Pharmaceutical Validation

Tuesday, April 20, 2010

Steam Sterilizer Validation Requirements

For decades, steam sterilization (autoclaving) has been an integral part in the manufacturing, cleanroom, and laboratory processes for the medical device, pharmaceutical, biologics, and human tissue/HCTP industries. It has been a common industry practice to validate steam sterilizers using the published guideline ISO 11134 Sterilization of health care products — Requirements for validation and routine control - Industrial moist heat sterilization,¹ issued in 1994. In late 2006, AAMI released the document intended to supersede 11134, with ANSI/AAMI/ISO 17665-1:2006 Sterilization of health care products — Moist heat — Part 1: Requirements for the development, validation, and routine control of a sterilization process for medical devices.² While other steam sterilizer guidance documents do exist,^3,4 it is anticipated that the new 17665 standard will be recognized by the FDA and will be commonly employed to validate autoclave processes. The good news to manufacturers or other users of these guidelines is that many of the current validation practices are the same in the new document. This article will outline the basic requirements for steam sterilizer validation via the halfcycle overkill method, and list some of the differences between the two documents.

REQUIREMENTS PRIOR TO VALIDATION
The 17665 document makes it clear in numerous locations that the user’s quality system must adhere to ISO 13485:2003 Medical devices — Quality management system — Requirements for regulatory purposes.⁵ So if a user wishes to claim full compliance with the new 17665 steam standard, then their quality system must also be in compliance with ISO 13485, including items such as preventive/periodic maintenance and regular calibration for the sterilizer, documentation, change control, purchasing, etc. When compared with the previous steam document, the new 17665 also has more information on product and process characterization, sterilizing agent characterization, installation qualification/IQ, and operational qualification/OQ. The new document also states more clearly that a fully compliant validation is not just a series of successful halfcycles, but is the full complement of successful IQ, OQ, and PQ.
Sterilization agent characterization will be simple for most users — moist heat/steam at 121 or 132 °C, and cycle selection (gravity, prevacuum, etc.). Process and equipment characterization means defining and documenting items like the sterilizer cycle parameters, products (or product families) to be sterilized, load configurations and limits, placement of biological indicators or chemical indicators (BIs/CIs), process tolerances, and equipment identification. Much of this type of information would be recorded in well-written validation protocols or validation final reports. Biological indicators often use spores of the bacterial species Geobacillus stearothermophilus at a titer of greater than 106per BI, although other species or titers are sometimes used.
The new 17665 document also has more information on IQ and OQ. It defines IQ as “obtaining and documenting evidence that equipment has been provided and installed in accordance with its specification.” Autoclave installations commonly document items such as the sterilizer identification numbers, location, line voltage and amperage, water supply piping and pressure limits, steam line requirements, filtration, chamber size, structure and support, piping materials, software certification, manuals, drawings and documentation, and calibrations (temperature, pressure, and timer). The sterilizer must be installed in such a manner to facilitate any necessary maintenance, repair, adjustment, cleaning, and calibration.
OQ is defined as “obtaining and documenting evidence that the installed equipment operates within predetermined limits when used in accordance with its operational procedures.” Autoclave OQs commonly test or verify items such as cycle operation and programming instructions, safety and alarm testing, error reporting, empty chamber temperature profiling and chamber temperature limits/specifications, air removal testing, leak testing, temperature control anomalies, full cycle full-load temperature profiles (if proposed fullcycle exposure time is known), and determination of any hot or cold spots within the chamber.
The product definition and process definition sections of the new document list things such as product specifications, product families, packaging, re-sterilization issues, package moisture, stability and potency of container products, re-usable container systems, process challenge devices/PCDs, sterility assurance level/SAL, BIs and CIs, and bioburden determination if necessary. PCDs are described as products or items that provide a known resistance to the sterilization process. They are commercially available or may also be created from the user’s product line by inserting spore strips, spore dots, inoculated threads, etc. into items or locations that are determined to be the most-difficult-to-sterilize product or location in the load.
There are many other activities or decisions to be made prior to or during the IQ/OQ, that are not necessarily detailed in either standard. Items such as:

Obtaining calibrated temperature recording devices or thermocouples

Ordering supplies such as BIs, CIs, Bowie-Dick test packs, packaging materials, etc. and noting if adequate laboratory facilities are available

Determining worst-case validation load and worst-case test product or PCD. The protocol or final report should contain a written rationale describing how the loads and product(s) were selected

Selecting cycle type: 121 or 132 °C, gravity or prevacuum cycle, etc.; and determining if drying time needs to be qualified

Is product bioburden testing necessary?

Is product resterilization to be allowed and what are the requirements for resterilization?

Is product stability or shelf life testing necessary for the user’s products?

Does packaging testing or packaging validation need to be included with the protocol?

VALIDATION – PERFORMANCE QUALIFICATION
AAMI TIR #13 states “Sterilization process validation is a documented procedure for obtaining, recording, and interpreting the results required to establish that a process will consistently yield product complying with its predetermined specifications.” For the purposes of this article, the primary specification will be sterility. The performance qualification/PQ or microbiological qualification is a series of tests that establishes that the installed and properly operating sterilizer will process the users desired chamber loads to achieve the specified sterility assurance level/SAL. It must be remembered that the load is part of the validation — that is, if the user makes significant changes to the load at any point in the future — then re-validation may be necessary. The previous ISO 11134 document gave relatively little guidance information and few specifications for conducting the test cycles necessary to qualify the user’s proposed fullcycle exposure time(s). The new 17665 steam document varies little from the previous standard in respect to the minimal PQ information that is provided. The 17665 describes bioburden validation methods and the more commonly used halfcycle “overkill” method. It should be noted that at the time this article was prepared, the proposed guidance document that is to accompany ISO 17665-1 was not yet available. This guidance document may provide more advice on microbiological qualification issues (ISO 17665-2 Sterilization of health care products — Moist heat — Part 2: Guidance on the application of ISO 17665-1). For this article, the general requirements for an overkill cycle PQ will be reviewed.
While many activities are required to complete the PQ, the primary goal for the commonly employed overkill validation is this: the user needs to complete three consecutive successful halfcycles in order to qualify their proposed fullcycle exposure for routine processing of sterilization loads. In our case, successful means all BIs are killed (no growth upon incubation) for the three consecutive halfcycles. If, for example, there was no BI growth for the three test cycles at ten minutes exposure at 121 °C, then a 20-minute exposure at the same temperature would be adequate for routine daily processing, assuming all other aspects or requirements of the IQ/OQ/PQ are successful, documented, reviewed, and approved.
But a description of the PQ needs much more detail than this. Validation protocols vary in format from company to company, but most will capture similar information for the final report. An example of validation protocol and final report sections would be:

Title page with approval signatures

Purpose, background information, or general goal(s) of validation

Scope with more specifics about methods, cycles, facility, SAL, products and load, exclusions, etc.

References with published standards and company SOPs

Equipment, supplies, validation loads, BIs, etc.

Rationale for selection of products, load, cycles, PCDs, etc.

Procedure or methods (more details on this below)

Acceptance criteria which list the pass/fail requirements

Deviation report which lists any unexpected results, with potential effects on the validation, along with accept/reject rationale

Results and conclusions which assign a pass/fail decision to each acceptance criteria, summarize study, and include any requirements for revalidation

Attachment which lists any data sheets, diagrams, certificates, temperature records, etc., for inclusion with final report

Approvals section for final report.

To conduct the halfcycles, the user assembles the worst-case validation test load, temperature loggers, BIs/PCDs, and CIs if necessary. The temperature loggers and BIs are seeded throughout the load to represent various chamber locations, keeping in mind any cold spots or previously determined most-difficult-to-sterilize locations. For small chambers, as few as five or six BIs and temperature loggers may be needed. Ten is a common sample size for many chambers. Large, multi-pallet-sized chambers may require many more samples per run. The sterilizer is programmed for one-half of the proposed full-cycle exposure time. Upon completion of the test cycle, the BIs are immediately removed and incubated, and the test load must be allowed to return to normal temperature prior to starting another test cycle. Temperature recorder data is downloaded and printed immediately to determine if any unusual temperature conditions existed. Information is entered on the data sheets (data sheets that would have been one of the attachments to the written protocol), and all temperature records and data sheets are retained for the final report. BIs are checked regularly throughout the incubation period, and include positive control (unprocessed) BIs which must show growth. As stated before, all processed BIs must show no growth in order for the validation runs to be considered successful.
Final reports should contain: 1) all sterilizer run data or recorder charts, signed and reviewed; 2) all temperature recorder data, signed and reviewed; 3) all data sheets with BI, CI, or any other test results, reviewed and signed; 4) any deviations recorded and investigated, with final disposition; 5) results, conclusions, and discussion; 6) calibration documents for any measuring instruments used during the study; 7) the approved full-cycle parameters and acceptable placement locations for BIs for normal processing; and 8) manufacturers’ certificates of analysis for any items such as BIs, growth media, growth promotion test cultures, etc. Including digital photographs of sterilizer, load, PCD, etc. can be quite helpful for an auditor who may be reviewing the report at a later date. The completed final report packet must then be routed for review and signed for approval.
POST-VALIDATION
There are still issues to be addressed when all activities seem to have been completed. The sterilizer must be added to a regular and documented calibration program. The sterilizer must be included in a regular and documented periodic/preventive maintenance program. And the sterilizer must be added to the validation schedule for its annual requalification. The user needs to verify that all personnel that will be using the autoclave are trained using applicable operation and safety SOPs. Untrained staff should not be allowed to run the sterilizer. Approved products, loads, cycles, and load limit information must be readily available to all operators. SOPs for daily processing must list all requirements for data that is to be reviewed and retained from the sterilizer runs, with logbook, filing system, or archive for run records. SOPs must also address items such as 1) segregation of processed and non-processed product, 2) storage requirements for processed products if necessary, 3) notification of management or maintenance if sterilizer malfunctions or if recorder chart lists any errors, cautions, or warnings, 4) immediate notification of management for BI test failure, including investigation and product quarantine procedure as appropriate, and 5) resterilization requirements if resteril-ization is to be allowed.
In summary, there seem to be no drastic or revolutionary changes in making the transition from ISO 11134 to ISO 17665. The new 17665 steam document provides more information and more guidance in some areas, while leaving other areas (such as PQ) relatively unchanged. While users would be advised to obtain the 17665-2 guidance document when it becomes available, it is anticipated that manufacturers will not find any great difficulties in applying the new standard.
References

ISO 11134:1994. Sterilization of health care products — Requirements for validation and routine control — Industrial moist heat sterilization.

ANSI/AAMI/ISO 17665-1:2006. Sterilization of health care products — Moist heat — Part 1: Requirements for the development, validation, and routine control of a sterilization process for medical devices.

AAMI TIR No. 13-1997. Principles of Industrial Moist Heat Sterilization.

PDA Technical Report #1. Validation of Steam Sterilization Cycles. Parenteral Drug Association.

ISO 13485:2003. Medical devices — Quality management systems — Requirements for regulatory purposes.

Mark Dott performs consulting work in the areas of sterilization, sterilizer validation, and microbiology test methods. He can be reached at Mark Dott, LLC, Castle Rock, CO 80104; 303-437-49

Validating High-Purity Water Systems

By: Dan Laux
January 2001

In the production of pharmaceuticals, the most widely used raw material is water. As a raw material, high purity water is unique in that it is the only component, which must be produced by the manufacturer, because it is not available from a vendor in a ready-to-use form. Water is utilized in the production of every type of pharmaceutical; in some products, such as parenterals, it is a critical component. In such applications Water-For-Injection (WFI) systems are used to generate water for use in manufacturing applications.
Regadess of the system used to generate high purity water, under Federal regulations 21CFR 210 and 211, it must be validated. One of the primary references used in the validation of high purity water systems is the Parenteral Drug Association’s Tech nical Report No. 4, “Design Concepts for the Validation of a Water for Injection Sys tem.” According to the report,
Validation often involves the use of an appropriate challenge. In this situation, it would be undesirable to introduce micro organisms into an on-line system; therefore, reliance is placed on periodic testing for microbiological quality and on the installation of monitoring equipment at specific checkpoints to ensure that the total system is operating properly and continuously fulfilling its intended function.
So while there are several strategies that may be employed in the validation of high purity water systems, the following strategy contains all the necessary elements.
A Design/installation review. While not always considered an actual part of the validation process, the installation review is a critical step in ensuring that the validation is not put at risk and is successfully completed. Once the installation is finalized, a complete and up-to-date description and design drawing of the system should be added to the file and included in the final report. It is important that the design drawing include all components of the system and clearly identify all sample points and their designations. If the design drawing does not include these elements, the water system is considered to be in an “objectionable condition” and the validation is at risk.
It is advisable to review the design drawing annually to ensure that it is accurate and up to date. These reviews often identify unreported changes and are effective in confirming reported changes to the system.
B SOP development and confirmation. Once the system design and installation has been finalized, the next step is to develop the operational parameters and cleaning and sanitizing protocols. Once developed, these procedures become the SOPs for the system’s normal operation. During this step, data are collected over a period of two to four weeks, and samples should be collected daily after each purification step and from all points of use. At the end of the period, if the system has successfully generated water of the appropriate quality, these procedures are established as the water system’s SOPs.
C Demonstration of effectiveness. During this phase of the validation the objective is to demonstrate that the water system consistently produces water of the desired quality when operated within the parameters outlined in the SOPs over a long period of time. It is important that the data is collected in accordance with the SOPs. WFI system samples are taken daily at a minimum from one point of use and weekly from all points of use. This type of operation should identify any inconsistencies in the feedwater quality due to seasonal variations or other changes in the quality of the source water. A water system cannot be considered validated until the manufacturer has a year’s worth of operational data.
D Data compilation and sign-off. The final step in validating a high purity water system is assembling the data into a validation report. The final report should include all the data collected in Steps B and C, along with any conclusions derived from the data. Once the final report is complete, it is important to ensure that the appropriate personnel review and sign off on it.
Any validation strategy should include the elements outlined above: development of the SOPs through data collection, a demonstration that the SOPs are effective, and assurance that the system is capable of consistently producing, over a long period, water that meets the quality specifications. While including these elements in the validation strategy increases the odds of successfully validating the water system, even a well thought out strategy is susceptible to failure because of often overlooked details. The validation process is long and complex and small details can often be overlooked.
The following are some of the more commonly overlooked considerations:
1 Feedwater. During a water system validation, consideration has to be given to the quality and seasonal variation of the feedwater. In some instances, it is also beneficial to consider the quality of water in surrounding municipalities in the event that water must be diverted from an alternate, neighboring source. (Feedwater may be diverted as a result of such events as construction or an emergency such as a major fire. In such cases, the feedwater entering the facility may be contaminated with elevated levels or different types of flora.)
2 Air contamination. A common omission from SOPs is a list of the correct procedures to preclude contamination from non-sterile air after a water system is drained. Point-of-use piping extensions, particularly those that utilize tubing or hoses for application, can allow non-sterile air to come in contact with the system when the valves are not opened in the proper sequence. The SOPs should be reviewed to ensure that proper valve sequencing prevents contamination from non-sterile air.
3 Component design is an important consideration. While component design has become more sophisticated in recent years, each of the following system elements can benefit from further thought:
Carbon beds remove organic compounds from the feedwater. One of the most common organic compound removed is chlorine, which municipalities use to control bacterial growth in drinking water. Since carbon beds filter the organic material needed for bacterial growth, this material becomes concentrated in the carbon beds; if the beds are not properly maintained, they can harbor bacteria and endotoxins. Hot water or steam should be used periodically to purge the system of such contaminants. It is important that the SOPs include these maintenance procedures.
Holding tanks. The design element that causes the most concern vis-a-vis the holding tank is the vent filter. Most new tanks utilize jacketed vent filters to prevent condensate or water from blocking the hydrophobic filter. It is important that maintenance SOPs include procedures for regular checking of the vent filter integrity. For this reason, the filter should be located in a position that provides easy access for testing. The SOPs should also include complete flushing or draining of the holding tanks on a regular basis.
Heat exchangers should be designed to prevent distillate contamination from feedwater. Double tubesheet design and positive pressure are the two most common methods used; if positive pressure is utilized in the design, monitoring systems should ensure that higher pressure is constantly maintained on the distillate side.
Distillation stills are used in the production of WFI because they kill microbial organisms, deactivate endotoxins, and eliminate dissolved solids not removed by previous filtration steps. It is important that the condenser be designed with double tubesheet to ensure that the distillate will not come in contact with the coolant, thus preventing recontamination. Another consideration for distillation stills is the quality of the steam supplied to the process; the quality of the steam must be controlled to prevent recontamination.
Pumps. All pumps experience wear and some burn out; it is therefore important that the maintenance SOPs include a program for the upkeep of all pumps in the system. If a pump is not in continuous operation, the reservoir is a potential source of contamination; when the pump is not in use, water may collect in the low point of the pump housing, potentially harboring microorganisms. It may be advisable to install a drain in the low point of the pump housing.
Piping. Most WFI and other high purity water systems utilize stainless steel (SS) piping in their construction. Where low level metal contamination is a concern, polyvinylidene fluoride (PVDF) piping has been used in place of the SS piping. Systems utilizing PVDF piping, however, require additional support in the piping layout. While the system is in use, the circulation of hot water may reduce the rigidity of the piping, causing it to sag. In cases where the piping sags or bends, stress can create fissures in joints, which may result in leakage and/or contamination. Other considerations for the piping include the elimination of “dead-legs” and the use of welding or sanitary fittings for all joints and connections in the system design.
4 Microbial Limits. When establishing the microbial specifications for a high purity water system, the most commonly used reference is the USP 24 (Table 1). It is important to understand that the limits set forth by USP 24 are not absolute, and as such the FDA does not view them as pass/fail limits. Instead, they are viewed as action limits and in some cases may not be stringent enough. It is important that users take into account not only the USP guidelines but also their understanding of the dosage form in which the high purity water will be used when setting alert or action limits. In, for example, situations in which the final dosage form does not have a preservative system, more stringent action limits may be required to produce safe and effective products. Conversely, some dosage forms that have low moisture content may tolerate higher microbial levels and as such the action limits may be established at higher values.
In WFI systems it is possible that a system may pass either the microbial or endotoxin action limit but fail the other. It is therefore import that both endotoxin and microbial levels are closely monitored.
When alert and action limits have been established, it is imperative that the user have an SOP for investigating deviations. Once a deviation is detected, the user must investigate the cause, determine a corrective action, and assess the impact of the contamination on adulterated product. Throughout this process, the findings and conclusion should be documented and assembled in a corrective action report. Finally, there should be a process in place to confirm any changes to the system or SOPs as a result of the corrective action.
5 Cost of operation. While not a factor in validation, cost considerations are important. High purity water systems, which operate between 65Þ and 80Þ C, are generally recognized as self-sanitizing. While these systems cost more initially than “cold” systems, the savings realized through reduced operations, maintenance, and testing—and the prevention of potential problems—may make the investment worthwhile.
The quality of the high purity water generated by WFI and other systems is critical to the processing of pharmaceuticals. Validation of the high purity water system and close adherence to the SOPs are essential to maintaining the quality and integrity of the generated water. When conducting a high purity water system validation, considering the points outlined in this article will increase the odds of a successful validation and preserve the integrity of process water.

The Leaning of Thermal Validation

By: Kevin Bull
January 2010

Validation professionals spend extensive time validating temperature to ensure the integrity of controlled environments and to fulfill compliance requirements.
Pre- and post-calibrations—a necessary part of the process of thermal validation—typically take up 50-80% of the time it takes to map a given area. Carefully distributing and re-distributing thermocouple wires (after re-calibrating with each placement) is not only time consuming, it entails cessation of normal operations and—as this article will show—actually degrades measurement accuracy.
Despite a move toward ever leaner operations in regulated industries, thermal validation is one area that has eluded the cost and time savings associated with improving measurement technologies. In part, this is because of the imperative that cost-saving measures do not increase the risk of inaccuracy; especially when the application involves temperature-sensitive product and requires complete documentation.¹ This may explain why validation is still performed using thermocouples that require time-consuming preand post-calibrations.
The following article will discuss the major differences between thermistors and thermocouples, their appropriate measurement ranges, and give some real-world calibration statistics for thermistorequipped data recorders. These statistics provide evidence that the stability of thermistors supports their use in multiple validations with the benefit of time saved by fast deployment and the reduction of nonessential pre- and post-calibrations.
THERMOCOUPLES: A BRIEF HISTORY
Thermocouple systems have long been used for thermal validation. Their function is based on the thermoelectric effect discovered in 1821 by Thomas Seebeck, who found that when two dissimilar metals were joined and a temperature difference was present, a voltage was produced. Known as the Seebeck effect, this forms the basis of all thermocouples.
The modern thermocouple is composed of two high purity wires welded at the tip. Available in a variety of standard materials, Type T (Copper and Constantan) is used most often for thermal validation. However, a common source of error with thermocouples is separation at the junction point, which often occurs with repeated use. While most validation professionals have dealt with common problems like a break at the junction (J1, Figure 1), there are some lesser known subtleties in thermocouple function that have a large impact on their accuracy and usability in certain applications.
Any imperfections along the length of the wire also increase error. This is because the entire length of a thermocouple is a sensor. Thus, voltage is not only generated at the junction, but over the entire length of thermocouple.

THERMOCOUPLES: WHERE AND WHEN TO USE (AND LOSE)
Many applications (warehouses or walk-in chambers), require long thermocouple lengths. Unfortunately, the longer the wire length, the greater likelihood of degradation in the wire; the more imperfections in the wire, the greater the sources of measurement error in the sensor. Each imperfection in the thermocouple wire, created either at the time of manufacture or during handling, will cause “micro-thermocouples” to be formed along its length. This is because each of these micro-thermocouples produces a slightly different voltage per °C and thus introduces measurement errors.²
Thermocouples produce a small output signal; 40uV (microvolts) per °C of temperature difference.³ Such a small output requires a high amount of signal amplification (gain) in the measuring system, which often introduces measurement drift. These very small signals are also susceptible to external noise sources, a particular problem with long wires; therefore, the longer the wire, the greater the potential noise pickup.
Every junction of dissimilar metals produces a Seebeck- voltage when a temperature difference is present. For example, a copper to copper junction that has formed an oxide will produce a voltage 10 times greater (>500uV per °C) than the intended (thermocouple) junction (See Figure 2). This can produce one of the largest sources of error, swamping the measurement of the intended junction.
Another source of error comes from the secondary cold junction temperature measurement system, which is a necessity with thermocouples. Thermocouples do not respond to an absolute temperature, but rather, to the difference in temperature across the length; no difference will result in no output voltage.⁴ As a result, each thermocouple measuring system must have this secondary measurement system, with its own sources of error.
With so much potential for error, it is understandable why thermocouple systems need continual re-calibration during mapping. Potentially unstable when shifted from one application to the next, thermocouples must be calibrated before and after every single test run.⁵

THERMISTORS: WHERE AND WHEN TO USE (AND CHOOSE)
Many QA/QC and validation professionals have realized that, within certain temperature ranges, mapping with thermistor-equipped recorders can result in accurate test results in a significantly reduced time.
While thermocouples are the only way to validate extreme temperatures, in environments from -90°C to 130°C, thermistor sensors are far more accurate and stable. This is because they sense temperature by significantly changing their electrical resistance. In a thermistor-based system, a signal of 35 mV (millivolts) per °C is typical; nearly 1,000 times greater than a thermocouple- based system. The large signal results in a far more stable measurement. Also, the high resistivity of the thermistor allows a measurement lead resistance that produces a typical error of 0.05°C.⁶
A major difference in the measurement accuracy of thermocouples and thermistors is that the latter has no other dependencies. Thermistors produce an output which is proportional to the absolute temperature. This is why they are ideal for thermal mapping when placed inside a small data recorder that is equipped with a wrapping memory, a long life battery, a clock, and a microprocessor.
Although designed for more limited temperature ranges than thermocouples, thermistor-equipped data recorders offer numerous advantages such as faster setup, greater accuracy, long-term in-calibration performance, and data redundancy. Data recorders can provide temperature accuracies to 0.1°C and some models are tamperproof and 21 CFR Part 11 compliant.
WHAT THE CALIBRATION SHOWS: (ONE YEAR LATER)
One manufacturer of thermistor-equipped data recorders reported that of the 2,427 routine service calibrations they performed on temperature recorders that had been in the field for at least one year, 99.7% of the devices were still within published specifications. Of the failed calibrations (0.3%), none were out-of-specification by more than 0.12ºC; the average out-of-specification value being 0.036ºC.⁷ This performance is well within acceptable limits for most pharmaceutical validations.
These statistics show that the recorder/thermistor combination is a safe substitute for difficult and errorprone thermocouple systems in validation. Post-calibrations are normally performed to avert product implication should the thermocouple system reveal a future calibration error. However, when a more stable thermistor-based device is used, the need for post-calibration is eliminated, which is a substantial savings in time, personnel, and costs.
CHOOSING THERMAL MAPPING EQUIPMENT: KNOW THY TEMPERATURE RANGE
In any regulated environment, calibration is not optional. However, there is also no requirement for excessive calibration. The ultimate goal is to use a method that provides the highest degree of accuracy, at the lowest possible cost.
When choosing thermal validation equipment, buyers must obtain statistical data from the manufacturer that details recommended calibration intervals, product test specifications, and performance. Evaluating performance specifications on validation equipment will mitigate doubts over new equipment and protocols and justify the effort of changing over from an inefficient validation method.
As economic necessity forces regulated industries to periodically optimize their processes, eliminating waste is a constant challenge. Using data recorders equipped with thermistors for temperature mapping offers higher accuracy in temperatures from -90°C to 85°C,⁸ simple setup and operation, faster test completion, improved quality of data, and minimization of site disruptions.
The autonomy of thermistor-equipped data recorders (when they also have a self-contained power source and redundant recording), make them the ideal tool for large- and small-scale thermal validation projects. In addition, long-term stability of thermistors allow validation professionals to use the device for multiple validations, without spending excessive time on pre- and post-calibrations; the result being more efficient validations and significant savings in time and money.
References

GAMP® Good Practice Guide: Calibration Management ISPE (2001)
Kerlin, T.W. (1999). Practical Thermocouple Thermometry USA: Instrument Society of America
Temperature Measurement Thermocouples ISA-MC96.1 Instrument Society of America (ISA): (1982)
Manual on the use of Thermocouples in Temperature Measurement—4th Edition, (1993) ASTM Committee E20 on Temperature Measurement.
Daneman, H.L. Thermocouple Calibration – The Do’s and Don’ts of Good Practice (1991), NCSL Workshop & Symposium USA
Practical Temperature Measurements: Application Note 290: (2000) Reynolds, Geoff Aglient. Retrieved January 27, 2008, from
http://cp.literature.agilent.com/litweb/pdf/5965-7822E.pdf
One-year statistics from the calibration database of Veriteq Instruments showed that 99.7% of 2,427 data recorders, having been used in a variety of environments over a period of 10 to 14 months, were still within published accuracy specifications to 0.15°C.
Veriteq Instruments’ temperature accuracy specifications for thermistorbased data recorders are 0.15°C between the range of 20 to 30°C and 0.25°C between the ranges of -20 to 70°C.

Kevin Bull, CEO, Veriteq Instruments, Inc. 13775 Commerce Parkway, Richmond, BC, V6V 2V4; 1-800-683-8374. For further information, please contact jbennett@veriteq.com

Validation Requirements for Medical Device Manufacturing Controlled Environments

By: Scott Mackin
December 2004

Industrial sterilization and contamination control are critical in medical device manufacturing. This article reviews sterilization standards, FDA requirements, and critical factors in controlled environments.

Challenges Facing Manufacturers—Just What is Required ?
Having assisted scores of medical device manufactures in designing, implementing, and maintaining both their sterilization and environmental monitoring programs, we have found that the biggest challenge for the manufacturer is determining just what exactly is required. Device manufacturers have historically been forced to piece together a strategy which is coherent and defensible by choosing bits and pieces from an array of different standards, guidance documents, and corporate policies. For anyone other than a device manufacturing veteran, the task is daunting, and often times, no concrete program is implemented. Frequently, when programs are implemented, there is little confidence in their practicality or regulatory muster. When production operators do not buy into the value of the program, it often transitions to a system of documenting control failure rather than a program which demonstrates continued control and compliance.
Typically, larger companies will already have solid programs in place for commissioning new production areas, continued monitoring, and sterilization validation. Addi tionally, since many of these companies are experienced in considering and satisfying a melee of regulatory environments in order to market their products globally, their programs tend to be more comprehensive.
Particulate Characterization: Viable vs. Non-Viable
Since the early days of Federal Standard 209 (FS 209), requirements for testing air cleanliness and/or assigning cleanliness classes to clean zones, using measured levels of non-viable particulates, have been well defined. Initially, microbiologists and regulatory professionals struggled to draw some correlation between the levels of non-viable particles and viable particles present in the environment but a general consensus was reached acknowledging that no direct relationship could be defined.
Determining just what satisfies the microbial sampling requirement called out in many standards is often an ambiguous matter, especially in Class 10,000 (ISO Class 7) and 100,000 (ISO Class 8) areas. Since FS 209 has been sunset, the ISO 14644 series of documents have taken its place. ISO 14644 [1] is currently recognized as the worldwide standard for designing and validating controlled environments. The drafting of the ISO 14698 series of documents has provided manufacturers with concrete guidance in setting up the microbial portions of their programs. Still, the ISO 14698 (microbial) document stops short of providing a definitive method for determining just how much microbial sampling is sufficient. Many manufacturers elect to utilize the same calculation for their microbial sampling that is set forth in 14644 to sample for non-viable particulate. Even so, this still leaves the questions of what sample locations in the environment are most critical and what type of organisms (aerobic, anaerobic, fungal) must be recovered. This is open to interpretation and written justification must be provided in the overall environmental monitoring plan. Unfortunately, as sterilization validation programs rely more and more upon bioburden control and monitoring, this missing piece becomes even more critical.
Sample Plans: Written Justification vs. Selecting Sample Frequencies and
Volumes from Menus
Regulatory folks would almost always prefer to defer to a table or calculation for determining these parameters. When they are not available, the manufacturer must design their environmental monitoring scheme by identifying critical sampling areas such as product contact or manufacturing activities. The tendency is to err on the side of over-sampling. At first glance, this sounds like an easy solution but for many manufacturers it is simply not feasible from a cost or manpower perspective. The expense associated with purchasing, validating, and maintaining sampling equipment, supplies, and training personnel is often prohibitive especially because many sampling schemes and/or control parameters are verified somewhat infrequently, such as quarterly or semi-annually as set forth in ISO 14644 [2], especially in Class 100,000 (ISO Class 8) areas.
Validation: Controlling Cost and Validation Data
Before a room is commissioned, draw a flow chart that outlines which data is required for validation, and what the source for the data will be. Vendor coordination, responsibilities, and agreements need to be clearly defined and documented to avoid costly retesting. For example, during HEPA filter installation, most vendors will scan the filters and seals for leaks. This data is part of what is required in order to assign an ISO class designation to an environment; be sure to identify exactly what each vendor’s responsibilities are, what data they may or may not be generating, and whether it should be included in your qualification documentation. This can save both time and expense. ISO 14644 [3] offers an overview of important parameters of performance. It also provides guidance including requirements for start-up and qualification. Keeping the project on a timeline also helps to get your cleanroom online on time and to coordinate testing and equipment installations to coincide with the three ISO occupancy states.
Sterilization Method Selection: Coordinating Both Programs
The method of selecting the most appropriate sterilization method should not only be product material specific (gamma vs. EO) but should also be specific to the level of bioburden on the product and within the facility. There seems to be a growing awareness among device manufacturers that there is an important relationship between their environmental monitoring and sterilization programs. It comes down to bioburden and control of that parameter. This is especially true given the rising popularity of using the VDmax method for sterilizing products. In fact, ISO 11137 [4], 11737 [5], 13409 [6], and TIR 27 [7] all refer to the need to have in place an environmental monitoring program.
The push to use VDmax [8] initially involved mostly larger, well established companies. These were manufacturers with plenty of historical data regarding the normal ranges of environmental and product bioburden. It was easy to document justification for using the newer method. Experienced manufacturers could feel confident that the programs they already had in place were sufficient to support product bioburden control, reducing the potential of verification dosing failures. These days, we are seeing more and more start-ups and component manufacturers using the VDmax method on new product validations.
Impact on Cost
The use of VDmax significantly reduces the amount of product required during quarterly dose audit testing, which reduces the cost of testing. This makes the method especially attractive to start-up manufacturers. However, the method is not always the best fit for everyone, especially for companies without experience in controlling bioburden. AAMI TIR 27-2001 [7] clearly states that this method cannot be used when the estimated average bioburden for product is >1000 cfu. Cost and/or product savings can also quickly vanish during quarterly audits if problems due to high bioburden are encountered. It’s important to remember that the verification dose is performed at an SAL [9] of 10-1, and on a statistically smaller sample set. An influx of undetected resistant organism can ultimately result in retests, if not revalidation to another method, even in situations where the bioburden count itself did not increase over historical levels. This makes understanding the nature of the typical bioburden as important as the levels themselves. Trending seasonal bioburden variations and identifying in-house isolates a couple of examples of how we see manufacturers do this.
Critical Factors
There are a number of other factors which are an integral part to any bioburden control that are not always obvious to manufacturers.
Raw Materials: Precautions should be taken to ensure that external bioburden does not travel into the production areas along with components and materials. These materials should typically be removed from their original shipping containers, cleaned, and stored for staging in controlled areas within or adjacent to manufacturing suites. For example, every effort should be made to reduce or eliminate cardboard and paper products from the controlled environment.
Personnel Activities and Hygiene: There should be written and posted procedures for support of operations regarding proper gowning, hand washing, and of course basic microbiological principles involved in minimizing contamination from manufacturing personnel and their activities. Concepts as simple as where to stand while performing a particular function can have a major impact both on product and environmental bioburden. Training documentation should be in place for all personnel who will work in the manufacturing area. For example, it is common to require manufacturing personnel to execute some type of gowning validation, using touch plates or swabs, before they are deemed competent to work in the controlled environment.
Housekeeping: Similar to personnel hygiene, there should be written and posted procedures and training documentation. Close attention should be paid to cleaning materials such as mop heads and disinfectants, frequency of cleaning, and documentation of cleaning activities.
Unfortunately, there is not yet a single reference document for manufacturers to rely upon to design, validate, and demonstrate room class compliance. It’s not likely that one will be drafted any time soon. As anyone who’s been involved in the validation and monitoring process knows, the task would be monumental. The ISO 14644 series and the ISO 14698 documents have eased the task enormously and are indispensable resources for manufacturers of terminally sterilized products. The key is to bear in mind at all times that it’s really all about bioburden. We must step back and look at the manufacturing process, people, and environment as a whole when drafting our validation programs. By defining traffic patterns and identifying and limiting product and personnel contact areas, we can attain a solid understanding of bioburden. Characterizing, controlling, and understanding environmental bioburden levels and trends are the cornerstones to defining and implementing a solid environmental monitoring program which fully supports sterilization validation and release activities.
References
1 ISO 14644, Cleanrooms and associated controlled environments: Part 1: Classification of air cleanliness
2 ISO 14644, Cleanrooms and associated controlled environments: Part 2: Specifications for testing and monitoring to prove continued compliance with ISO 14644-1
3 ISO 14644, Cleanrooms and associated controlled environments: Part 4: Design, construction and start-up
4 ISO 11137: 1995, Sterilization of health care products: Requirements for validation and routine control—Radiation sterilization
5 ISO 11737-3:2004, Sterilization of medical devices: Microbiological methods: Part 3: Guidance on evaluation and interpretation of bioburden data
6 ISO/TS 13409:2002, Sterilization of health care products: Radiation sterilization: Substantiation of 25 kGy as a sterilization dose for small or infrequent production batches
7 AAMI TIR27:2001: Sterilization of health care products: Radiation sterilization: Substantiation of 25 kGy as a sterilization dose—Method VD max
8 VDmax: Maximum acceptable verification dose for a given bioburden and verification dose sample size.
9 Sterility Assurance Level: The probability of a microorganism being present on a product unit after sterilization
Scott Mackin is Manager of Technical Sales at MicroTest Laboratories Inc., 104 Gold Street, P.O. Box 848, Agawam, MA 01001. He can be reached at 413-786-1680 or at smackin@microtestlabs.com.

Steam Sterilizer Validation Requirements Per The New Standard ISO 17665-1:2006

By: Mark Dott

For decades, steam sterilization (autoclaving) has been an integral part in the manufacturing, cleanroom, and laboratory processes for the medical device, pharmaceutical, biologics, and human tissue/HCTP industries. It has been a common industry practice to validate steam sterilizers using the published guideline ISO 11134 Sterilization of health care products — Requirements for validation and routine control - Industrial moist heat sterilization,¹ issued in 1994. In late 2006, AAMI released the document intended to supersede 11134, with ANSI/AAMI/ISO 17665-1:2006 Sterilization of health care products — Moist heat — Part 1: Requirements for the development, validation, and routine control of a sterilization process for medical devices.² While other steam sterilizer guidance documents do exist,^3,4 it is anticipated that the new 17665 standard will be recognized by the FDA and will be commonly employed to validate autoclave processes. The good news to manufacturers or other users of these guidelines is that many of the current validation practices are the same in the new document. This article will outline the basic requirements for steam sterilizer validation via the halfcycle overkill method, and list some of the differences between the two documents.

Obtaining calibrated temperature recording devices or thermocouples
Ordering supplies such as BIs, CIs, Bowie-Dick test packs, packaging materials, etc. and noting if adequate laboratory facilities are available
Determining worst-case validation load and worst-case test product or PCD. The protocol or final report should contain a written rationale describing how the loads and product(s) were selected
Selecting cycle type: 121 or 132 °C, gravity or prevacuum cycle, etc.; and determining if drying time needs to be qualified
Is product bioburden testing necessary?
Is product resterilization to be allowed and what are the requirements for resterilization?
Is product stability or shelf life testing necessary for the user’s products?
Does packaging testing or packaging validation need to be included with the protocol?

Title page with approval signatures
Purpose, background information, or general goal(s) of validation
Scope with more specifics about methods, cycles, facility, SAL, products and load, exclusions, etc.
References with published standards and company SOPs
Equipment, supplies, validation loads, BIs, etc.
Rationale for selection of products, load, cycles, PCDs, etc.
Procedure or methods (more details on this below)
Acceptance criteria which list the pass/fail requirements
Deviation report which lists any unexpected results, with potential effects on the validation, along with accept/reject rationale
Results and conclusions which assign a pass/fail decision to each acceptance criteria, summarize study, and include any requirements for revalidation
Attachment which lists any data sheets, diagrams, certificates, temperature records, etc., for inclusion with final report
Approvals section for final report.

ISO 11134:1994. Sterilization of health care products — Requirements for validation and routine control — Industrial moist heat sterilization.
ANSI/AAMI/ISO 17665-1:2006. Sterilization of health care products — Moist heat — Part 1: Requirements for the development, validation, and routine control of a sterilization process for medical devices.
AAMI TIR No. 13-1997. Principles of Industrial Moist Heat Sterilization.
PDA Technical Report #1. Validation of Steam Sterilization Cycles. Parenteral Drug Association.
ISO 13485:2003. Medical devices — Quality management systems — Requirements for regulatory purposes.

Mark Dott performs consulting work in the areas of sterilization, sterilizer validation, and microbiology test methods. He can be reached at Mark Dott, LLC, Castle Rock, CO 80104; 303-437-4946, dottmj@mho.com, www.MarkDottLLC.com.

Cleaning Validation Issues For Combination Devices

By: Ed Kanegsberg, Barbara Kanegsberg and Jeff Phillips
March 2008

Manufacturers of medical devices or of pharmaceuticals or biologics know that establishing a cleaning validation protocol is a challenge. Combination devices that combine traditional device substrates with an active drug delivery system present unique regulatory and assembly challenges. There are critical considerations in customizing cleaning validation protocols and in both defining and maintaining appropriate surface quality.
REGULATION OF DEVICES AND DRUGS
As with any medical device or pharmaceutical product, quality must be carefully controlled and is regulated. A challenge for combination devices is that the quality regulations for medical devices and drugs must be met simultaneously. In the United States, different portions of Federal regulations govern pharmaceuticals and medical devices. Pharmaceuticals are regulated through 21CFR210/ 211. If the drug is a biologic, derived from living organisms, it is regulated through 21CFR610. Medical devices are regulated through 21CFR820. Pharmaceutical manufacturing must use and document current good manufacturing processes (cGMPs).¹ Medical device manufacturing requires a quality management system (QMS).² With cGMP, the “how-to” of the process is specified; with QMS, the emphasis is on “how do we know that it is correct.”
FDA is required by Section 503(g) of the Federal Food, Drug, and Cosmetic Act (FDCA) to assign a lead center that will have primary jurisdiction for pre-market review and regulation of a combination product. The FDA has addressed the area of combination devices and has established the Office of Combination Products (OCP). The OCP neither reviews nor specifies any methods to validate the cleanliness or safety of a combination device. The OCP is primarily a steering organization, designed to determine which branch of the FDA should have primary jurisdiction over a new device. The OCP performs this assignment by determining the primary mode of action (PMOA).³ That is, it determines whether the primary mechanism for the device is pharmaceutical (e.g., delivering a drug) or a medical device (e.g., keeping an artery open). It also determines which of these mechanisms poses the greatest challenge to demonstrating safety and considers several other factors. Based on these determinations, the OCP assigns an application to the FDA division most suited to review it.
The PMOA may not always provide a good basis for selecting which of the requirements stated in the drug, biologics, and device regulations should apply to a particular combination product in specific circumstances. Whichever FDA division reviews the application, for the product to be manufactured successfully and reliably, the device fabricator must be exquisitely concerned with the surfaces and with contamination control.
IS IT CLEAN ENOUGH?
The answer may be yes for classic implantable devices. The question needs to be rephrased: is it clean enough now that a biologic or pharmaceutical is present? Issues arise as to how the combination of biologic and classic materials impacts the cleaning process and also how cleaning impacts the interaction of the drug and product with each other. Related issues include when to clean, how to clean, and how to minimize contamination during assembly.
Proximal to the biologic or pharmaceutical
One area involves preparing the surfaces immediately proximal to the biologic or pharmaceutical. In general, surface residue must be minimized to a level that assures that the biologic or pharmaceutical will not be compromised. This may make a difference in the activity of the medicine due to local or possibly systemic immune responses the body may have to the medical device portion of the combination device.
Materials compatibility must also be reconsidered. Any cleaning or manufacturing process has the potential to react with or to modify the surface. The challenge for combination devices, as well as for other newer medical devices, is to define what the surface ought to look like. Perhaps a limited, controlled level of surface modification or controlled incompatibility is called for. For example, trace amounts of residue are often removed by plasma cleaning immediately prior to application of a specific engineered coating. Plasma cleaning might be the appropriate surface pre-treatment prior to application of certain pharmaceuticals or biologics. Plasma also has the potential for surface modification; this attribute is often used advantageously as a sort of controlled incompatibility. Chemical cleaners containing caustics, corrosives, or chlorine often modify the surface of devices that may positively or negatively impact the system as a whole. Some surface modification may make implantation easier in one example but weaken the device in another. Also, this change may alter the interaction the drug has with the device. It likely becomes a more complex issue to select cleaners when they are being used on combination products. An MSDS alone may not contain all the relevant information needed to determine the impact of a cleaner on the device. Therefore, being able to partner with a knowledgeable supplier becomes more important.⁴
In essence, for classic devices determining appropriate surface qualities or attributes has in part involved historical, pragmatic performance. Testing has often been for general levels of contamination, for example, total organic carbon and non-volatile residue. In contrast, for combination devices, it is important to understand and document the appropriate surface proximal to the pharmaceutical. Documenting the appropriate surface will involve more specific analytical characterization and metrics.
CORROSION/EROSION
Corrosion is a natural process. It cannot be prevented, only forestalled. Corrosion and corrosive products have the potential to negatively impact combination devices. In combination devices, corrosive products can interfere with functionality. Corrosive products are perhaps most productively thought of as contaminants or as an undesirable surface modification. Control of corrosive product means detection at the micro-level⁵ along with appropriate protection of the surface. Any cleaner or disinfectant used with iron containing alloys should not contain chlorine.
CLEANING VALIDATION
When the variable of a drug delivery system is added, it is appropriate to reassess the approach to validation of the cleaning process. Specifically, the level of surface residue, the location of surface residue, the chemical nature of the residue, and the potential for interaction with the pharmaceutical must be determined. Given the large number of variables involved in cleaning, validations for combination devices are best accomplished through a risk-based approach.
Thin-film residue
Minimizing thin-film residue is of increased importance with implantable devices. Residues from detergents, organic solvents, and from other process chemicals that might be insignificant in classic implantables must be reassessed in terms of the potential to alter or to inactivate the biologic or pharmaceutical. This is especially true when dealing with biopharmaceuticals and the issue of bio-films that may form as a result of contamination from water lines.
Particulates
Particles can interfere physically with drug delivery systems; they can also interfere chemically. Defining and maintaining a low level of particles in the cleanroom is important but will not necessarily assure the absence of particles on the surface.
Outgassing
Plastics, elastomers, and epoxies can adsorb alcohol and other solvents. The release of such solvents is often assessed for many classic devices. For combination devices, determination of residual adsorbed solvent will become even more important to assure that the pharmaceutical is not inadvertently altered.
CLEANING PROCESS DESIGN
Initial cleaning process design is important to assure a reliable, consistent process. For example, minimizing outgassing involves selection of the appropriate cleaning agent. Many high boiling solvents are readily adsorbed into plastics. Even additives to aqueous cleaning agents have the potential to outgas. Determining the drying or bakeout time that is adequate to drive off residual cleaning agents and then allowing additional time as a safety measure can be helpful. However, heat can also modify the surface. Therefore, using cleaning agents where the ingredients are well defined and well supported by the manufacturer becomes increasingly important.
The cleaning process must be clearly defined. For large, classic medical devices, cleaning more and cleaning more forcefully may be a reasonable practice. For combination devices, and for other advanced, micro devices, over-cleaning may result in undesirable surface modification. Under-cleaning may leave interfering residue.
This takes us back to cleaning basics. Cleaning has three steps: washing, rinsing, and drying. The cleaning agent, the cleaning action or force, the temperature, and the elapsed time cannot necessarily be extrapolated from performance with classic devices. Instead, the process must be reevaluated for combination devices to assure that the surface is not compromised and that undesirable residue does not remain.
This includes the quality of water used. Issues of cleaning and the type of water used for medical device or pharmaceutical may be different than those in the combination product. The use of water for injection may be considered to cut down on water born biobur-den and/or endotoxins.
DESIGN FOR MANUFACTURABILITY
Classically, devices have been designed by one group and manufactured by another. The two groups (the product designers and the product manufacturers) worked independently, in isolation, and sometimes at odds with each other. A design may be functionally exquisite, but if manufacturability is not considered, the product may be a logistical nightmare in terms of assembly, cleaning, and contamination control. It is encouraging that the device designers and the manufacturing groups are meeting early on in product development. This is a desirable trend not only for combination devices but also for medical devices in general and for many other high-value products. When combining metals and plastics, moisture retention may be an issue partially due to different coefficients of thermal expansion that can cause varying gaps, allowing intrusion and trapping of water. This trapped moisture could then be a source of biocontamination.
STERILIZING
For combination devices, cleaning cannot be an afterthought; and the same holds for sterilization. Selecting the appropriate method for sterilization for combination products can be a challenge. Steam may be an alternative to ethylene oxide in some instances.⁶ Changing the physical state of the bio-portion of the device, for example through lyophilization, may be an option in some instances.⁷ Given the diversity of materials in combination devices, it is reasonable to expect that customized sterilization regime will be developed and validated.
Radiation sterilization may be a more complex issue in combination devices. Radiation may not only alter the structure/activity of the drug (small or large molecule) but may affect the release of drug in certain cases. Radiation normally affects polymers in two basic manners, both resulting from excitation or ionization of atoms. The two mechanisms are chain scission, a random rupturing of bonds, which reduces the molecular weight (i.e., strength) of the polymer, and cross-linking of polymer molecules, which results in the formation of large three-dimensional molecular networks.⁸ Plastics that are absorbed must be checked for structural and chemical alteration after gamma sterilization. An example is the network structure formed after irradiation reduced significantly the OFdUrd (oxobutyl-5-fluoro-2-deoxyuri-dine, an antitumor agent) release from EVA [poly(ethylene-co-vinyl acetate)] films. In this manner, the radiation dose applied to the polymeric matrix modulated the release of OFdUrd, avoiding the high concentrations that may cause severe systemic toxicity.⁹

ORCHESTRATING THE ASSEMBLY
For combination devices, the specifics of the assembly process, the cleaning process, and the sterilization process must be coordinated early on in product development (Table 1). This holds true especially if manufacturing is to be out-sourced. It involves an understanding of the following:

Materials compatibility
Stability of biological materials
Surface quality
Critical cleaning
Sterilization
Sources of contamination
Approaches to minimizing contamination

Contamination encompasses microbes, endotoxins, and any organic or inorganic material that could impact product per formance.
In summary, remember that a combina tion device is a way of getting the best of two worlds, a medical device and an on board drug delivery system. However, get ting to those worlds involves understanding the contamination pathways that could affect either of those worlds and dealing with them in a way that does not compro mise the other. In addition, there can be pathways that are unique to the combina tion of these worlds and, therefore, would be new even to people who are well versed in both technologies separately.
References

B. Kanegsberg and E. Kanegsberg, “Contamination Control and cGMP”, Controlled Environments Magazine, Feb. 2008.
B. Kanegsberg and E. Kanegsberg, “Recent Developments in Medical Device Cleaning and Standards”, Controlled Environments Magazine, Jan. 2007.
Federal Register: August 25, 2005 (Volume 70, Number 164) Pages 49848-49862
http://www.fda.gov/OHRMS/DOCKETS/98fr/05-16527.htm.
B. Kanegsberg, “The Joyful Dawn of a New Era”, Process Cleaning Magazine, May/June 2007.
B. Kanegsberg and E. Kanegsberg, “Must it Rust, Part II: Microbial Corrosion”, Controlled Environments Magazine, July 2006.
W. Rogers, “Steam: Uses and Challenges for Device Sterilization,” MDDI, March, 2006. http://www.devicelink.com/mddi/archive/06/03/003.html .
V. Reitz, “The Best of All Worlds,” Medical Design, Sept, 2006. http://www.medicaldesign.com/articles/ID/13166.
K. Hemmerich, “RADIATION STERILIZATION Polymer Materials Selection for Radiation-Sterilized Products”, MDDI, February, 2000. http://www.devicelink.com/mddi/archive/00/02/006.html .
Alvaro A.A. de Queiroz, Gustavo A. Abraham, and Olga Zazuco Higa, “Controlled release of 5-fluorouridine from radiation-crosslinked poly(ethylene-co-vinyl acetate) films”, Acta Materialia Inc. Published by Elsevier Ltd, Volume 2, Issue 6, November 2006, Pages 641-650.

Barbara Kanegsberg and Ed Kanegsberg are independent consultants in critical and precision cleaning, surface preparation, and contamination control. They are the editors of The Handbook for Critical Cleaning, CRC Press. Contact them at BFK Solutions LLC., 310-459-3614; info@bfksolutions.com; www.bfksolutions.com.
Jeff Phillips is a primary investor and Principal Consultant with Atzari Consulting.He has established and performed cleaning processes and procedures including cleaning validations in the pharmaceutical and medical device industries.He can be reached at jeff@atzari.com.