Thursday, 26 March 2009

Guide to Cleaning Validation in API plants Potential residues

The Active Pharmaceutical Ingredient Industry involves (in general) the manufacture of
Active Pharmaceutical Ingredients by both chemical and physical means through a
series of multiple step processes. Plants or individual pieces of equipment, including
ancillary equipment, may be used in multi-product manufacture or dedicated to
individual products.
The result of inadequate cleaning procedures is that any of a number of contaminants
may be present in the next batch manufactured on the equipment such as:
1. Precursors to the Active Pharmaceutical Ingredient
2. By-products and/or degradation products of the Active Pharmaceutical
3. The previous product
4. Solvents and other materials employed during the manufacturing process.
5. Micro-organisms
This is particularly the case where microbial growth may be sustained by the
6. Cleaning agents themselves and lubricants

Keep Your Products off the 2009 Recall List

In late December, Stryker announced that its Custom Cranial Implant Kits from its craniomaxillofacial (CMF) business unit were subject to a Class I recall. The company had originally initiated a voluntary recall in October after determining that the sterilization validation of the product was not performed according to appropriate standards, Stryker CMF reported on its Web site. The kits “could pose an imminent hazard to health,” the firm reported. “Because the company could not assure the sterility of the product, implantation could result in serious health problems including infection (e.g., meningitis), intracranial abscess, wound infection, sepsis. . . . Death can occur if an infection is not diagnosed quickly.”

These frightening scenarios brought to mind some conversations I had last year. A few industry experts worried aloud that some medical device manufacturers (MDMs) may not be doing all they should to validate their packaging and processes, let alone their package testing methods.

Granted, Stryker’s situation involved sterilization, not packaging validation. But given the crucial role of a primary package—i.e., the sterile barrier system—couldn’t inadequate packaging validations pose similar health risks?

I asked PMP News editorial advisory board member Tim Early, who spent 24 years working for MDMs and now provides packaging consultation and testing services, to describe package validation activity in the industry. Early is the director of business development for Packaging MD (, a division of Atlas Box & Crating (Sutton, MA). Early did not want to reveal any company names, but he did say that in many small- to medium-sized MDMs, packaging is not a core competency. “An R&D or manufacturing engineer is balancing packaging duties with other responsibilities. Companies that treat packaging as a core competency and have integrated packaging design, development, and validation into their product development process are in the minority,” Early says.

Corners may be cut when it comes to ISO 11607 compliance. Calling the standard comprehensive, Early says it details “all the requirements necessary to provide a validated sterile barrier system. No longer can a company simply seal, sterilize, and ship with no testing because they have been doing so for years with no history of complaints,” he says.

The risk these companies take is significant. Questionably sterile packages risk product safety and efficacy and patient health. “Also, when FDA issues a regulatory warning letter, it takes a few years before the MDM obtains clearance that the quality system’s deficiencies have been addressed and they can then move PMA submissions forward. Often, the time frame required to adequately address these issues results in product launch delays that cripple even the largest firms,” says Early.

In an era when Medicare is eliminating coverage of most hospital-acquired infections, perhaps the importance of the sterile barrier system—and validating that system—will take center stage in your company. If you can force packaging into the spotlight, you could keep your company from issuing packaging-related recalls, saving lives and money.

Daphne Allen

Sealers Offer More Control Than Ever

Touch screen controls and validatable systems make the packager's job easier.

Two benchtop tube sealers handle a wide range of tube sizes in short-run production cycles and are suited for laboratory, clinical trial, or sampling programs. The single-tube Model TC-L and multiple-tube Model TP-30 feature simple push-button operation. The machines uniformly crimp any laminated plastic tube up to 30 in. long by 12 in. high. The tube sealers are designed to serve as cost-effective laboratory-scale alternatives to larger, more expensive sealing equipment. Scientific Instruments & Technology Corp., Englishtown, NJ.

A fixed-speed, continuous hot-air sealer meets the requirements of FDA process validation guidelines. The medical sealer does not use Teflon-coated bands, which means less replacement cost and a decrease in downtime. The absence of bands also means fewer particulates in the cleanroom. The sealing temperature is fully PID controlled, and the seal pressure is air regulated, allowing for complete system calibration of the dynamic parameters that affect the seal integrity. O/K International Corp., Marlborough, MA.

A two-station medical heat sealer features the ability to control 10 of the company's heat sealers from one PC. The two-acquisition heat sealer is designed to meet the stringent process validation requirements of medical tray packaging. Operators can use the system's recipe management of setup parameters for fast, accurate changeovers. Alloyd Company, Inc., DeKalb, IL.

A validatable tabletop heat sealer is designed to provide high seal quality while remaining cost-effective. The MPS 6340 continuous rotary heat sealer is suited for lightweight applications of pouches up to 8 oz. Its adjustable head handles sealing angles from 0° to 45°. Teflon bands ensure high-quality, clean seals. The unit uses air-pressurized heating and cooling bars, and a fully digital control panel manages temperature, pressure, and speed. The MPS also offers audio alarms, an external thermocouple jack, and reverse feed for the validation of the sealing parameters. Emplex Systems Inc., Scarborough, ON, Canada.

Impulse bag-sealing equipment is fully validatable, requires no outside air, and uses a Hitachi microprocessor to measure the sealing parameters for ease of validation. The Fuji Impulse machine features a series of alarm codes to lock out the unit in the event that the desired sealing parameters are unable to be met. The medical pouch sealer is activated by a tray switch, a foot switch, or a user-defined semiautomated mode. Van der Stähl Scientific Inc., Wrightwood, CA.

A tabletop sealer provides many of the advantages of its larger counterpart. The standard PVT Med sealer comes with 20-, 25-, and 30-in.-long seal bars that provide a 5/16-in.-wide seal. Its high seal pressure provides consistent seals over a wide range of bag materials, and its selector switch allows the lower jaw element to be turned on and off. The PVT Med is validatable and calibratable. Packaging Aids Corp., San Rafael, CA.

A medical tray sealer has a powered shuttle to increase productivity. The validatable sealer features polished 304 stainless-steel construction and is equipped with powered shuttles that advance the tooling into and out of the seal press automatically. Process controls and alarms ensure that packages are manufactured to specified operating limits. Calibrated instrumentation includes contact dwell timer, temperature controller, thermocouple, and pressure transducers and gauges. EMD Products LLC, Libertyville, IL.

Heat sealers are designed primarily for the medical and pharmaceutical industries. The Models PW5200 and PW3600 precision sealers produce consistent seals and can be validated. The heat-seal band is also the temperature sensor, which ensures accuracy and repeatability. Time, temperature, and pressure are monitored with the RES-470 controller. Failure to meet the preset parameters will activate an alarm and shut the machine down. Packworld USA, Nazareth, PA.

Sealers for midrange volumes are available in models ranging from rotary tables to shuttle tables. The Series KST shuttle table features a dual servomotor press and shuttle action, which is suitable for a cleanroom environment. The KST allows for RF or thermocontact sealing and cutting, or a combination of both, allowing the sealing of a wide range of materials. Three sizes are available. A complete line of automatic standard and custom in-line machines is available for the packaging industry. Kiefel Technologies, Hampton, NH.

A medical tray sealer has fully integrated, network-compatible Windows NT data acquisition software capabilities that include real-time monitoring and recording of time, temperature, and pressure for every seal cycle. The BMPC medical tray sealer features a large, easy-to-read touch screen display, which simplifies setup and seal monitoring. The dual shuttle permits independent time and pressure setup to ensure flexibility and productivity. Belco Packaging Systems Inc., Monrovia, CA.

A tabletop heat sealer is designed specifically for medical device and pharmaceutical packaging. The Z-Med features a single-sided, aluminum roller shuttle tray with tool-locating pins to utilize quick-change-style seal tools. The standard machine includes controls and components to ensure that validation protocols can be established and seals can be consistent. The 15-TM dual-shuttle heat sealer features a color touch screen that stores data from the previous 25 cycles. The 15-TM is also equipped with pressure and temperature monitors, a scratch-resistant Teflon-coated hot plate, greaseless bearings, a low-pressure shutoff alarm, and a coalescing exhaust filter. Zed Industries Inc., Vandalia, OH.

A tabletop blister sealer has been designed with the entry-level and low-volume manufacturer in mind. The Model AS-1012 has a 10 x 12-in. sealing area and will accept blisters up to 3.25 in. deep. The unit features full controls, including a precision electronic temperature control, a main off/on switch, and an adjustable seal timer. The hot plate is Teflon covered to prevent packaging from sticking. Custom seal tools are available to accommodate customers' specific package designs. Visual Packaging Systems Inc., St-Laurent, QC, Canada.

A continuous dual-heat band sealer handles difficult-to-seal materials. The Model VBS-DH-3/8-10-V is designed for sealing medical devices in pouches. Its temperature, speed, sealing, and cooling-bar pressure can be validated. The unit can seal Tyvek/Mylar, nylon, polyethylene, polypropylene, laminates, Kraft/polyethylene, and foil. Seals are achieved with special heavy-duty, wear-resistant laminated Teflon bands. All Packaging Machinery Corp., Ronkonkoma, NY.

Validation and other process controls: Prioritizing remediation activities for on-market products

Donald M. Powers

Over the past few years, warning letter trends and other regulatory actions have signaled that FDA is increasingly targeting IVD companies for failure to meet contemporary validation standards. Ronald M. Johnson, executive vice president of Quintiles Consulting (Rockville, MD), contends that companies that have not kept up with evolving validation standards place themselves and FDA in a difficult position. "The agency cannot ignore potential threats to the public health," said Johnson at a recent seminar sponsored by the Institute for Validation Technology. "Companies that fail to identify and remediate these threats place themselves and the FDA in an untenable situation. FDA is forced to act." Johnson initiated numerous regulatory actions against device firms while he was director of the Office of Compliance at FDA's Center for Devices and Radiological Health (CDRH).

Manufacturing processes and test methods for products introduced since 1997, when FDA implemented design control requirements as part of its quality system regulation, should already be in compliance with the current validation standards. However, chances are good that products that have been on the market for many years have suffered from neglect.

In this regard IVD manufacturers are no different from the rest of the medical device industry. Companies already under FDA scrutiny, or whose quality metrics have raised warning flags about its process controls, or who treated validation as a perfunctory, one-time exercise, are likely skating on thin regulatory ice. To compound the situation for IVD manufacturers, the deadline for mandatory CE marking of IVD products is now less than two years away, and some company official will shortly have to sign a declaration that the company's products and manufacturing processes conform to the requirements of the European Union's IVD Directive.1

Companies should recognize that substandard validations and other inadequate process controls place them in a precarious compliance position. To avoid risking the consequences of a regulatory action, such companies need to know how to begin a remedial compliance program.

Remediation Approaches

When executing a remedial compliance program, device companies commonly use one of two approaches. The first is to assemble a team of product and process experts who can draw upon their extensive experience and knowledge to determine what needs to be fixed. Such a brainstorming session can often develop a compliance plan within a few hours. To execute the plan, the company will then spend the next year involved in an impressive (and costly) flurry of activity. In the end, the most obvious compliance gaps will have been closed.

A second approach is to assemble the same team of experts, but with a different goal in mind. In this case, the team is asked to map out the company's manufacturing processes, to examine them in detail, and to answer the following two questions.

  • Where is it possible for the company's processes to fail in a hazardous way?
  • What controls are required to ensure that the company's finished products meet specifications?

In this approach, the team uses recognized risk-assessment tools and actual experience (e.g., failure data) to guide its expert judgment. With the data provided by such tools, the team then identifies the essential control points, determines whether the right controls are in place, and evaluates whether the processes (including process verification methods and controls) are validated to contemporary standards. The deliverable product of this approach is documented evidence that the company's processes are in control and assurance that its products are safe and effective.

Although each of these two approaches probably requires about the same commitment of time and resources, why would a management team select the first approach? That method may enable a company to address obvious compliance problems, but it will not generate documentation sufficient to assure FDA that the company's processes are in control or that its products are safe and effective. Nevertheless, "brainstorming the compliance gaps" is precisely the approach that most companies in trouble choose to adopt.

Emphasizing the Essential

Ultimately, manufacturing must be in full compliance—which means that all processes must be either validated or fully verified. But if a company has been skating close to the edge of a compliance cliff, there simply isn't enough time to examine every process, test method, and software validation, and remediate them to today's standards. The next inspection could begin at any moment, and firms that are unable to demonstrate adequate control are in a precarious position. So the manufacturer's first priority must be to compile documented evidence that all its essential processes are in control—and that its products can therefore be considered safe and effective.

An effective approach to achieving this end is the risk-based product assessment and traceability (PAT) process developed by Quintiles Consulting.2 A cross-functional team is formed with representatives from the scientific, engineering, and clinical disciplines necessary to evaluate the product and associated manufacturing processes. The collective knowledge of the cross-functional team makes this a powerful approach. The process begins with identification of the essential user requirements for a safe and effective diagnostic assay, which are typically described in the product's labeling. Hazards to the patient are defined as failures to meet the essential user requirements, such as accuracy, precision, and other performance characteristics. The corresponding hazards would be inaccurate results, imprecise results, and so on.

To determine the essential control points associated with each process, the cross-functional team performs a top-down hazard analysis, such as fault tree analysis, and a bottom-up analysis, such as failure mode effects and criticality analysis (FMECA).3,4 By combining the use of these analytical tools, the PAT process minimizes the possibility that an important failure will be missed and helps to focus FMECA on the most important potential failures. To lend objectivity and credibility to the process, the team agrees on criteria for hazard severity, probability of occurrence, and detectability before starting the hazard analysis. Each point in the process that exceeds the predetermined risk criteria is defined as an essential control point. The essential control points identified in this way are traceable back to the product's essential user requirements.

To be complete, the risk assessments must consider all of the following elements of the manufacturing process.

  • Raw materials.
  • Production and control equipment.
  • Manual and automated processes.
  • Control and monitoring systems.
  • Test methods.
  • Product storage.
  • Distribution systems.
  • Operators.

The risk assessments should also encompass all elements of the diagnostic system, including reagents, calibrators, control solutions, instruments, accessories, and the end-user. Since the primary focus is on demonstrating that production processes are in control, product design issues might be considered outside the scope of the risk assessment for the moment. Nevertheless, adequate design validation is important to demonstrate that the product is safe and effective.

In its emphasis on risk analysis and essential control points, the PAT process resembles FDA's hazard analysis and critical control points (HACCP) method. In fact, the process borrows from HACCP principles and methodology.5 In the end, risk analysis and risk management simply represent common sense.

Although the design control sections of FDA's quality system regulation require manufacturers to perform risk analyses, design controls do not apply to products on the U.S. market if no design or process changes have been made since mid-1997, when the quality system regulation became effective. As time goes on, however, products exempt from design control requirements will be increasingly rare.

Perhaps more pressing is the timeline for full implementation of the European Union's IVD Directive, which has no grandfather provision for products already on the market. In contrast to FDA's quality system regulation, the IVD Directive requires manufacturers to conduct a formally documented risk assessment for all products sold in the EU after December 2003.1,6

Analysis of Essential Control Points

Once the essential control points have been identified, the cross-functional product assessment team then determines which quality attributes are critical to the manufacturing process and must be well controlled to prevent unacceptable failures from occurring. These are termed critical quality attributes (CQAs). For an IVD assay, examples of such quality attributes might be clarity, uniformity, solubility, stability, accuracy, specificity, homogeneity, precision, bioburden level, and so on.

At this point, the team is ready to examine existing process controls and determine whether they are sufficient to control the process's specified CQAs. In this part of the PAT process, the most important activity is systematically assessing existing process validations and verification activities associated with each essential control point, including test method validations, software validations, and equipment qualifications.

To ensure consistency among those doing the assessments, the PAT process uses objective compliance checklists. The completed checklists also provide documented evidence of compliance or remediation requirements. Checklist questions are based primarily on FDA and Global Harmonization Task Force (GHTF) guidance documents on process validation, the quality system compendium published by the Association for the Advancement of Medical Instrumentation, and current industry practices.7–9

Typical checklist questions address such validation requirements as whether acceptance criteria were predetermined, study designs were based on statistical rationale, worst-case conditions were challenged, protocols were approved prior to execution, instruments and equipment were qualified, the CQA was adequately addressed, documentation is complete, and other requirements were met. The assessor notes deficiencies along with recommended remediation activities.

During the risk assessment process, test methods used for product release are almost always identified as essential control points. If not, it is a good idea to consider release tests as such. Validation requirements for test methods in the medical device industry have not been defined as clearly as other process validation requirements. Although CDRH has not published guidelines for the validation of test methods, both the Center for Biologicals Evaluation and Research and the Center for Drug Evaluation and Research have endorsed the guidelines of the International Conference on Harmonization (ICH), which were designed for the validation of analytical test methods in the pharmaceutical industry.10,11 Since the same analytical performance characteristics and scientific principles generally apply to all analytical test methods used in the IVD industry, it makes sense for IVD manufacturers to adapt the ICH guidelines for their test methods.

Written operating procedures and work instructions are also important process controls. In the PAT process, checklists based on regulatory requirements and guidelines enable consistent and objective assessment of compliance. Questions address common deficiencies stemming from lack of such necessary elements as clear, unambiguous instructions; defined responsibilities; completeness; criteria for satisfactory completion of a task; and so on. Other controls, such as reference materials and standards, engineering drawings, blueprints, test fixtures, inspection and evaluation methods, and operator certification, are evaluated for their adequacy in controlling CQAs.

In addition to process controls and monitoring systems, product and process specifications should be reviewed against requirements and performance data to determine if a detailed specification assessment is warranted.

The Remediation Phase

Identifying essential control points provides a defensible rationale for giving higher priority to activities associated with their remediation, and for deferring remediation of less-essential process controls. But having defined an essential control point in a process, it is important to remediate any deficiencies with due urgency. After all, if an essential control point is not adequately controlled, what can be concluded about the safety and effectiveness of the product made by that process?

Most companies can expect to identify some deficiencies that must be remediated. The amount of required remediation work depends on the number of essential control points and the nature of the deficiencies.

A detailed remediation plan should include timelines, milestones, resources, and assigned responsibilities. At the same time, manufacturers should remember to take into account other quality system requirements—particularly those for corrective and preventive actions (CAPA) and design control. Since the deficiencies being addressed are quality system nonconformities, the remediation plan must tie in to the manufacturer's CAPA system in such a way as to comply with company procedures, ensure that potential consequences are adequately assessed, and receive active management oversight. And, of course, any significant changes to a product or its manufacturing processes must follow the established design control procedures.


Following a logical assessment and remediation process enables the company to systematically document its conclusions, decisions, and rationale. Such a process provides complete documentation about the selection of the essential control points. And perhaps more importantly, it documents the reasons that other control points are not considered essential for ensuring safe and effective product. The latter requirement is often overlooked.

The documentation produced by the product assessment team becomes part of the product's design history file, subject to review by FDA investigators and European competent authorities. It is therefore important that the completed project files document all of the following elements.

  • Credentials and participation of PAT team members.
  • Approved procedural instructions followed by the team.
  • Essential user requirements and corresponding hazards.
  • Predetermined hazard assessment criteria.
  • Hazard analysis results.
  • Quality data used to support the assessment.
  • Events that may have affected the team's assessment.
  • All issues identified and resolved by the team.
  • Evaluation of existing controls.
  • Remediation plan.
  • Remediation activities.

A set of integrated worksheets facilitates capturing all relevant information as it is developed, so that in the end a controlled product assessment file is compiled to tell the entire story. A complete file should exist for each product that was developed prior to design control requirements.

Achieving Full Compliance

Once essential control points are identified and remediated, companies may be tempted to stop. Although the GHTF guidance document allows a company leeway to decide whether a process requires validation based on risk, FDA has not accepted this strategy. Instead, agency officials have maintained that the quality system regulation requires all processes that cannot be fully verified to be validated.

For this reason, manufacturers should establish a plan to evaluate and remediate all other process validations to bring them into compliance. This plan can be carried out on a less-urgent basis, once the essential control points have been addressed.

Going forward, having a well documented product risk assessment will make it easier for companies to evaluate changes to manufacturing processes. Any change that modifies the validated design must be implemented under design controls. Once a firm has conducted and documented a baseline assessment for its existing products, each change can be evaluated for its effect on the state of control, using the FMECA scoring rules and risk criteria already developed. Following this procedure will provide the firm with solid evidence that its manufacturing processes remain in control after each change.


1. "Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on In Vitro Diagnostic Medical Devices," Official Journal of the European Communities L331 (1998): 1–37.

2. Product Assessment and Tracebaility Process Training Manual (Rockville, MD: Quintiles Consulting, 2001).

3. WE Veseley et al., Fault Tree Handbook, NUREG-0492 (Washington, DC: U.S. Nuclear Regulatory Commission, 1981).

4. Analysis Techniques for System Reliability—Procedure for Failure Mode and Effects Analysis (FMEA), IEC Standard Pub. 60812 (Geneva: International Electrotechnical Commission, 1985).

5. HACCP for Medical Devices [on-line] (Rockville, MD: FDA, Center for Devices and Radiological Health, 1997 [cited 12 February 2002]); available from Internet:

6. "Quality System Regulation," Code of Federal Regulations, 21 CFR 820.

7. A Shaw, Guideline on General Principles of Process Validation (East Brunswick, NJ: Center for Professional Advancement, May 1987) reprint in CDER Home Page [on-line] (Rockville, MD: FDA, Center for Drug Evaluation and Research, 1993 [cited 12 February 2002]); available from Internet:

8. "Process Validation Guidance," in GHTF Home Page [on-line] (Rockville, MD: Global Harmonization Task Force, Study Group 3, 1999 [cited January 2002]); available from Internet:

9. AAMI Quality System Compendium: GMP Requirements and Industry Practice (Arlington, VA: Association for the Advancement of Medical Instrumentation, 1998).

10. "Guideline for Industry: Text on Analytical Method Validation, Q2A," in CDER Home Page [on-line] (Rockville, MD: FDA, Center for Drug Evaluation and Research, 1995 [cited 12 February 2002]); available from Internet:

11. "Guidance for Industry: Q2B Validation of Analytical Procedures," in CDER Home Page [on-line] (Rockville, MD: FDA, Center for Drug Evaluation and Research, 1996 [cited 12 February 2002]); available from Internet:

Donald M. Powers, PhD, is president of Powers Consulting Services (Rochester, NY), an independent IVD regulatory and quality consulting firm.

Tamper-Evident Thermoformed Packaging

Users can reap the benefits of tamper-evident packaging without compromising sterilization quality.

by Pete Colburn, technical manager,
Cyro Industries (Rockaway, NJ)
Figure 1. Tensile elongation after E-beam sterilization

Medical device manufacturers can incur significant costs due to package failure. Additional loss is incurred when someone other than the intended user opens packaging to illegally retrieve valuable medical products.

Such tampering is not always apparent. External seals can be opened, removed, and discarded without trace evidence. Some materials can be cut open or punctured with little noticeable evidence of failure. As a result, tamper-evident packaging has become an important component of the medical and pharmaceutical industries.

Supplying Tamper Evidence

Alexis Swan, corporate contract coordinator for Yale–New Haven Hospital in New Haven, CT, deals with packaging-integrity issues with medical and surgical supplies. “One of the biggest issues of healthcare providers is the ability and need to maintain a sterile field,” she says. “You want to be able to open a package and introduce the product into a sterile field, making sterilization reliability very important. We assume that the package has an appropriate level of integrity, so it is important that if a package fails, the failure is obvious. The people handling packages in a hospital inspect them to ensure that the sterile barrier in the package has not been compromised. We must be able to see any type of failure in the package immediately.”

Figure 2. Notched izod impact strength after EtO sterilization

There are materials available that have been designed to show evidence of failure instantly, so that the judgment of sterile reliability can be made quickly and easily. Engineered compounds such as some acrylic-based multipolymer extrusion compounds are formulated to show that tampering with the rigid package is readily apparent.

Such compounds present strong evidence of tampering in two ways. First, if the rigid tray itself is tampered with, by tearing or cutting into it with a knife or even by sticking a needle through the sidewall, the material turns from a transparent blue tint to a highly visible, opaque white where the breach occurred. Second, once sealed, if the lidding stock is separated from the tray, the optical properties of the thermoformed compound make that seal separation evident by an apparent color change, even with the lidding stock laying against the tray edge. This is because the seal provides a certain amount of color depth when viewed through a specialized packaging compound.

Questions have been raised about whether such tamper-evident features could lead to packages being falsely identified as having had their integrity compromised, for example, after being knocked around during shipping. This is unlikely to happen. To activate the tamper-evident features, the package must be struck fairly hard. And if they are triggered, this should be a signal to check the package, not to dismiss it automatically as compromised.

Heat sealing forms strong visible bonds with rigid tamper-evident acrylic-based trays. A range of lid-stock substrates can be used to seal the trays, including coated Tyvek, manufactured by DuPont Medical Packaging (Wilmington, DE). The adhesive used with coated Tyvek is activated at 250°–265°F. When sealing with coated Tyvek, it is important to use a rigid material, such as a tamper-evident acrylic-based compound, with a thermoforming temperature well below this.

Streamlined Sterilization

Packaging materials should not yellow or become brittle after the sterilization process. Some materials may show some yellowing depending on thickness. Tamper-evident acrylic-based compounds may slightly yellow in packages 0.040 in. thick, but thinner gauges that are typical for packages (0.010–0.020 in.) will show very little color change, if any.

Ethylene oxide (EtO) sterilization temperatures can deform the shape of some packages but will not warp acrylic-based thermoformed trays. Acrylic-based products such as XT polymer can be used in packaging applications that are EtO sterilized without concern about package deformation due to the temperatures used in that process. EtO sterilization is generally done at temperatures in the range of 145º–165ºF. With a DTL (deflection temperature under load) of 192ºF, XT polymer is not affected by EtO sterilization temperatures. PETG products, however, have DTL values in the range of 145º–149ºF, and can therefore become deformed in the sterilization process if the temperature exceeds the DTL value.

Radiation sterilization can affect the mechanical properties of plastic compounds, but again, acrylic compounds exhibit no changes in mechanical properties up to 5 Mrd or 50 kGy of radiation. With gamma radiation, a material is considered to be significantly affected when it loses about 25% of its tensile elongation. This will occur with XT 375TE, the tamper-evident brand of XT polymer, at about 7 Mrd of radiation. Typical sterilization levels are 2.5 to 5 Mrd. When subjected to E-beam radiation, XT polymer retains its strength properties at radiation levels up to 75 kGy (Figure 1).

XT polymer shows significant impact strength and resistance to crack initiation and propagation both before and after EtO and E-beam sterilization. This resistance to cracking further demonstrates the ability of acrylic-based materials to maintain the integrity of the package when impacted in handling. While PETG materials exhibit high tensile elongation properties, their resistance to cracking is about 25% of that of XT polymer before and after EtO sterilization (Figure 2), and about 30% of XT polymer’s impact strength after high E-beam sterilization doses of 75 kGy.

An additional benefit associated with tamper-evident acrylic-based compounds is postpackaging sterilization. Once thermoformed, acrylic-based polymer trays can be filled and sealed before final sterilization of the contents and the package. A sealed acrylic-based package can be sterilized using gamma, E-beam, or EtO sterilization methods. This method of sealed-package sterilization ensures both the contents and the packaging are free of contamination, and avoids numerous component sterilizations and the need for a sterile packaging line. Final validation testing is required to ensure the medical components are sterilized effectively inside the package. Manufacturers looking to streamline their packaging operation and provide effective tamper-evident packaging can take advantage of this.

Improving Package Design

The ability of some compounds to be thermoformed over a wide temperature range allows the flexibility to use higher temperatures in order to obtain good definition on intricate parts without losing melt strength. Thermoformed rigid trays with deep-draw designs require a material with relatively high melt strength. Where deep draws can be limited with polyesters or crystalline materials due to their low melt strength, tamper-evident acrylic-based compounds can easily be thermoformed to draw ratios of 7:1 with good quality.

Package decoration can be an important component of design and validation. Decorating techniques can be used for a number of identification, information, or instructional purposes on thermoformed trays. Some thermoforming compounds contain lubricants that may interfere with decorating processes. Compounds such as acrylic possess excellent denesting properties and will not require silicone or lubricants to denest trays and prevent blocking. So lubricant interference with the decorating process is not a factor. Standard pad printing, screen-printing, and hot stamping techniques can be used with many extruded plastics. Acrylic-based inks are recommended for sharp graphics and vibrant color printing on acrylic-based substrates. Manufacturers seeking brand distinction or eye appeal in consumer arenas can use foil embossing decorating methods with rigid packaging trays.

A major trend that has taken root in the medical device and pharmaceutical industries is brand distinction. Acrylic-based thermoformed compounds offer manufacturers the advantage of embossing an anticounterfeiting holographic stamp into the packaging. The holographic embossing offers a clear visual anticounterfeiting validation for medical and pharmaceutical devices without adversely affecting the material’s tamper-evident or sterilization properties.

How Design Controls Affect Sterilization Process Development and Validation

Design control demands that all factors affecting a product's performance be considered before production. For sterile medical devices, that means the sterilization process should be addressed during each phase of the design control process.

Robert R. Reich

By this time, everyone within the medical device community knows that the new quality system regulation mandates design controls for many medical devices. Many in industry, however, may not fully understand how to incorporate manufacturing processes into the act of complying with design controls. This may well result from the fact that most manufacturers have long since subjected their manufacturing processes to process validation, as required by the now-superseded good manufacturing practices regulation. What's new is that under design controls, manufacturers are now required to undertake and document process development and validation early in the design phase for each and every applicable medical device.

The extent to which design control concepts are applicable to process development and validation depends on the nature of the process in question. The sterilization process, of course, is a critically important step in the manufacture of sterile medical devices. For that reason, it is subject to the design control requirements as outlined in section 820.30 of the quality system regulation.


The multifunctional design control process must involve many departments to be effective. This is especially true with sterilization. Sterilization cycles cannot be designed without input from the R&D and manufacturing functions, and conversely, designers cannot develop a safe and effective device without input from the sterilization function. Management with executive responsibility must play an active role in the design process by creating an environment where the concept of interdepartment communication and cooperation will flourish.

The effectiveness of a sterilization process for a specific medical device derives from the relationship between the robustness and the capability of the two proceses. Process robustness is the ability of the process to withstand product variations while maintaining its quality attributes­in this case a minimum, validated sterility assurance level. The process capability, by contrast, is a measure of the ability of the process to reproducibly manufacture product. In the case of sterilization, this means that the process for a specific device must be designed to be able to effectively sterilize a product or product family within the expected range of acceptable product variation.

The primary objective of design controls in the sterilization process is to ensure that an effective, reproducible cycle is routinely used to process a particular device or device family. Because of the importance of consumer safety in sterilized medical devices, risk management associated with sterilization cycle development is directed toward the ultimate safety of the processed device. Risk can be considered the probability of occurrence of a hazard causing harm; safety, the freedom from unacceptable risk. A 10­6 sterility assurance level (SAL; the probability of one nonsterile unit out of one million units processed) is generally considered an acceptable risk of nonsterility and is therefore used as a basis of sterilization cycle design.

The design control features of the new quality system regulation are outlined in section 820.30 and encompass the following elements:

  • Design and development planning.

  • Design input.

  • Design output.

  • Design review.

  • Design verification and validation.

  • Design transfer.

  • Design changes.

  • Design history file.

Many organizations have historically conducted sterilization validation studies under defined, preapproved protocols that used worst-case challenge conditions encompassing many of the concepts outlined in 820.30. Following the current domestic standards for sterilization validation­i.e., ANSI/AAMI/ISO 11135 for ethylene oxide, 11137 for radiation, and 11134 for steam­ensures that many of the elements of design control are addressed. However, the application of each section of the design control requirements may not be immediately obvious. The following discussion is intended to help clarify these requirements.

Design and Development Planning. This section of the regulation outlines the need for the design to be addressed in a plan prepared before starting the development process. For sterile devices, a sterilization master plan is often prepared that meets this objective. This plan usually addresses the equipment to be validated, defines in general terms the methodology and schedule to be used, outlines the responsible departments, and defines milestones where management reviews are required. The master plan is a dynamic document that should be updated throughout the product development life cycle. Copies of the plan and its updates must be placed in the design history file.

Design Input. FDA recognizes the design input stage, sometimes referred to as the requirements stage, as the basis of a successful sterilization validation program. The developers must match the product and packaging specifications to the sterilization process capabilities, taking into account such factors as gas access, material compatibility, safety, manufacturing process requirements, bioburden, and exposure. If requirements are not defined in this phase, the sterilization validation will be inadequate.

After being converted to specifications, the requirements of the design input stage should be testable. In the development of a sterilization process, these requirements are that the product have a defined SAL (10­6) and that both the product and packaging remain functional after sterilization. Since these requirements involve different aspects of product development, the input to a sterilization development program and its review are multidisciplinary, requiring the participation of R&D personnel, sterilization scientists, and packaging engineers.

Design Output. The design output stage supports specification development and results in establishing essentially all of the product specifications. Design output includes a description of the complete specifications and provides the basis for the development of the remainder of the device master record. In the case of sterilization, this should include a description of any restrictions on product or packaging temperature, moisture, or vacuum, as well as all the quality checks required for sterilization cycle control and monitoring. It should culminate in a description of the final sterilization cycle parameters.

Design Review. This stage occurs after each step in the design plan. The final cycle documentation must be reviewed and approved by the appropriate individuals, who should include as a minimum a sterilization engineer, a packaging engineer, an R&D engineer, and someone from quality control or regulatory affairs. A regulatory affairs specialist is especially pertinent if the intent or claim of the sterilization cycle validation program is to conform to a specific domestic or international standard.

Loaded cobalt 60 rods will provide gamma radiation sterilization.

Design Verification and Validation. It is common industry practice to validate all sterilization processes. This is commonly done under a comprehensive, preapproved protocol that clearly defines the acceptance criteria of the sterilization validation study and references a particular standard or guideline. The validation is performed under limit conditions or worst-case operating conditions and conducted with multiple lots or batches to demonstrate reproducibility.

The results of the sterilization validation must be detailed in a final report that is reviewed, approved, and signed. The final report and associated protocols should be permanently archived in the validation file, which should be a part of, or referenced, in the product's design history file.

Design Transfer and Changes. After the validation is completed, the specifications are transferred to a manufacturing function. This functional group is typically responsible for assuring that the validated sterilization cycle parameters are accurately incorporated into approved specifications.

Any subsequent design changes must be controlled through a formal change-control process. Any changes to the product-process specification must be subjected to the same level of controls and reviews as the initial development effort. That is, changes must be made under the design control requirements and reviewed and approved by individuals in the same functions and departments as those who approved the original design documentation. Changes to documents, such as correcting text or graphic errors or adding procedural text, must be made under the document controls section of the quality system regulation (820.40).


To effectively integrate sterilization process development and validation into a design controls program, medical device manufacturers may need to structure their procedures to integrate the additional review and approval steps at the appropriate intervals as defined in the regulation. While at first the necessity of these numerous review and approval steps may seem overly burdensome, redundant, and unnecessary, in the long run this comprehensive review process should lead to a reduction of errors and deviations. Adherence to these concepts will provide assurance that the sterilization cycle will be effective and will meet all quality requirements­which is, after all, the primary goal of all manufacturers.

Robert R. Reich is president of Pharmaceutical Systems, Inc. (Mundelein, IL).

Illustrations by Brad Hamann

Buying and Integrating Packaging Equipment

Machinery suppliers offer high-tech options, validation services, and anticounterfeiting features to meet manufacturers’ needs for more-complex, sophisticated packaging.

by John Conroy
Contributing Editor

MGS Machine Corp. offers end-of-the-line options, like the Stealth Cartoner.

Validation support, service bundling, and product safety remain daily concerns for the medical and pharmaceutical industry. Now, add the needs of an aging population, upgraded material-handling machinery, and a search for cheaper production materials to the list of potential trends affecting both packaging equipment providers and their customers.

Pharmaceutical companies are adjusting their product packaging to make it easier to open, and equipment providers are finding they, in turn, need to offer the proper systems to match their clients’ requirements, says Matt Croson, director of member services for the Packaging Machinery Manufacturers Institute (PMMI; Arlington, VA).

“From a pharmaceutical perspective, the biggest thing you’re seeing is much more marketing toward consumers,” says Croson. “That means packaging tends to have a little bit more of a direct marketing approach, whereas in the past you just had a straight bottle with the label on it.”

Croson says that drug manufacturers want packaging for older consumers that’s “a little easier to open and a little easier to close.” The trend is having an impact on the trade association’s 508 member companies. “There are a lot of one-dose units being produced,” he notes. “That’s a big challenge for operational procedures. Machines have to be very precise and fast and efficient.”

Tony Miller, marketing and product coordinator for Bosch Packaging Technology (Minneapolis) has seen this trend firsthand. “Everything is becoming more consumer oriented, and, yes, you do have to adjust your outlook,” he says. Cartoners in particular are seeing this rapid shift, where machines are required to place “two items in the same carton instead of having separate packaging. They’re adapting existing technology,” he says.
However, tinkering with existing toolsets soon will no longer suffice, Miller says. “In the next year you’ll start seeing machinery that’s more adept at doing the more-specialized [work].” He points out that the cost of producing a machine “to make one specific package is astronomical.”

Over the past year, PMMI’s members have seen an upsurge in sales of inspection and coding equipment, Croson points out. Between 2003 and 2004, sales of inspection and checkweighing systems have risen 8.4%. “There is a need right now to ensure the safety of the product throughout the production line.” Manufacturers are installing process automation and light readers for this purpose, he says.


Bill Leib, a senior packaging engineer with B. Braun Medical (Allentown, PA), says he’s seeing more tool suppliers offering validation services. Multivac recently installed a horizontal form-fill-seal system for B. Braun Medical’s line of fluid-transfer sets and epidural kits. “They offered a validation package that saved us a lot of time,” he notes. The information qualification process had been “pretty much all set up for us.”

Working on a new project, Leib is collaborating with a supplier to evaluate different and cheaper materials for blister pack webs, “where, basically, you’re getting more yield out of a pound of material.” He says B. Braun Medical is writing protocols in order to launch a pilot program by the end of 2004. “We’re going through a lot of testing up front to determine whether it will or won’t work.”

Two and a half years ago, Bosch Packaging Technology opened a division, called Valicare, dedicated to validation support, says Miller. “That part of the business has grown faster than any of the other parts of the business. It has done very well.”

Validation support is a “huge, huge issue” for customers, agrees Tim Allen, regional sales manager for the cartoning and case packing group of MGS Machine Corp. (Maple Grove, MN), which recently introduced the new Eclipse Intermittent Motion Cartoner. “One of the things I do see starting to happen in the industry is that customers are looking for total integration services.” Allen says MGS “has a lot of options to offer at the end of the packaging line.” Integrating services offers clients advantages over competitors that provide just cartoners or that lack a variety of infeed solutions, for instance.

Technical expertise alone, however, does not guarantee a competitive edge, Allen says. In his view, the pressure of meeting FDA regulations may even trump technical prowess. “It’s an evolving process,” he says. “One of the hard things to sell and to articulate to customers is that you don’t just buy a validation package. Customers must partner with a supplier that can provide you with correct documentation to assist in their validation process.”

IWKA PacSystems (Fairfield, NJ) combines validation services and integration, says Bernie Conlon, director of sales and marketing. “The ability to integrate a line at our factory allows the customer to have the factory acceptance test (FAT) protocol parallel the validation protocol. In this way, when the line passes the FAT, the customer can be assured that the validation at the customer facility will go smoothly.” IWKA, which recently introduced new blister packaging machinery, also offers 21 CFR Part 11 compliance as part of its standard validation package, Conlon points out.

This validation requirement extends to the code written to control the machines, says John Wenzler, packaging industry account executive with Bosch Rexroth Corp., a technology supplier separate from Bosch Packaging (Hoffman Estates, IL). “The IEC61131-3 programming standard includes the ability to create custom function blocks,” he says. “Once a machine is complete, the builder can have his code validated, and then encapsulate it in a password-protected function block. This block can then be used elsewhere on the machine, or in other machines without going through the certification process.”

Integration capability continues to run neck and neck with validation support as a customer requirement, Conlon notes. “As a German manufacturer, we find that customers want to take advantage of the fact that they can come to our factory and do one FAT of a complete or partial line.” Because the majority of pharmaceutical machine suppliers are European, clients can save both time and money by dealing with just one supplier, he says.

“They do not have to go to six European factories to do individual FATs before machines are shipped to the United States,” Conlon says. “We have seen this more and more over the last two years. We will integrate and take responsibility for the line. This gives the customer more time to focus on other issues. It also gives the customer confidence that the line will run when it is set up in the plant.”

Safety Concerns

Proper validation can ensure product approval, but once the product leaves the plant the risk of tampering remains. An Ohio-based company believes its updated line of sealing and die-cutting equipment can provide anticounterfeiting product safety. Peter Zelnick, CEO of Zed Industries (Vandalia, OH), says the industry has grown increasingly worried over the past two years about the integrity of wallet packages.

The adhesive can be a problem. “The adhesives that have been developed over the years are not being used because of environmental issues, or because of the Wal-Mart syndrome of trying to drive prices down,” Zelnick says. He asserts that adhesive properly applied “cannot be opened without destroying the package.” However, now that some companies have been shipping product with “cheaper alternatives,” rumors abound that black marketeers in Eurasian countries have been opening packages and replacing the contents with bogus product, he claims.

Zelnick says it has been difficult to manufacture a child-resistant wallet package “because you’re just pushing the medication through a foil or die-cut window, and it’s out.” Multifold wallets with three to four layers of paper are difficult to process at efficient speeds, he says. In response, Zed has developed an entire new line of equipment to meet 1-second or 1.25-second cycle times for speeds exceeding 300 wallets per minute and still offer anticounterfeiting and child-resistant features.

Called the HH series, the machinery can be fully automated, Zelnick says. He notes that clients are looking to automate their plants as much as possible in order to maintain production on shore. Medical customers reason that automation and workforce reductions can help lower costs when overhead and employee benefits remain unchangeable. Very little tooling is required to change jobs, Zelnick says, noting, “If you were changing blister or vial sizes or changing the literature, all within reason, you could use the system without changing parts.” As a result, the client can “tool up for less than $10,000.”

Regarding anticounterfeiting measures, Conlon says IWKA’s cartoning machines “can install labelers that will place a holographic label on the carton. Also, in our blister packing machine, a holograph can be used on the blister card lid stock.”

Robotics on the Rise

The semiconductor industry’s pain may be the medical device industry’s gain, according to Craig Howard, president of Zmation (Portland, OR). As its electronics industry sales have fallen in the last three years, Zmation has seen the medical device industry pump fresh blood into its business. Sales of the company’s robotics equipment to the medical device industry have risen steadily during the same period, says Howard.

In 2003, sales to medical device companies made up more than 50% of Zmation’s business. One of the main reasons for the increased sales is that “so much of our business used to be in the surface mount and computer-related industries, and most of that manufacturing left here so fast.” Zmation has always had a small but steady percentage of business from medical device customers, Howard notes. But, he points out, “In the last three years you really have seen our classic manufacturing industries just disappear or become extremely slow, and the reality is that the medical industry [business] hasn’t so much increased as it has remained steady.”

The industry, he says, has been immune to the downturn that hit the semiconductor sector. “Device manufacturing is one of the few industries where I can walk into a factory in the United States and see hundreds of people manually assembling parts. Almost all of the other industries that do that here are gone.”

Howard has seen “a lot of cross pollination,” as Zmation has picked up sales leads “from people in electronics and the SMT world.” In his automation market segment, “the semiconductor industry and the medical industry have more similarities than differences,” including the use of stainless steel and the obvious need for cleanliness, Howard says.

Machine efficiency is at the root of at least one new industry trend, according to Conlon. The development of servo motion control tools “allows each machine to share precise product position and speed data.” This capability ensures smoother product transition among machines than previously available.

“This new technology offers unprecedented speeds and efficiencies and overcomes some of the pitfalls normally associated with material-handling issues,” he says. “In some cases, it also allows transfer designs that simply were not possible with the previous generation of machines.” Rexroth’s Wenzler says the use of OMAC (Open Modular Architecture Controls) tools such as the PackML State Model and PackTags makes this machine-to-machine communication easier. “PackTags are naming conventions used for standard information needed from packaging machinery,” he explains. “If OEMs implement this convention, machine information flow can be accomplished easier, regardless of the control architecture.”

Wenzler says that in the same manner, the PackML State model is a controller-independent machine operation flowchart. “By using this template to develop the machine code, each machine will have a similar look and feel to the operator, regardless of the OEM or control architecture,” says Wenzler. “This openness allows customers to access information within the individual machines and gives them an increased level of interoperability between the machines on their production lines.”

Wednesday, 25 March 2009

You can transport temperature-sensitive products with confidence.

By Carli Derifield

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.