You can transport temperature-sensitive products with confidence.

By Carli Derifield
EnviroCooler

When writing this article, a poem by Terry Kettering came to mind: “The Elephant in the Room.” Certain lines kept whirling around my head as I tried to figure out how best to convey what we have to say:

“We all know it is there…For, you see, it is a very big elephant…But we do not talk about the elephant in the room.”

Don’t you think it’s time to talk about the elephant in the room? If the transportation of temperature-sensitive products (TSPs) is such a hot topic, then why are we not talking about it? Why do conferences, articles, papers, and conversations focus on the negative when there are solutions that are in practice today? Are they creating fear and adding to the confusion?

Organizations are overcoming the apparent challenges and actually transporting TSPs safely and compliantly around the world. They are confident that end-users will receive products safe and fit for their intended use. They can prove it to FDA, EMEA, USP, TGA, or to WHOmever they need.

How do these organizations do it? They acknowledge ‘the elephant in the room’—that process validation principles apply to transporting TSPs and that there is no ‘quick fix.’

Validation principles are nothing new to those that manufacture medicinal products. GMPs require that manufacturers identify what validation work is needed to prove control of the critical aspects of their particular operations. Significant changes to the facilities, the equipment, and the processes that may affect product quality should be validated. A risk assessment approach should be used to determine validation scope and extent.

Product transportation falls into the category of a “process which may affect the quality of the product.” Hence, it needs to be validated. So then, what has changed?

What has changed is that healthcare biotechnology is increasingly playing a role in conventional drug discovery. Biotech medicines such as proteins, antibodies, and enzymes now account for more than 20% of all marketed medicines and more than 50% of those in clinical trials. Because these active biological medicines are sensitive to changes in temperature and vary widely in their tolerance of short-term exposure to heat and cold, temperature has now become one of the more significant characteristics in maintaining product quality throughout the distribution pathway. So, temperature has become a critical aspect of the supply operation that needs to be controlled in relation to the product. And the supply pathway for TSPs becomes a critical process that needs to be validated.

Assessing the Risk

According to the U.S. Census Bureau’s industry survey of the pharmaceutical preparation and manufacturing industry, in 1997, the biotech industry shipped $66.7 billion worth of products. In 2002 this had climbed to $114 billion, for an annual growth rate of 11.3% per year. Projections through 2006 would result in approximately $150 billion worth of biotech products shipped.

Given the fact that in 2002, 11 out of the 76 blockbuster products were biologicals and that biotechnology plays a key role in new drug discovery, it is no surprise that each year more and more emphasis is being placed on the importance of distributing these TSPs safely and effectively. Regulatory bodies around the globe are widening their regulatory reach. Industry observers consider the area of clinical development to be the next major area of government investigations and urge companies to focus on the design and implementation of processes and controls that will mitigate developmental risks.

This responsibility falls neatly into the lap of the organizations developing TSPs. While it is positive that risk responsibility is being assigned and that the issue is being given the attention it warrants, it is important that decisions and guidelines are not made or mandated prematurely. A deeper understanding of the myriad temperature profiles through which TSPs are transported is required, as is a more in-depth study into the complex dynamics of current distribution pathways.

For example, current practices by many cold-chain packaging providers use only generic tenuous thermal profiles to prequalify one-size-fits-all TSP packaging. At first glance, this approach may look attractive to many organizations wanting quick solutions. However, those that do research and map the thermal profiles through which their products must be distributed realize that a quick-fix generic approach falls vastly short of meeting individual distribution requirements for each of their TSPs’ unique thermal profiles.

Risky Business

Biotechnology and pharmaceutical organizations invest billions of dollars in R&D and in clinical trials annually. These companies need to move new products into the market quickly to obtain sufficient benefits from limited patent lives and to compensate for development costs. These firms are ultimately aiming to develop effective and safe treatments, while ensuring organization growth and continuity.

Given the substantial capital, the long development cycles, the value of biological products, and the risk to human lives, is a transport solution that has not been designed for your products, not developed to ensure performance throughout your thermal profile, and not thoroughly qualified as part of your master validation plan worth the risk?

A series of case studies over the next year will show how three organizations that have said ‘no’ to the above questions and have acknowledged the elephant in the room have implemented successful solutions for the transportation of their TSPs in partnership with EnviroCooler. The series kicks off in a future issue with a case study from Amgen.

EnviroCooler develops and provides custom-made thermally controlled shipping solutions. Since its inception more than 12 years ago, the company has patented science-based design innovations and robustly engineered testing methodologies, extending across the portfolio of solutions, from unit vials to pallets to cryovessel loads. Current partners include Amgen, Eli Lilly, ICON, CSL, Allergan, Smith and Nephew, BioRad, Baxter, Wyeth, Cook International, Fort Dodge, Dendreon, Boehringer Ingelheim, and Cell Genesys. Future articles will explore the solutions that EnviroCooler developed for these partners.

FDA Wants You in Control

FDA has thrown a lot your way lately. Bar code rules, RFID use for anticounterfeiting, and new electronic labeling requirements are just a few of the recent edicts to come out of the agency. As inundated as you must feel, don’t worry—FDA is not trying to micro-manage you. In fact, the agency may begin managing you a bit less.

Sound too good to be true? It is all part of FDA’s risk-based approach to regulation. During the opening address at Interphex 2004 in March, FDA deputy commissioner Janet Woodcock reported progress toward the agency’s initiative, “Pharmaceutical CGMPs for the 21st Century—A Risk-Based Approach.” Part of that risk-based approach is the use of emerging science to maintain product quality.

FDA knows that you know science better than it does. “We want to make sure that up-to-date science is incorporated in regulations,” Woodcock explained. “Manufacturers are much more advanced in quality systems than we are. We are looking at how GMPs stack up against modern quality systems.” (For more on Woodcock’s speech, see the news story on page 12.)

FDA’s latest feat in its initiative is its policy guide, “Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval,” released in March. It replaces “Process Validation Requirements for Drug Products Subject to Pre-Market Approval.” This new policy will guide agency staff during compliance decisions.

The agency’s Web site says that the new guide recognizes “the role of emerging advanced engineering principles and control technologies in ensuring batch quality. For drugs produced using these new principles and technologies, this [guide] provides for possible exceptions to the need for manufacturing multiple conformance batches prior to initial marketing.” In other words, manufacturers submitting NDAs do not necessarily need to submit three batches produced
at commercial scale as proof of process validity—a specific number of batches is no longer suggested.

During her speech, Woodcock said that since FDA and industry really have the same customer—the patient—the two can work together to achieve the same goals. “FDA regulates product quality. If processes are in control, then quality is under control,” she said.

FDA, therefore, will be watching to see how much control you have over your processes. And packaging is one of those processes. “We see nothing worse and more inefficient than batch inconsistencies,” she said. And all firms will be expected to demonstrate that they can maintain control. “For no product category will we give up inspections. It just means for some products, some inspections will be more intense.”

Perhaps the good news is that FDA won’t be so quick to tell you how to control your quality. “We now have a dispute resolution process whereby companies can appeal technical decisions,” said Woodcock. “We encourage people to use it. If our approach doesn’t contribute to the quality of your product, you should stand your ground. Science is about the open exchange of ideas.”

In other words, don’t hold back. Show FDA that you are in control.

Validation of the Thermal Modeling Process for Cold-Chain Shippers

One company shows a strong parallel between phase change simulations and actual data.

By Richard M. Formato, Cold Chain Technologies Inc., and Iftekhar Ahmed, Maya HTT Ltd.

In “Bringing Cold Chain Shippers to Market Faster with Thermal Modeling” (Pharmaceutical & Medical Packaging News, May 2008), we discussed Cold Chain Technologies’ (CCT) use of predictive thermal modeling to simulate multiple design scenarios to arrive at an optimal configuration before making prototypes and conducting chamber testing. A computer program used during the modeling process lets the user pass through a number of required steps, including analysis selection, geometry creation, element selection, boundary condition application, and program execution.

As this modeling process makes certain approximations and assumptions, model validation must occur before the process can be confidently utilized over CCT’s full array of products. This article discusses the thermal modeling validation process that is being undertaken by CCT to accomplish this task, along with some of its initial results.

Thermal Modeling Validation Method

To successfully simulate thermal packaging, modeling (and validation) of the complete transient thermal response must be completed. This validation process includes, but is not limited to, the following coupled areas:

• Phase change of refrigerant(transient).

• Free convection in shipper (transient).

• Conduction in shipper (transient).

• Payload geometry approximations.

• Material properties of shipper components.

By validating each of the above areas separately, the complete thermal package can be simulated with much more certainty. In general, the validation process consists of the following steps:

• Design and execution of experiment (data generation).

• Develop simulation to model experiment.

• Run simulation and generate results.

• Compare actual data versus simulation.

• Repeat above steps until data and simulation agree within desired tolerance.

Validation of Refrigerant Phase Change

Figure 1: 316F Foam Brick (back to back) Phase Change Experimental Setup. In this experiment, two CCT water-based foam bricks (CCT 316F, 7 × 5 × 1 in.) were placed back-to-back with three TCs in between them. (click image to enlarge)

Phase Change Experiment. A robust modeling process needs accurate simulations of phase change in thermal shippers. The phase change validation process began by designing a simple, controlled experiment to model the phase change process in a similar way to what actually occurs during shipping. In one experiment, two CCT water-based foam bricks (CCT 316F, 7 × 5 × 1 in.) were placed back-to-back, with three thermocouples (TCs) in between them, and secured together. This approach eliminates the need to insert the TCs directly into the frozen bricks, and makes exact TC geometric location easy to control. The taped brick assembly was placed into an environmental chamber at –20ºC, and once all three TCs verified that the bricks were completely frozen, the assembly was suspended in a temperature-controlled (ambient, 22ºC) chamber with the configuration and direction of gravity as shown in Figure 1.

The thermal response of the brick assembly, including phase change, was measured via TC, at the locations shown in Figure 1, namely: a) 1 in. from the bottom left corner, b) the absolute geometric center, and c) the midpoint between the geometric center and the top edge. The data were collected, and temperature versus time graphs were constructed for each of the three TCs and the chamber (ambient).

Phase Change Simulation and Comparison of Results. The brick geometry was generated via solid modeling software and input into the analysis program, along with the thermal properties—density, specific heat, and thermal conductivity—of solid ice. To account for phase change from solid ice to liquid water, thermal conductivity and specific heat variation with temperature were input into the program, along with the corresponding latent heat of fusion. The brick geometry was meshed using solid elements. The air surrounding the brick was assigned room temperature properties and meshed using fluid elements (perfect thermal contact was assumed between the two bricks).

Table 1: The location of each thermocoupling shown in Figure 1 can be referenced here. (click image to enlarge)

A 3-D transient thermal model, including both conduction and free convection was then executed. To replicate the above testing conditions, an initial condition of –20ºC was assigned to the entire solid brick volume, and an initial air temperature of 22ºC was assigned to the brick surroundings. The transient model was run for 14 hours, saving data every hour. Variations of fluid volume, brick mesh size, and solver time step were completed to determine a satisfactory trade off between accuracy and solve time. The results of the simulation, and the corresponding actual data for the three TC locations “A”, “B”, and “C” are shown in Figures 2a, 2b, and 2c, respectively.

As shown in the figures, the agreement between the actual TC data and the simulation results is reasonably good. The ramp rate from –20º to 0ºC and the phase change time for each TC location are close to actual data. As the phase change time is of critical importance, these initial results are certainly promising.

Figure 2a: Foam Brick Phase Change Data vs. Simulation for TC location “A.” The agreement between the actual TC data and the simulation shows the phase change time for each TC location are close to actual data. (click image to enlarge)

Figure 2b: Foam Brick Phase Change Data vs. Simulation for TC location “B.” Here, and in Figure 2a, the values of the simulations at the end of phase change are higher than actual data, but the trends appear correct. (click image to enlarge)

Figure 2c: Foam Brick Phase Change Data vs. Simulation for TC location “C.” Here the shape of the simulated phase change curve at the end of phase change is not accurate compared to actual data. (click image to enlarge)

To improve upon the simulation, however, deviations with actual data must be analyzed and corrected via compounding. In TC locations A and B, for example, the values of the simulations at the end of phase change are higher than actual data, but the trends appear to be correct. In location C the shape of the simulated phase change curve at the end of phase change does not match the actual data. These deviations can be explained by considering the material properties input into the analysis program. Specifically, the variation in specific heat with temperature was input into the program as a “step” function (one value for solid that is switched to a different value for liquid).

In reality, the specific heat versus temperature will be smooth, showing much more of a curve. As such, the shape of the transient simulation curve will tend to “mirror” the specific heat versus temperature curve input into the program. Specific heat versus temperature data are being generated at CCT, as part of the model validation process, and will be used during future simulation runs to further compound and validate the model.

Validation of Free Convection, Conduction, Payload Geometry, and Material Properties

Experiments, similar to refrigerant phase change described above, are being designed to extend the validation process to:

• Free convection.

• Conduction.

• Payload geometry.

• Material properties.

Free convection and conduction experiments will involve the use of simple geometry, known boundary conditions and initial conditions via thermal chamber, and continually improved material properties. Steady-state analysis will be used whenever possible. Payload geometry experiments will be completed and followed by simulation to determine the relative importance of free convection and conduction. The overall goal is to find how much detail is needed for solid modeling of the product load to obtain satisfactory results. Material property determination will include all key transient thermal characteristics—thermal conductivity, specific heat, and density—for the range of components used at CCT such as shippers, refrigerants, corrugate, and dunnage. It should be noted, too, that the above phase change validation process did incorporate free convection, even though that was not the focus of the validation work. This fact provides additional evidence for the robustness of the thermal modeling techniques being used by CCT.

Comparison of simulation results and actual chamber test data has shown that CCT now has the capability to reliably model phase change of its refrigerants in a stagnant air (free convection) environment. Additional phase change model compounding will be completed as material properties (for example, specific heat versus temperature) are further developed. In addition, this validation process can, and will be, extended to other key areas for shipper simulation, including free convection, conduction, payload geometry, and material properties. Once simulation of each of these individual areas has been completed, validation of total representative shipper solutions will follow.

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.

Checkweighers: Weighing the Options

Checkweighers can hardly be considered interchangeable. They vary greatly in size, function, performance, and price, depending on the applications they are used for and the requirements of the end-user. As such, pharmaceutical companies looking to add or replace a checkweigher in a plant must carefully consider exactly what they expect from the equipment.

Will the machine need to weigh contents before packaging or to weigh the package after filling? Often a technology that is optimal for one use is not necessarily optimal for another.

How accurate must the checkweigher be? Some models have tighter tolerances than others, and some drug products can withstand a greater margin of error than others.

Will it be used for every product or package as part of the production line, or will it be an off-line unit used as an occasional quality assurance/quality control measure or for a potentially problematic batch? In-line, every-product checkweighers tend to be larger, more complex, and more expensive than those that are off-line and used occasionally, so users must determine their needs before buying.

Will the checkweigher need to be networked with other equipment? Will it need to provide data analysis of everything that it weighs? Will it need to be validated? The more these requirements come into play, the more complex a machine may need to be.

ACCURACY

The KKE 2500 capsule checkweigher from Bosch includes an automatic fault clearance system and integrated data recording and evaluation.

Weigh cells are a popular checkweighing method, and often the most accurate, says Bill Kohl, product manager for capsule fillers and checkweighers at Bosch Packaging Technology (Minneapolis). "Our hard-gelatin capsule checkweigher uses a weigh cell," he says. "Other capsule checkweighers use capacitance, which sends an electrical charge across the capsule, measures the density, and converts it to weight. We actually weigh the capsules, which is a more reliable and more accurate method. The deviation for our weigh cell is 2 mg. It has a much tighter tolerance range than a capacitance weighing system, and the end result is a higher acceptance rate of filled capsules."

The configuration of the weigh cell is important, he says. "Something unique to our machine is that our weigh cells hang," he notes. "We surround the capsule placed in the weigh cell. Any powder that may have normally built up in a weigh cell would fall out. There are no dust deposits on the weigh cell and the electrostatic charge is not affected."

Thermo Ramsey (Minneapolis) offers a dynamic load cell, says Don Bina, marketing communications director. "All of our weighing is done dynamically, in-line," he says. "As the product passes a photo eye, the photo eye sends a signal to the scale to start weighing the product. As the product passes through, it is weighed thousands of times. The calculated average is digitized, the compression of the load cell times the rate of product across the load is devised, and it is averaged out as a digital readout. It is done very accurately, ±50 mg for the pharmaceutical industry. If a plastic container has 100 tablets and one is broken, we can detect it, and the bottle is rejected off-line. The checkweigher can now be used in everything from case sealers down to the finite weighing of blister packs."

Mark D'Onofrio, vice president and general manager, Lock Inspection Systems (Fitchburg, MA), says users must consider both accuracy and speed requirements, as sometimes increasing one means decreasing the other. "Our most accurate checkweigher can handle up to 200-g bottles, with accuracy to ±50 mg at speeds up to 100 bottles per minute. It can handle up to 300 bottles per minute, but then the accuracy decreases to some degree," he says.

To ensure high accuracy, D'Onofrio says that Lock's Weighchek checkweigher "takes raw signal data from the weigh cell and sends it into five digital filters. The output signal is processed at 400,000 samples per signal to ensure high accuracy."

IN-LINE VERSUS OFF-LINE

If an in-line system is needed, a number of logistical questions arise. How will the checkweigher be integrated with other equipment, and how will product be transported to and from the weigher in a way that ensures that accuracy will not be compromised?

"Getting bottles to and from the checkweigher can be difficult. Often, bottles are not stable because they have narrow diameters," says D'Onofrio. "If the bottle is not stable on the weigh cell, you can't be sure that you are getting good accuracy. It all starts with applications engineering. Companies that have done well with pharmaceutical checkweighers have experience with transfer systems that can take care of that problem."

D'Onofrio says that "the conveyor medium used at almost all pharmaceutical plants is the tabletop chain with a large plastic chain belt. Butting that up against a checkweigher creates a big gap. One way to resolve this is with a side-belt transfer mechanism. The vertical belt system grabs the bottle, carries it across the gap, and places it smoothly on the checkweigher infeed. Also, a timing screw can bridge the gap and create proper spacing."

To counter similar concerns with prepackaging weighing, Bosch has come up with a way to get capsules from the capsule filler to the checkweigher, says Kohl. "The transfer used to be done more or less by gravity, and the capsules would often fall 12 in. into the checkweigher. But if the capsule were brittle, it could break and spill on the weigh cell or in the machine," he says. "In the case of potent drugs, that could mean an exposure issue for the workers on the line. Now, we positively control the capsule. It is grabbed with mechanical fingers that advance it to the next stop, and a star wheel advances it to the weigh cell. Others use pneumatics that can become expensive because they require a lot of compressed air. Our unit uses very little compressed air, just for the accept/reject flaps."

There is no requirement, however, that 100% of pharmaceuticals be checkweighed, and some firms may not wish to have an in-line system and deal with networking and integration. If a manufacturer wants a checkweigher only as a quality assurance tool, it may want to consider an off-line model.

"We get a lot of panic sales from people who have gotten out-of-specification tablets and do not want to spend money on a big checkweigher," says Paul E. Schaa, president, AC Compacting LLC (North Brunswick, NJ), which distributes off-line checkweighers made by CI Electronics (Salisbury, UK). "The customers we get do not have to weigh everything they produce. In fact, some say that if you do that, there is something wrong with your process. Off-line models are for when you think you might have a bad batch, or are doing clinical trial manufacturing, and have to make sure the weight is dead-on. We offer it as an added-value benefit for contract houses for an added level of security."

Those that don't want a checkweigher as part of their line should strongly consider having one off-line, he says, because it is too costly to throw out a batch perceived to be bad when further verification might find it to be acceptable. "Tablet presses are accurate, but I've seen circumstances in which they don't always produce uniform tablets," Schaa says. "If the product shows variability, the checkweigher can save a batch. When tablet presses fail, these work."

ANALYSIS AND VALIDATION

With the increased emphasis on recordkeeping, users may find they need a checkweigher that can produce real-time data. Similarly, there is more need for checkweighers to be validated.

"More communication output data are required, as is validation of the systems," says Bina. "These newer products have validation procedures geared up for the pharmaceutical market. And we can provide validation services in our plant or at the customer's plant as part of aftermarket service."

Even the smaller, less complex models are often validatable now. Schaa says the validation for off-line models is "similar to how you'd validate a scale. You put a calibrated weight on and take it off, see if the checkweigher verifies it, and see if it zeros itself out after the weight's off. Some take samples of tablets and run them, but then you get attrition. If you keep using the same tablets, they will degrade and not give an accurate reading."

Complying with ISO 11607: What Will TIR 22 Do for You? Part II

In part two of a two-part series, the Sterilization Packaging Manufacturers Council offers guidance on designing and evaluating a packaging system for a medical device, keeping ISO 11607 and the AAMI TIR 22 close at hand.

By Jon Anderson, Director of Quality Assurance
Alcan Packaging

Jackie Daly Johnson, President
Beacon Converters Inc.
Cochair AAMI WG 7 Packaging

Dhuanne Dodrill, President
Rollprint Packaging Products Inc.
Chairperson, ASTM F02.50 Package Design and Development

Geoff Pavey, Principal Engineer,
Packaging Development
Oliver Medical
Richard Peterson
Senior Research Associate
Alcan Packaging

Dennis Redding
Senior Manager of Technology
Perfecseal, A Bemis Company

Marie Tkacik
Director of Technology
Tolas Healthcare Packaging
Chairperson, SPMC Technical Committee
Chairperson, ASTM F02.20 Physical Properties

The entire packaging system must be validated. Photo courtesy Beacon Converters Inc.

Continuing our review of AAMI Technical Information Report (TIR) 22, “Guidance for ANSI/ AAMI/ISO 11607, Packaging for Terminally Sterilized Medical Devices, Part 1 and Part 2,” we examine the characteristics for the validation of sterile barrier system manufacturing processes and final package design validation. We also identify the cases in which revalidation is required. The process begins with manufacturing and ends with the validation of the entire packaging system design as one integral unit. The final steps for demonstrating the effectiveness of the sterile barrier system must be proven through documented validation efforts. We also define the requirements for revalidation if acceptance criteria are not satisfied or should changes occur in materials, process, or design.

In part one, we reviewed the importance of identifying the proper design inputs and selecting and evaluating the right materials to provide a foundation for designing and evaluating an effective packaging system. We also discussed the design of the sterile barrier system and protective packaging as well as packaging process feasibility and sterile barrier system design feasibility evaluation.

VALIDATION OF STERILE BARRIER SYSTEM MANUFACTURING PROCESSES

A Google search of the Internet for process validation can yield more than 70,000,000 results. Surprisingly, at the top of that search list is FDA’s Guideline on General Principles of Process Validation, originally written in 1987. While one might compare the subject of process validation to chemistry (the subject matter just doesn’t change that frequently), the new 11607-2 standard and the accompanying TIR 22 provide new clarity regarding the requirements of process validation for manufacturing processes.

The basics for installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ) are the prerequisites for validation of sterile barrier system manufacturing processes. These topics are detailed in the standard and the TIR (Sections 11 and 12 and Annex G). The new TIR covers these issues in depth and provides step-by-step actions for engineers to follow, including the key requirements for documentation, inclusion of process stakeholders, and approvals by these same personnel. It also includes recommendations for process controls and process monitoring for the manufacturing process; these are becoming standard requirements for medical device manufacturers and their suppliers.

In the end, the output for process validation must be the same: a high degree of confidence that the manufacturing process will repeatably produce a package that meets the design specifications. The new standard and the TIR provide the medical device community a roadmap to complete this critical step successfully.

FINAL PACKAGING SYSTEM DESIGN VALIDATION

After the materials and equipment have been determined and the manufacturing process validated, it becomes time to validate the entire packaging system as a whole. This is the opportunity to prove that the entire system—process, package, sterilization, and device—can be validated as effective for the intended use.

Once again, the new TIR stresses the requirement to have a planned protocol in place, along with defined inputs, outputs, and acceptance criteria. The TIR provides the details necessary to thoroughly develop the actions and documentation to successfully prove the effectiveness of the entire system. It also includes plans for revalidation should the defined criteria not be met.

REVALIDATION

Revalidation is required when significant changes have been made to the device, the packaging system, the packaging process, or the packaging equipment. Revalidation is frequently addressed in the quality system procedures or the original validation protocol.

Periodically, the device, packaging system, packaging process, and test methods should be reviewed to evaluate whether the accumulated effect of multiple small changes results in a need for partial or total packaging system revalidation (ANSI/AAMI/ISO 11607-2:2006 Clause 5.7.4).

Conclusion

The process of designing and evaluating a sterile barrier packaging system can be complex. Fortunately, the medical device community has an established network of organizations whose members collaborate to create standards and forums that provide a compass for the navigation of this environment. The work of regulatory agencies such as FDA and organizations such as the SPMC, AAMI, ISO, IoPP, and ASTM International have all contributed to the new ISO 11607-1 and ISO 11607-2:2006 standard and the advancement of medical device packaging technology.

The addition of focused work groups such as AAMI WG7 support these standards and bring them to life for packaging professionals through the issuance of Technical Information Reports (TIR).

AAMI’s TIR22:2007 provides an excellent guide. Complex requirements of the standard are interpreted and explained to assist users in reaching compliance and consensus in the development of sterile barrier packaging systems.

The authors are all members of the Sterilization Packaging Manufacturers Council (SPMC) Technical Committee, as well as of ASTM, IoPP, and AAMI WG7 on Packaging. The SPMC is composed of leading manufacturers of sterilizable flexible packaging and materials. These companies work proactively and voluntarily as FPA-SPMC members to develop test methods and guidance documents for the flexible sterilization packaging of medical devices. SPMC member companies include Alcan Packaging, Amcor Flexibles Healthcare, Beacon Converters Inc., Oliver Medical, Perfecseal, Rollprint Packaging Products Inc., Technipaq Inc., and TOLAS Health Care Packaging. The SPMC is part of the Flexible Packaging Association. Visit the SPMC Web site at www.sterilizationpackaging.org.

Food and Drug Administration Amendments Act of 2007 (H.R. 3580—131)

ection 913: ASSURING PHARMACEUTICAL SAFETY

Source: http://www.fda.gov/oc/initiatives/HR3580.pdf

Chapter V of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 351 et seq.) as amended in section 403, is amended by inserting after section 505C the following:

SEC. 505D. PHARMACEUTICAL SECURITY.

(a) IN GENERAL.—The Secretary shall develop standards and identify and validate effective technologies for the purpose of securing the drug supply chain against counterfeit, diverted, subpotent, substandard, adulterated, misbranded, or expired drugs.

(b) STANDARDS DEVELOPMENT.—H. R. 3580—131

(1) IN GENERAL.—The Secretary shall, in consultation with the agencies specified in paragraph (4), manufacturers, distributors, pharmacies, and other supply chain stakeholders, prioritize and develop standards for the identification, validation, authentication, and tracking and tracing of prescription drugs.

(2) STANDARDIZED NUMERAL IDENTIFIER.—Not later than 30 months after the date of the enactment of the Food and Drug Administration Amendments Act of 2007, the Secretary shall develop a standardized numerical identifier (which, to the extent practicable, shall be harmonized with international consensus standards for such an identifier) to be applied to a prescription drug at the point of manufacturing and repackaging (in which case the numerical identifier shall be linked to the numerical identifier applied at the point of manufacturing) at the package or pallet level, sufficient to facilitate the identification, validation, authentication, and tracking and tracing of the prescription drug.

(3) PROMISING TECHNOLOGIES.—The standards developed under this subsection shall address promising technologies, which may include—

(A) radio-frequency identification technology;

(B) nanotechnology;

(C) encryption technologies; and

(D) other track-and-trace or authentication technologies.

(4) INTERAGENCY COLLABORATION.—In carrying out this subsection, the Secretary shall consult with Federal health and security agencies, including—

(A) the Department of Justice;

(B) the Department of Homeland Security;

(C) the Department of Commerce; and

(D) other appropriate Federal and State agencies.

(c) INSPECTION AND ENFORCEMENT.—

(1) IN GENERAL.—The Secretary shall expand and enhance the resources and facilities of agency components of the Food and Drug Administration involved with regulatory and criminal enforcement of this Act to secure the drug supply chain against counterfeit, diverted, subpotent, substandard, adulterated, misbranded, or expired drugs including biological products and active pharmaceutical ingredients from domestic and foreign sources.

(2) ACTIVITIES.—The Secretary shall undertake enhanced and joint enforcement activities with other Federal and State agencies, and establish regional capacities for the validation of prescription drugs and the inspection of the prescription drug supply chain.

(d) DEFINITION.—In this section, the term ‘prescription drug’ means a drug subject to section 503(b)(1).

System Reduces Cost, Improves Efficiency

Since the launch of its Mucinex brand of expectorants, Adams Respiratory Therapeutics (Chester, NJ) has become a strong company in the OTC respiratory market. Thanks in part to an award-winning advertising campaign that introduced U.S. consumers to the company’s animated Mr. Mucus mascot, Mucinex product sales have skyrocketed. The company—recently acquired by Reckitt Benckiser—needed to expand its manufacturing capacity and output to meet this increased demand.

Adams made a strategic decision to reacquire the manufacturing operations of the Fort Worth, TX, facility from Cardinal Health in July 2006. Adams’s goal is to turn the site into a center of excellence by including state-of-the-art packaging lines to meet the needs of its adult oral-solid Mucinex products.

For one of its new packaging lines, Adams had used desiccant canisters and dispensing equipment to protect its Mucinex SE, Mucinex DM, Maximum Strength Mucinex, and Maximum Strength Mucinex DM products from drug-formulation degradation. To improve production efficiencies, however, Adams decided to switch to Multisorb’s StripPax System.

The new system saved costs and added to much-needed production-line flexibility and mobility. Adams operations staff estimates that Multisorb’s StripPax System provided approximately $25,000 in monthly costs savings, by minimizing material costs and increasing production efficiencies. Consequently, Adams foresees an annual cost savings of approximately $300,000.

Rethinking Protection

Sidebar: Mr. Mucus

Chris Collins, a packaging engineer at Adams, said his team needed to ensure that new equipment and processes could handle the company’s revised output requirements without expanding production foot space. “Our sales have gone up dramatically over the past couple of years, and we realized we had to take a hard look at our packaging systems,” he says.

The other consideration for Adams was cost. To protect its products from moisture degradation, Adams was dispensing 1- and 2.5-g desiccant canisters in its adult oral-solid Mucinex bottles using dispensing equipment. The per-unit cost of the canisters was a concern, especially with the anticipated increase in packaging volumes.

Adams was also experiencing some quality-control issues with canisters used during dispensing operations. “We had problems in the past with machine jams,” Collins says.

Adams started looking at desiccant packets as an alternative to canisters. One of the options under consideration was the StripPax System from Multisorb Technologies (Buffalo, NY), which incorporates Multisorb’s StripPax desiccant packets and APA-2000 StripPax dispensing equipment. A simple review of the per-unit costs appealed to Adams.

Decision at Pack Expo Show

The Adams packaging team met with Multisorb technical and sales representatives at the 2006 Pack Expo International show in Chicago. APA equipment was in operation at Multisorb’s booth, and the Adams team was impressed with what it saw, particularly the APA-2000 StripPax dispenser.

“It was evident that Multisorb was an industry leader,” says Kevin Johnson, an Adams associate operations ERP/DAX.

Given the manufacturing demands for Adams’s production, the company needed to minimize the amount of time to switch over to the new equipment and run validation testing and training. Adams outsourced testing to SMB Validation and Compliance Services Group Inc. (Kirkland, Quebec, Canada), a validation and pharmaceutical engineering firm that has long worked closely with Adams.

SMB developed User Requirement Specifications (URS) for packaging equipment suppliers that included the usage, speed, rate, and desired ROI and cost-savings based on Adams’s needs. Multisorb responded to the URS, and SMB recommended Multisorb’s APA-2000 dispensing unit. The decision was based on cost savings and the ability of Multisorb’s technical staff to assist with validation, testing, and documentation. “We have validated Multisorb equipment in the past, and have been impressed with the company’s high level of service and documentation practices,” says David Buckley, validation engineer at SMB.

The APA equipment is designed to be used with StripPax packets, which are compact, nondusting packets that are accurately dispensed from StripPax dispensers at high speeds. Multisorb offers customized packets depending on the requirements for each drug formulation. For its adult oral-solid Mucinex line, Adams used 1-, 2.5-, and 5-g silica gel StripPax packets.

Factory Acceptance Test

Working within a short time frame, Adams required additional validation and factory acceptance testing (FAT) above and beyond what is typically involved for such equipment installations. “Adams wanted to minimize time spent on installation qualification by performing extensive testing during the FAT execution,” Buckley says. “We produced FAT documents that tested all equipment functions, and Multisorb was very cooperative and facilitated the process at their location. They obviously knew what was required from a current Good Manufacturing Practices (CGMP) point of view, rather than just from an engineering point of view.”

During the FAT testing, SMB performed high- and low-speed runs of multiple packet sizes, along with different bottle sizes (ranging from 100 to 625 c). The qualified accepted reject rate was specified at 0.05%. The end result, however, was even better. “We actually achieved reject rate during multiple qualification runs of less than 0.01%,” Buckley says.

In addition to cGMP, the testing was performed in accordance with Good Documentary Practices, and the documentation produced became part of the regulatory package, enabling it to be referenced rather than repeated once installed at Adams’s facility. “The process was painless; not a single discrepancy came out of the FAT, which is highly unusual,” Buckley adds.

The new packaging line became operational in May 2007, and so far the results have impressed Collins and his team. “The efficiency and reliability of this machine is very good and dependable,” he notes.

The APA-2000 StripPax dispenser is designed to dispense more than 300 units per minute, which is faster than Adams currently needs, but which will accommodate future requirements. Adams previously dispensed about 100 bottles per minute with its canister line, but based on new volume demands, the Multisorb dispenser runs at rates of up to 180 bottles per minute, with room for additional capacity in the future.

Small Size and Mobility

The dispenser occupies a relatively small footprint and is separate from the unwind system. In Adams’s facility, the dispenser operates in one corner of the line, and the unwind system stays out of the way until needed—a flexibility that maximizes available space.

The mobility of the unit has also proven to be an asset to Collins and his team. “We had some work to do on a conveyor, and we were able to take the machine off-line very easily, reducing our downtime,” Collins says.

Managing the higher volumes has kept Collins extremely busy. As Adams prepares for new product launches, the switchover to this system has helped the company in its efforts to extract greater efficiencies as it ramps up production.

Sterilization Validation of an Isolator System

Manufacturers who use vapor phase hydrogen peroxide–sterilized isolators need to take a comprehensive, ongoing systems approach to validation.

Anne F. Booth

Isolation technology has been developing rapidly in recent years. Implemented in the pharmaceutical industry to raise the sterility assurance levels of aseptically manufactured products, the technology is also finding a niche in the medical device industry. Isolators can be custom designed and built to segregate a specific process, allowing aseptic manipulation of products without human intervention. Isolators meet predetermined performance criteria, including a sterility assurance level (SAL) of 10^–3 to 10^–6, depending on the application.

One method used to sterilize an isolator is vapor phase hydrogen peroxide. There are four phases in the sterilization process. The process begins with dehumidification of the air in the isolator chamber. In the second phase, conditioning, hydrogen peroxide (H₂O₂) from a generator is vaporized and injected into the isolator at a high flow rate. The isolator is usually at atmospheric pressure, but may be operated under a vacuum. The dispersion efficiency and vapor uniformity of the H₂O₂ are critical to efficient sterilization, which is the next phase of the process. When sterilization is complete, an aeration process removes all traces of H₂O₂ from the isolator.

It is essential that all isolator systems are validated before use. Validation studies should include a qualification of the isolator and all associated equipment, including the H₂O₂ generator, which is separate from the isolator itself. The validation of the system should be documented by protocol and contain the same elements as the validation of any process: installation qualification, operational qualification, and performance qualification.

INSTALLATION QUALIFICATION

The installation qualification phase of the validation program consists of an engineering evaluation of all equipment. It should include detailed documentation of the isolator system, complete with dimensions, internal configuration, and all materials used in construction. Comparable documentation of the H₂O₂ generator should be done separately. In both cases, the description should include a diagram of the unit layout, with interface and transfer systems clearly indicated and their dimensions given. The following items should be included in the documentation:

• Equipment description.

• Manufacturer specifications.

• Construction materials.

• Instruments (including calibration status).

• Utility specifications.

• HEPA filter certifications.

• Computer software.

OPERATIONAL QUALIFICATION

For the system to be fully validated, both the isolator and generator systems must operate as intended, which is the purpose of the operational qualification. During this phase of the validation process, all sensors, indicators, and other critical components are tested to ensure that they are operational and properly calibrated. In systems where more than one isolator is used, each isolator should be checked independently. Data should be collected on all critical operational parameters that affect operation. During operational qualification, users should:

• Perform a mock run to check all cycle alarms and alerts in both the isolator and generator.

• Perform an integrity test to check for leaks, especially around transfer ports, gloves, and half-suit connections.

• Conduct a pressure test to ensure that positive pressure can be maintained in the isolator.

• Establish preventive maintenance procedures.

• Test for proper air exchanges.

• Verify cleaning procedures.

• Ensure that the piping system properly connects the generator to the isolator and the isolator to outside exhaust.

Operational considerations for the H₂O₂ generator should include an evaluation of each phase of the sterilization cycle—dehumidification, conditioning, sterilization, and aeration—and establish the reliability of the following systems:

• HEPA filter integrity.

• Computer alerts and alarms.

• Drier capacity and status.

• Sterilization cycle verification.

• Temperature distribution and mapping in the isolator.

• Uniform sterilant distribution using chemical indicators.

PERFORMANCE QUALIFICATION

The actual operation of the isolator system is initiated in the performance qualification phase, during which several initial steps should be performed to ensure success. To begin with, a determination must be made of the appropriate cycle parameters given the isolator configuration, room temperature, and loading. Isolator systems need not be installed in a controlled environment, but because most isolators are influenced by their environment, they should be located in a room maintained at constant temperature and relative humidity. Access to the system should be limited to trained operators.

Because the half-life of the H₂O₂ gas decreases as the mass of the material in the load increases, operators need to determine the maximum fixed-load requirements for their specific system before validating the isolator. Fixed-load configurations will vary depending on isolator size and specific functional requirements. In a sterility test system, for example, the isolator would contain sterility test supplies appropriate for the number of tests to be performed each day. Operators should fill each isolator with the identified items while ensuring that the loading does not interfere with gas distribution. Items should be placed on stainless-steel shelving and separated to allow the maximum diffusion of H₂O₂. The most effective sterilization occurs on the surfaces of unwrapped items, such as glass and metal, but surfaces of wrapped items can be sterilized when packaged in Tyvek. Paper or plastic bags should be avoided.

After the load configuration is determined, temperature mapping should be performed to determine heat distribution. This is conducted during the dehumidification phase (when the isolator air is circulated through a drier). Thermocouples are placed throughout the isolator and among the items. Heat-distribution analysis identifies any cold spots within the isolator, enabling operators to calculate the maximum safe concentration of H₂O₂ that can be used without causing condensation. H₂O₂ concentration is dependent upon the temperature of both the room and the isolator. A dehumidification setting of 20% should be established. In some climates, achieving set points lower than 20% can add considerable time to the total sterilization cycle.

Figure 1. Chemical indicator color-change range. Cumulative numbers of chemical indicators showing change.

During temperature mapping, chemical indicators (CIs) should be placed adjacent to thermocouples to evaluate gas distribution. The color change from white to gray-violet, which indicates increasing H₂O₂ concentration, is gradual but should be complete within 25 minutes (Figure 1). CIs should be placed under the gloves, in folds of half-suits, within the load, and in the corners. Uniform gas distribution can be enhanced using fans mounted within the isolator.

Figure 2. Vapor phase hydrogen peroxide (VPHP) and water concentration (milligrams per liter) versus time in minutes, with fans on (top) and off (bottom). Scale for VPHP measurements is on the left vertical axis of each graph; the water measurements are on the right vertical axes.

During these initial runs, the isolator should be closely observed for the formation of condensate. Condensation occurs when the gas concentration exceeds its saturation point at a given temperature. Condensation of H₂O₂ vapor indicates a gas concentration that is too high for the temperature within the isolator. Condensate can also indicate a situation similar to that seen when fans are not used: a less-uniform gas concentration in some areas causes the concentration to be too great for the isolator's temperature (Figure 2).

CYCLE DEVELOPMENT

Most generator manufacturers supply standard tables to aid in determining the proper H₂O₂ concentration. These tables indicate the maximum allowable concentrations for isolators of various sizes and take into account temperature, relative humidity, load mass, and flow rate. Using the tables, operators can select the proper cycle parameters for the dehumidification, conditioning, and sterilization phases.

Figure 3. D-value vs. steady-state hydrogen peroxide gas concentration.

In sterilization, the time in minutes required to reduce a microbial population by 90% is referred to as the D-value. Approximate D-values for different cycle parameters are available to isolator operators to help in the selection of appropriate injection rates and exposure times of H₂O₂. The D-value in most isolators falls between 2 and 5 minutes (Figure 3).

Once the proper cycle parameters have been determined, initial fractional H₂O₂ sterilization cycles can be run using biological indicators (BIs). The sterilization of all internal surfaces of the isolator, in addition to the external surfaces of the items placed inside, are validated as for any sterilization method, using resistant BIs. Bacillus stearothermophilus has been identified as the most resistant organism to H₂O₂ vapor sterilization. To validate to a SAL of 10^–6, BIs with a spore population of 10⁶ are used. It is possible that the carrier material for the BIs could absorb the H₂O₂; to prevent this from occurring, the spores should be inoculated onto stainless-steel coupons and packaged in Tyvek pouches. Also, the population of the indicators should be verified before validation.

At this point, operators are ready to determine the appropriate half cycle for H₂O₂ sterilization. One of two approaches can be used to accomplish this: users can perform sequential fractional cycles, increasing the gas-exposure time for each cycle, which is commonly practiced in EtO validation; alternatively, users can test exposed BIs in duplicate at intervals during a single gas exposure cycle. In the first approach, where all cycle parameters remain constant and only the gas-exposure time changes, the sterility of the BIs is tested after exposure to each fractional cycle; the gas-exposure time that yields a total kill of all the BIs is deemed the appropriate half cycle. In the second approach, users place media tubes and pairs of BIs in the isolator's worst-case location. At the start of gas inject and every 2 minutes thereafter, the BIs are placed in the media tubes. Meanwhile, controls are also exposed to assess the effect of the gas on the growth of the BIs. The time which produces total kill of all BIs is then selected as the half cycle gas-exposure time.

STERILIZATION VALIDATION

Once the half cycle gas-exposure time has been determined, three consecutive cycles should be run using BIs and thermocouples. Sterility testing should yield all negatives (no surviving BIs) to successfully validate the selected cycle parameters. The appropriate BI growth controls should all be negative and media growth promotion tests should be positive.

After acceptable sterility levels are achieved, a full cycle should be run to determine the time required to completely aerate the isolator. The goal during aeration is to reduce H₂O₂ gas to an acceptable level, typically 1.0 ppm or less. When injection of the gas ceases, the generator's catalytic converter breaks down the H₂O₂ gas into water vapor and oxygen. The aeration time depends on the isolator volume, the mass of adsorptive material, and the rate of outgassing from the materials. Creating higher air-exchange rates by using the generator fan can optimize aeration rates. Aeration efficiency can be routinely monitored in the sterilant return lines using a semiquantitative Drager gas detection tube capable of detecting H₂O₂ gas between 0.1 and 21 ppm.

Several times during the validation process, regeneration cycles may be required to remove humidity from the drying agent. This phase takes approximately 18 hours and should be performed overnight so as not to interfere with the scheduled cycle runs. The lower the drier capacity, the longer the dehumidification phase will be.

OTHER VALIDATION ISSUES

Several additional tests must be performed to demonstrate that the gas does not penetrate product containers, supplies, environmental samples, etc. Wrapping items in metal foil or placing them in a sealed container will prevent contact with the sterilizing agent, but note that wrapped items must be previously sterilized by other means since the H₂O₂ gas cannot reach the product. Both sterility test media and environmental control media must pass growth-promotion testing. It is essential to demonstrate that exposing the test articles to H₂O₂ sterilization does not interfere with the ability of the sterility test to detect low levels of organisms.

The maintenance of isolator sterility over time should be established and continually monitored. Monitoring should involve a schedule of routine sampling. For example, sampling could occur on the first day after isolator sterilization, on each subsequent day of use, and on the last day of operation. Surfaces can be sampled using premoistened swabs and with settling plates placed within the isolator during operation. It is always advisable to check the fingers of gloves and all transfer ports. Periodic inspection of gaskets, ports, and gloves to detect imperfections are also an important part of maintenance. Worst-case situation tests, including loss of power to the isolator or the transfer of additional supplies, also should be performed during routine sampling tests. And finally, since the primary route of contamination within the isolator is through the addition of supplies, special precautions must always be taken to ensure that only sterile items are added to the isolator.

BIBLIOGRAPHY

Akers, James E, James P Agalloco, and Colleen Kennedy. "Experience in the Design and Use of Barrier Isolator Systems for Sterility Testing" (paper presented at the PDA International Symposium, Basel, Switzerland, February 1994).

Amsco/Steris. VHP 1000 Biodecontamination System Cycle Development Guide. Mentor, OH: Amsco/Steris, 1991.

The Design and Monitoring of Isolators. Regional Quality Control Subcommittee of Regional Pharmaceutical Officers, September 1993.

Fritz, Claire, Don Eddington, and Dennis Cantoni, "Real-time Monitoring of Vapor Phase Hydrogen Peroxide for Cycle Development," American Glovebox Society Publication 11, no. 1 (1998).

Nieskes, Rick. "Validation of a Hydrogen Peroxide Gas Decontamination System for Isolators." The Booth Validator 2, no. 5 (1995).

Rickloff, James R and Joseph P Dalmasso. "Hydrogen Peroxide Gas Steril-ization: A Review of Validation Test Methods." Apex, NC: Amsco Sterilizer Co.

Rickloff, James R and Leslie M Edwards. "Modern Trends in Isolator Sterilization." In Isolator Technology. Eds. Carmen Wagner and James Akers. Buffalo Grove, IL: Interpharm Press, 1995.

Sintim-Damoa Kwame. "Other Gaseous Sterilization Methods." In Sterilization Technology: A Practical Guide for Manufacturers and Users of Health Care Products. Ed. Robert F Morrissey and G Briggs Phillips. New York: Van Nostrand Reinhold, 1993, 335—347.

United States Pharmacopeia. "Sterility Testing—Validation of Isolator Systems." In USP XXIII Informational Chapter 1208, Pharmacopeial Forum 23 no. 6, (1997).

Anne F. Booth is the principal consultant in her own firm, Booth Scientific Inc., a company that provides GMP and sterilization consultation for medical device manufacturers. She holds a master's degree from the University of Michigan and is an active participant in numerous industry organizations.

Photos courtesy of Steris Corp. (Erie, PA).