the test?

No, you do not have to perform a test method validation every time a test is run. You would consider redoing a test method validation if you have a significant change in the method.

In the case of the dye test, while it is not required to prove it again every time, you may want to verify the sensitivity of the dye solution with every new batch by testing it with a known 0.002-in. channel leak or by controlling the production of the solution to maintain a high level of assurance of repeatability.

Streamlining the Inspection Process

An FDA pilot program gives firms with a history of proper GMP compliance hope for less-demanding future inspections.

An FDA pilot program testing a new format for drug manufacturing and packaging inspections could lead to a less cumbersome inspection process for firms with a history of proper compliance.

The pilot program, which began January 1 and ends June 30, covers the Philadelphia, Los Angeles, New Jersey, New York, Dallas, and San Juan, PR, inspection districts. The agency has not given a timetable for expanding the program nationwide if it proves successful.

According to a program guidance document issued by the agency's Office of Regulatory Affairs, the pilot program streamlines the inspection process by dividing it into six systems: quality, facilities and equipment, materials, production, packaging and labeling, and laboratory control. If any one system is deemed out of control, then the firm as a whole is deemed out of control.

When a firm has a record of "satisfactory GMP compliance, with no significant recall, or product defect or alert incidents, or with little shift in manufacturing profiles . . . within the previous two years," FDA's inspection team may choose to do an "abbreviated inspection." This option allows for as few as two of the six systems to be audited but specifies that one must be the quality system and that the other five systems be examined on a rotating basis. Inspection of the quality system may require limited coverage in the areas not being formally examined.

The "full inspection," which involves auditing at least four of the six systems with the quality system mandatory, is to be used when "little to no information is known about a firm's GMP compliance; or for firms where there is doubt about GMP compliance; or follow-up to previous regulatory actions."

The systems-based method came about because FDA recognized that it does not have enough resources to audit every aspect of GMP compliance for each facility. The current system bases reviews on "profile classes," which enable the agency to generalize inspection coverage from a small number of specific products to all the products in that class. The systems approach further generalizes inspection coverage from a small number of profile classes to an overall evaluation of the firm. "Coverage of a system should be sufficiently detailed . . . so that the system inspection outcome reflects the state of control in that system for every profile class," the agency states. "Multiple visits to a firm will not be needed to cover all profile classes [and] delays in approval decisions will be avoided because up-to-date profile class information will be available at all times."

Among other things, inspection of the quality system should consider discrepancy and failure investigations related to manufacturing and testing, documentation, evaluation and approval of change control, the impact of reprocessing and reworking on validation and stability, correct courses of action on rejects and stability failures, and the status of required validations and revalidations.

Evaluations of the facilities and equipment system should include air-handling systems, cleaning procedures and validation, contamination prevention controls, as well as qualification, calibration, and maintenance of storage equipment.

Some of the considerations for evaluating the materials system are identification, inventory, and testing or validation of a supplier's test results for components, containers and closures; and the rejection and quarantine of any material not meeting acceptance requirements.

The production system is more relevant to processing than it is to packaging, but considerations include preventing objectionable microorganisms in nonsterile drug products and validation and security of the data-handling system.

The packaging and labeling system's evaluation includes considering the acceptance operations for packaging and labeling materials; the control system for making changes to packaging and labeling operations; adequate storage for labels and labeling; control of labels similar in size, shape, and color; proper examination of the finished labels; proper use of lot numbers and destruction of excess labeling bearing lot numbers; adequate packaging records including specimens of all labels used; proper inspection and documentation of printers; conformance to tamper-evidence requirements; and validation of all packaging and labeling operations.

A packaging and labeling system failure could entail failure to establish or follow a control system for implementing packaging and labeling changes, a pattern of failure to document investigation of discrepancies, a lack of validation of computerized systems, anything that may introduce a potential for mislabeling, and a lack of packaging validation.

Because the laboratory control system has little relevance to packaging, it will not be discussed here.

The document can be viewed at http://www.fda.gov/ora/cpgm/7356_002/7356-002-Draft.html.

Improving Parenteral Packaging

Advancing technology and upcoming guidance documents promise to make parenteral packaging more reliable and user-friendly than ever before.

by Karen G. Beagley, Midwest Editor

To protect and ship highly sensitive pharmaceutical powders and liquids, drug manufacturers rely on high-barrier vials, bottles, and syringes. These packages must keep the pharmaceuticals sterile yet allow healthcare practitioners to use them efficiently, safely, and quickly. To ensure that such packages remain sterile, both industry groups and FDA are working on guidances that assist both the manufacturers and the users of parenteral packaging.

Industry is also involved by developing high-tech aseptic systems such as barrier isolators to nearly eliminate contamination associated with the filling and sealing of vials, bottles, and syringes. Industry is also creating systems that help users deliver drugs quickly and efficiently yet minimize accidents such as needle sticks and overdoses.

GUIDANCE DOCUMENTS

The Parenteral Drug Association (PDA) and FDA are both working on guidelines to assist pharmaceutical manufacturers who use parenteral packaging. PDA is currently formulating a guidance document on sterile product filtration processes. "The guidance will affect integrity testing and validation of filter processes," says Edmund Fry, president of PDA. "The technical guidance our expert committee is preparing should be published in the next few months."

PDA has also submitted comments to the European Commission regarding the latter's guidance document on aseptic processing, specifically on sterile medicinal products, requesting that the guidance reflect the benefits of using isolator systems. "In Europe, the initial experience may have been with isolators in hospitals," explains Fry. "Isolators in hospitals are often not used in the same manner that drug companies use them. In the United States, FDA regulates industry's use of isolators under the stringent standards of GMPs."

FDA is producing an updated version of its 1987 "Guideline on Sterile Drug Products Produced by Aseptic Processing." Richard Friedman, consumer safety officer for the agency's Center for Drug Evaluation and Research, explains that "there will be new sections on personnel, design, and endotoxin control. The guideline will also have new definitions and address technologies such as barrier isolation and form, fill, and seal."

NATURAL RUBBER RULE

A regulatory development that will affect the labeling of pharmaceuticals that are packaged in bottles, vials, and syringes is FDA's final rule on latex-containing devices and packaging. Published on September 30, 1997, "Natural Rubber—Containing Medical Devices: User Labeling" will take effect one year from its publication date. According to Michael Gross, director, corporate regulatory affairs for Becton Dickinson and Co. (Franklin Lakes, NJ), "The rule mandates that manufacturers label, using specific statements, all over-the-counter and prescription medical devices, in vitro diagnostic products, and drug-device and biologic-device combination products and their packaging when they or their components are manufactured from natural rubber. The regulation applies to all products manufactured either by dipping molds into liquid suspensions of natural rubber latex particles or by molding dry natural rubber, if they are intended to, or are likely to, contact humans."

FDA has received 62 comments on the proposed rule, and all of them reportedly support it, but differ in their reactions to FDA's proposal to label latex-containing medical devices for the protection of latex-sensitive individuals.

Schott Pharmaceutical Packaging's glass containers feature a high purity, ultrainert inner surface that allows safe packaging of sensitive or aggressive products.

"Drug-device and biologic-device combination products are subject to certain intercenter agreements published in 1991," says Gross. "Through a novel use of two of these intercenter agreements, FDA has also stated that it has the authority to apply the final rule to combination products that contain natural rubber and are regulated solely under drug or biologic authorities. It will require manufacturers of such products to comply after the applicable intercenter agreement has been amended to reflect that prefilled vials, patches, infusion pumps, and prefilled syringes are subject to the final rule, or by the effective date of the final rule, whichever is later."

The regulation requires manufacturers of products containing or packaged with natural rubber latex to include the following statement in product labeling: "Caution: This product (or the packaging of this product) contains natural rubber latex which may cause allergic reactions." For products containing or packaged with dry natural rubber the label must read, "This product (or the packaging of this product) contains natural rubber."

Even though latex is used more for devices than for packaging, parenteral packaging often contains components made of latex. "This ruling affects vial stoppers and syringe plungers," says Edward Smith, vice president of technical affairs, Helvoet Pharma Inc. (Pennsauken, NJ). "The drug and medical device manufacturers will have to label their products with this warning. It is to prevent an allergic reaction in people who are sensitive to the rubber protein."

"The interesting thing about this ruling is that FDA made it based on regulations that apply to medical devices," says PDA's Fry. "Combination products of drugs and devices are falling under this ruling."

SYRINGE ADVANCES

Many parenteral packaging suppliers are devising new ways to hold and deliver pharmaceuticals to help make an end-user's job easier. "Prefilled needleless syringes are gaining popularity," says Ken Muhvich, senior regulatory pharmaceutical consultant for The Validation Group (Baltimore). "Hospital personnel can tap the syringe into an existing IV line. Since the medication isn't drawn from a vial it reduces the possibility of medication error. And because the syringe is needleless, it also prevents the possibility of a needle stick."

Needleless or not, prefilled syringes are convenient for end-users. Because they eliminate the need to draw medication from a vial, they ensure that the correct dosages are given.

"Prefilled syringes cut down on medication errors and the chance of infection," says John J. Racik, senior product manager, pharmaceutical systems division, Becton Dickinson. "They also increase the efficiency of the manufacturer's production line. When filling a prefilled syringe, the manufacturer doesn't have to compensate for overfill as you do in a vial. The overfill is 50% less in a syringe than it is in a vial."

Currently in the United States, vials are still used more than prefilled syringes. But, says Racik, "as more companies are looking to stand out in the marketplace, prefilled syringes will become more prevalent. We did a study that showed that 85% of healthcare professionals prefer prefilled vaccine syringes. In the future, the delivery system will become more of the selling point."

"More manufacturers are making prefilled syringes because of the ease-of-use factor," agrees Jeff Turns, vice president of sales and marketing at Pharma-Turm Inc. (Yardley, PA). "Healthcare providers appreciate that they do not have to manipulate the syringe to ensure the correct medication."

VIALS AND STOPPERS

To protect highly sensitive substances, vials are often lined with a coating to prevent interaction between vial and pharmaceutical. "We have lined the vial with pure, fused silica to eliminate the interaction between the glass surface and the contents," says Robert Swift, scientific services manager, Schott Pharmaceutical Packaging (Cleona, PA). "In addition to the essential inertness, the vials are completely compatible with existing depyrogenation and filling processes."

Parenteral packaging components made from Resin CZ. Photo courtesy of The West Co.

Some pharmaceuticals degrade, depending on the moisture content of the finished formula. But the use of packaging materials that absorb moisture can significantly stabilize pharmaceuticals. "Calcium oxide and molecular sieves are known to have good desiccating capacity, and both will absorb water at relatively low humidities," says Val Romberg, director of Westar, multimaterial product development, at The West Co. (Lionville, PA). "We are developing stoppers that contain molecular sieve powder, and they effectively act as desiccants for injectable drug formulations."

BARRIER ISOLATION TECHNOLOGY

Many companies are at various stages of developing barrier isolator systems to fill parenteral packaging. Barrier isolation involves using a closed filling and packaging environment, which some consider to be superior to aseptic processing. "People are the greatest contaminant in an aseptic process," says Ben Webb, associate engineering consultant, Eli Lilly & Co. (Indianapolis). "We all want to produce a sterile product. FDA requires media fills to prove that a process is aseptic. We plan to submit media fill data later this year proving that our system is equivalent, if not superior, to conventional aseptic processes."

FDA does acknowledge the potential benefits of a barrier isolation system. "If the isolator is properly designed, maintained, and controlled it should offer a tangible advantage over classic aseptic processing," says Friedman. "But the jury is still out. FDA will wait until we see the data."

Another factor creating the need for barrier isolation technology is the advent of biochemical drugs, which cannot be terminally sterilized. "For products that can't be terminally sterilized, barrier isolation technology gives users the confidence that the package maintains its sterility," says Ron Filipski, director, Pasteur Merieux Connaught (Swiftwater, PA). "Biologicals cannot be terminally sterilized, so barrier isolation technology gives users a better confidence level of sterility."

Jack Lysfjord, vice president of technology and international sales, TL Systems Corp.—Bosch Group (Minneapolis), agrees. "Biological products are becoming more prevalent, so the industry needed to create a system for them. Barrier isolation technology answers this need."

Products that cannot be terminally sterilized will most likely continue to be handled in an aseptic system. And further, companies that use aseptic processing may benefic from using barrier isolation.

"What we have to prove now is that barrier isolation technology works properly. We are doing this through validation and documentation," says Paul Chimino, sales engineer, Bausch + Stroebel Machine Company, Inc. (Clinton, CT). According to Friedman, some of the key issues to developing barrier isolation technology are finding suitable construction materials, maintaining adequate positive air pressure from the isolator to the surrounding environment, meeting Class 100 standards for the interior of the isolator, and at the very minimum maintaining a Class 100,000 environment in the surrounding room.

"Companies should examine whether or not they have products that can be terminally sterilized. If a product can be heat sterilized it should be, because heat sterilization is the more reliable, robust process," explains Friedman. "It comes down to product safety. Ultimately, both industry and FDA agree that product safety is the most important issue."

CONCLUSION

With product safety in mind, both industry and FDA are working to improve parenteral packaging. Designed to protect latex-sensitive patients, a new FDA ruling regarding the labeling of latex-containing packages affects pharmaceutical manufacturers, who will need to either institute the new labeling or find nonlatex alternatives. New guidelines from FDA and PDA along with developments in barrier isolation technology should help industry refine filling and packaging processes. And industy is devising safer, more reliable ways to package and deliver drugs. As much as these developments affect pharmaceutical packagers, their impact will be felt most by healthcare practitioners, who will be able to deliver drugs more safely and efficiently while minimizing nosocomial infections and allergic reactions.

Photo courtesy of Becton Dickinson, Pharmaceutical Systems Div.

Packagers Set Sights on WestPack and More

The upcoming four-day show features a new automation technology expo.

WestPack, collocated with Medical Design & Manufacturing West and other events, will span four days, bringing a wide range of conference topics and packaging options to attendees and exhibitors. More than 500 exhibitors and 13,000 packaging buyers are scheduled to attend the expo at the Anaheim Convention Center (Anaheim, CA).

The West Coast’s largest packaging show will be held from Tuesday, January 31, to Thursday, February 2. Conference sessions begin on Monday, January 30.
Pharmaceutical & Medical Packaging News will again sponsor the Pharmaceutical and Nutraceutical Packaging Pavilion in WestPack. The pavilion offers specialty equipment for the pharmaceutical industry as well as packaging for vitamins and nutritional supplements. Attendees who are interested in packaging for these industries will also find another special-focus pavilion at WestPack serving their needs, the Material Handling & Logistics Pavilion.

The MedPak Pavilion, also sponsored by PMP News, in MD&M West, brings attendees and the leading suppliers of medical packaging technology together. High-speed fillers, dispensers, sealers, thermoformers, labelers and printers, flexible pouches, and barrier films will be on display.

The Automation Technology Expo (ATX) West is a new addition to the show. ATX brings attendees displays in custom automation, robotics, vision systems, and motion control. It also features control software, sensors, assembly systems, and drives.

Two sessions at MD&M West on January 30 are particularly relevant to the medical packaging industry: Packaging Engineering, in the morning, and Packaging Validation and Compliance, in the afternoon. Douglas Stockdale, president of Stockdale Associates Inc., a consultancy for aseptic fill/finish and sterile packaging, will chair both sessions.

At the Packaging Engineering session, Curtis Larsen, package engineering consultant for Dupont Medical Packaging, will detail the past and future activities of the Institute of Packaging Professionals’ (IoPP) Technical Committee as well as what the device industry may expect from IoPP. At the same session, Anthony Bantug, senior packaging engineer at FedEx, will discuss packaging design software and how it can help reduce overall manufacturing costs.

During the Packaging Validation and Compliance session, Nick Fotis, director of the packaging technology center at Cardinal Health’s medical products and services group, will focus on the benefits of harmonization in and improvements to ISO 11607. Marci-Ann L. Ando, senior packaging engineer for Celera Diagnostics, will focus on how to perform a transport packaging validation for a product or package system using ASTM and ISTA standards.

For more information or to register for the shows, call 310/445-4200, or visit www.canontradeshows.com.