The Growth Of ODTs

By: Liesbeth Meeus

Orally disintegrating tablets (ODTs) are growing in popularity and their market value could exceed $13 billion in sales by 2015, based on current global growth trends.¹ Market studies have indicated that more than half of the patient population prefers ODTs to other dosage forms.² Most consumers would also ask their doctors for ODTs (70%), purchase ODTs (70%) or prefer ODTs to regular tablets or liquids (over 80%).³
The growth in the popularity of ODTs reflects the growth in the elderly and infirm population, who often find it difficult or unpleasant to take conventional tablets. ODTs separate in the mouth in contact with saliva, making it easy for a person to swallow the tablet without drinking water. They are also a convenient dosage form for other people, such as business travellers, as they can be taken without water, or for those who need to take tablets to combat travel sickness.
Over the past few years, there have been several innovations that have improved the appeal of ODTs. Key developments have been improvements in the speed of dispersal of ODTs, as well as the growing use of non-hygroscopic, zero-calorie sweeteners, with taste-masking properties, which have helped ODTs to be more palatable. Improvements in the dispersion speed will, in turn, facilitate higher drug loading. This can be combined with a well-selected binder to retain the non-hygroscopic profile, resulting in hard tablets with a high dilution potential, which will also help improve patient compliance.
The challenges of ODTsThe challenges of developing ODTs are similar to those for conventional solid oral dosage; for instance, one of the main issues for both forms is the need to establish compatibility of the active drug substance with both the excipients and process. For ODTs specifically, the key challenges are producing tablets with rapid disintegration and overcoming the bitter taste exhibited by many actives. These can be overcome, however, by using a good selection of sweetener/binder systems, combined with a super-disintegrant.
To overcome the bitter taste, sweeteners and flavours are often included to achieve a palatable formulation Additionally, a pleasant mouthfeel is also important. Again, manufacturers are approaching this using a sweetener/binder system with the desired characteristics.
At Cargill, we've overcome the challenges relating to ODTs by using a wet granulation of erythritol as an excipient. This excipient is non-hygroscopic, contributes to good mouthfeel and has taste-masking properties, and robust tablets can be made via wet granulation, combined with a disintegrant to provide faster disintegration. Erythritol also has taste-masking properties and is noncariogenic (toothfriendly), making it an effective ingredient for tablets that need to stay in the mouth for some seconds while dissolving.
In our research, using a placebo with a hardness of 148 versus our Zerose erythritol and C*Pharm IsoMaltidex formulation, including 2% disintegrant, with the same hardness, there was a significant decrease in disintegration time, from 127 seconds to 95 seconds.⁴
Another challenge is that ODTs are potentially less robust than conventional solid-oral dosage forms, given their formulation to achieve rapid disintegration, so packaging requirements, such as aluminium blister packs need to be considered.
In the future, innovations and developments in the ara of ODT will be around marketing and awareness relating to ODTs, as much as in particular technological solutions. Raising awareness of ODTs amongst healthcare professionals and developing market segmentation for specific end users will also be crucial.
References
1. Orally Disintegrating Tablet and Film Technologies — 6th Edition (Technology Catalysts International, September 2010).
2. K. Deepak, Tablets and Capsules, 7 , 30–35 (2004)
3. D. Brown, Drug Deliv. Technol., 3 (6), 58–61 (2001).
4. Internal Cargill research conducted by Cargill's Pharma Application Centre team.

Designing excipients for powder formulations

When designing and developing new excipients, we take all aspects of the finished dosage form into account and consumer expectations, such as taste, aftertaste and mouthfeel. The physicochemical requirements of bulk exipients for solid dosage forms are clear. For powder formulations, however, it is mandatory that excipients also need to have a natural, sweet taste and the particles should have dissolution kinetics that create a pleasant mouthfeel, as well as a prolonged sweet release effect. These factors are very important from an end-user's point of view. Moreover, as the dosage form dissolves in the mouth and remains in the oral cavity during dissolution, the excipient must also be noncariogenic. To make the final product suitable for diabetic patient groups, the excipient should be low glycaemic too.
Looking at the processing side, the excipients' characteristics will always depend on the final product. When manufacturing a blend, for example, it is important for the excipient to have a particle size appropriate for manufacturing. Additionally, there should be virtually no dusting within production. When the powder dusts heavily you will encounter difficulties in sealing the sachets properly because the powder will stick to the seal. Manufacturers will then loose a certain amount of the powder, which disappears into the vacuum system.
One answer to the issues mentioned above is to use multifunctional excipients. These combine technical (physical and chemical) and sensorial properties; however, these are very recent on the market and are facing the challenge of replacing traditional excipients that have been used for years.
Another challenge in manufacturing powder formulations relates to equipment. The idea of sachets as direct oral application dosage form was originally developed in the confectionery sector and so is not new to many food manufacturers. Within the pharmaceutical sector, however, there is a time lag in implementing such a nonestablished processing technology because of regulatory issues and lack of experience, and we find that few manufacturers have the necessary equipment to fill sachets — in particular, you need flat pouch machines that enable the form, fill, weigh and seal of the sachet. One way of overcoming equipment needs, however, is to use a CMO.
Innovation
In my eyes, innovation in powder formulations is mainly about taste masking, aftertaste and mouthfeel. APIs can be very bitter and need to be taste-masked successfully to develop a palatable product. If the dissolution rate of the API cannot be affected, masking can be very challenging. There are basically two broad approaches to achieve this: creating a barrier between the taste bud and drug, or overwhelming the unpleasant taste. Flavour houses do a great job of developing technologies to mask the bitter taste of APIs and these developments can be regarded as real innovations in improving the market penetration of direct oral applications form. Also, excipient manufacturers have launched new products such as aqueous polymer coating materials that facilitate taste masking. Such coatings release the API at the right pH, but not its bitter taste in the oral cavity.
In the future, I think that sachet applications for the OTCmarket will emerge as a crossover between confectionery and pharma, which used to be absolutely contradictory. Pharmaceutical products have a rather clean appeal, but are associated with chemicals and illness, whereas the confectionery arena always tries to create a positive image by attracting consumers with new packaging, new ideas and positioning. Of course, you can't and shouldn't compare all pharmaceuticals with confectionery! However, when it comes to patient appropriateness, I personally think that manufacturers should think about adopting some ideas from the confectionary industry, including form, appeal and marketing. This could possibly be done with sachets. To do this, packaging will be decisive — packaging is the outer appearance of a product and thus gives the first impression. Nowadays, various ways of packaging are possible; for instance, packaging can improve shelf life and identification. Sachets reflect a rediscovered dosage form in the pharmaceutical sector and combine innovative packaging with attractive palatability, which can help improve patient compliance.
Today, new technical possibilities in terms of excipients and packaging concepts are available, and excipient manufacturers — particularly those who have experience in the confectionery market — are well prepared to serve the pharmaceutical industry with the products and concepts needed to facilitate the development of powder formulations. I believe that companies that can adapt manufacturing and marketing concepts fast will be able to gain a good market share.

The Myth Called "Sterility"

Background
A common perspective underlying regulatory documents that call for a "proof" of sterility is the belief that industry can somehow use microbiological analysis and other select and, often-subjective, tests to prove that sterility has been attained. Such proof does not technically exist and is not scientifically possible. There are dangers implicit in regulatory authorities requiring industry to attempt to prove the unprovable. These misguided efforts create circumstances in which industry can never truly accomplish the intended objective and, as such, can always be found to have made insufficient efforts to support sterility-assurance programs.
Users of isolation technology, for example, have been asked to increase environmental monitoring (EM) to extreme levels because existing monitoring programs established for manned cleanrooms cannot detect contamination. Scientifically and legally, these standards have left industry with both feet firmly planted in mid-air. The result, as evidenced from recent inspections, is that if an inspector wishes to use these documents to insist that a firm lacks "sterility assurance," then there is virtually no way the manufacturing firm can defend itself.
It is always possible to start an inspection report with the following statement, "The firm failed to demonstrate sterility assurance in that...." It's impossible to objectively prove or disprove this allegation. Sterility is an absolute concept, and its presence cannot be proven, regardless of the effort to do so.
Examples of unprovable regulatory citations include claims of inadequate air visualization (smoke studies), claims regarding the conduct of media fills, the acceptability (or not) of a specific aseptic intervention, and charges regarding the adequacy of environmental monitoring. Metrics for smoke-test success are absent. This test is strictly an eye-ball exercise in which one party may see one thing and another sees something quite different. Although smoke tests are valuable for fine-tuning certain elements of critical-zone performance, they rarely lead to real performance improvements.
Airflow is another example. Airflow in cleanrooms is some-times incorrectly called "laminar," but in practice, laminarity cannot be achieved. No matter how well-designed or qualified an isolator or cleanroom is, there always will be turbulence and eddy currents. There is no objective standard for the point at which adequacy no longer exists or at which turbulence might affect sterility assurance, if it ever does.
Media-fill conduct is yet another issue without an endpoint. In recent years, regulators have required larger and longer media fills and placed an increased emphasis on using media fills as long as the longest production run. However, change does not enable proof of sterility. No media fill, no matter how large or intensive, can ever prove sterility. New conditions can always be added to a media-fill program, even if those conditions are atypical. Recently, FDA has expected that the production and filter sterilization of media parallel the compounding and filtration of product. Yet, media and product are two very different materials with different attributes. The most obvious of these differences is that media will amplify the presence of contamination, which the majority of products will not do. Also, media may contain insoluble particu-late in quantities not seen with most aqueous formulations which means prefiltration is a must. There is nothing to be gained from ever larger media fill tests with activities that really don't relate to process simulation being required
Another prevailing notion is that some aseptic processing interventions are inherently bad. There's no question that heroic efforts during aseptic processing should be avoided. But what makes a particular intervention good or bad? We have no useful metrics, to assess the difference, yet such categorization is all too swift and final. Furthermore, media-fill tests, no matter how intensive, cannot reliably demonstrate (or validate) that an intervention is low-risk, nor can they unequivocally prove that an intervention is bad. Neither media-fill or eyeball tests are inherently sound arbiters of sterility assurance. In absolute terms, they are both inadequate for such a task. Destroying a batch because an intervention is arbitrarily assumed to be "bad" is not much different than accepting a different batch made with a series of "good" interventions. EM has been increasing as a consequence of regulatory pressure for at least 20 years, but there is never any consideration of diminishing return or even patient risk arising from EM-related interventions. Quite simply, it is not possible to monitor quality into product (something we've known since the very origins of validation in the 1970s) and it will never be possible to use EM to prove sterility. EM is neither sensitive nor accurate enough to pinpoint when intervention might put a patient at risk. EM has significant and inherent, technical limitations and we have likely passed the point of diminishing return on it within even manned cleanrooms. This is an acknowledged fact that's never contemplated in current regulation.
The need foranewdirection. The absolutist thinking regarding sterility assurance plays a significant role in standards development. Both industry and regulatory authorities would benefit from a serious dialogue about the nature of aseptic processing regulation. Intensity and length of effort cannot alone ensure sterility. Monitoring, even if continuous, and smoke tests, even if comprehensive, cannot ensure sterility. Unfortunately, subjective evaluation of such data can result in regulatory observations that are not pertinent and may be irrelevant.
The authors are raising this issue now because we believe that evolving aseptic-processing technology has rendered the traditional evaluative methods less useful. These more advanced processes consistently operate below the limits of detection for the presently available microbiological assays.
As processes have improved and "zero" results have become the norm, the regulatory reaction has been to multiply the test and in-process workload which, while intuitively logical, is scientifically inappropriate and, unfortunately, valueless. We suggest that rapid microbiology, drawing increasing attention by industry, only provides the same imprecise information about the aseptic process we already have, albeit somewhat sooner. The use of that "information" is what the authors are concerned about, not the time it takes to obtain it. Rapid microbiology is very useful technology, but it cannot overcome the sampling limitations that exist. No analytical method (microbiological, chemical, or physical), regardless of how advanced and sensitive, can measure the complete absence of something. Sterility is, by definition, the complete absence of viable contamination.
The authors seek to highlight the increasingly arduous regulatory spiral into which we have been drawn. The most practical way forward is to carry out honest and detailed dialogue between all stakeholders. In many technical endeavors, there's a time at which paradigm shifts are required. Discipline of aseptic processing is now at such a point. Continuing to follow the same path of the past two decades will neither improve end-user safety nor the economics of manufacture.
A process-centric approach for superior performance
To successfully manufacture sterile products by aseptic means, it's necessary to redefine the process controls essential for success. Central to the authors' suggested approach is the use of the Akers-Agalloco (A-A) method for aseptic-processing risk analysis to support the evaluation and selection of the specific means for aseptic-process design and execution (1,2). Our preference for this over other methodologies is based upon the absence of inference from EM results. Katayama et al, in their review of aseptic-processing risk models, identified the A-A method as having the closest correlation to the operational performance evidenced for a variety of different installations (3).

Figure 1: Influences on aseptic processing (Adapted from L. Mastrandrea, Ref. 9).

Central to aseptic processing is the understanding that there are numerous factors that can influence the outcome (see Figure 1). The authors believe it's the decisions, selections, and approaches—made with respect to each of the factors depicted in Figure 1—that have the greatest effect on results. Poor choices, regardless of the monitoring outcomes associated with them, must be acknowledged as unsound. Our approach differs from those derived from EM expectations because of our focus on personnel and their impact on contamination levels. The rankings in the A-A method devolve from a singular focus on the operator. From that perspective, the authors established the following basic precepts to the A-A risk method and the recommendations outlined below (4, 5):

• Interventions are to be avoided at all times in aseptic processing
• Interventions always mean increased risk to the patient
• There is no truly safe intervention
• The "perfect" intervention is the one that doesn't happen.

In turn, these steps should be followed with respect to aseptic processing: separate personnel from the aseptic environment; limit employees' interaction with sterile materials; where possible, entirely remove personnel from the aseptic environment; and combinations of the above. The means for accomplishing these goals are embodied in following methodologies (6):

• The use of automation technology to reduce or eliminate personnel interventions and, thus, personnel-borne contamination
• The use of separative technologies to minimize the impact of personnel-derived contamination.

These methods are central to our recommendations for the supportive elements of aseptic processing. In defining these elements, the authors are adapting a quality-by-design (QbD) approach as defined in recent regulatory documents (7,8). The details for QbD in aseptic processing are somewhat different from the applications of this concept in the typical formulation or synthesis process. As we outlined in the first half of this paper, the establishment of direct linkage between a monitored condition and the outcome, with respect to an aseptic process, is uncertain. The situation, with respect to the definition of physical-design elements, is very similar. Contemporary aseptic-processing facility and process design include several seemingly rigorous design expectations for performance, including such precepts as:

• Air velocities of 90 FPM (0.45 m/sec) ± 20% for ISO 5 air in critical environments
• Air changes of > 150 per hour in critical environments
• Pressure differentials of NLT 0.05" water column between different classifications.

These expectations, and others like them, should be considered suggestions rather than definitive requirements because they have less correspondence to the process outcome than EM. The authors' recommendations for QbD, with respect to aseptic processing, are non-numeric because it is our strong belief that there are no ready means to demonstrate their suitability. Instead, we suggest that QbD for aseptic processing be driven toward eliminating the impact of personnel on the process. The means to accomplish this vary depending on the particular aspect of the overall process under consideration.
The following recommendations for various aspects of the aseptic processing facility adhere to our central premise of reducing the potential adverse impact of personnel on the core aseptic process. They are not intended to be inclusive—other suggestions could be added.
Facilities:

• Facilities should be designed for easy sanitization/decontami-nation through proper use of construction materials, ease of access, and design details that facilitate cleaning
• Facility layouts should minimize the potential for mixups and cross-contamination
• Air system should provide adequate air pressurization to preclude the ingress of contamination from surrounding less-clean environments
• Airflow patterns should facilitate the removal and exclusion of contamination from critical environments
• Air systems should be supplied with HEPA filters that are periodically integrity tested
• Differential pressure should be monitored and alarmed to demonstrate continuous integrity of the core aseptic area
• Temperature and humidity should be controlled to maximize personnel comfort during operations consistent with product stability/safety requirements
• Interlocks should be used to prevent pressure reversal
• Advanced aseptic-processing designs such as closed restricted access barrier systems (RABS) and isolators, should be given preference in selection of processing environments
• All facility and environmental surfaces should be resistant to the potential corrosive action of sanitizing and decontamination agents
• The aseptic portion of the facility should be maintained in clean state at all times and periodically sanitized or decontaminated
• Isolators and closed RABS should be treated with sporicidal agents on a periodic basis.
• A minimum of materials should be retained in the aseptic portion of the facility
• Smoke studies, air-velocity measurements, expectations for unidirectional airflow, absence of eddy's, and other subjective expectations imposed on aseptic-processing HVAC systems should be recognized as useful, but non-definitive means for assessing aseptic processing environmental performance.

Equipment and utensils:

• Product-contact surfaces of equipment must be sterilized using a validated method (vibratory feed systems may be exempted from this requirement provided they are high level decontaminated with a sporicidal agent in-situ)
• Sterilization-in-place and clean-in-place should be used wherever possible
• Equipment should be assembled to the fullest extent possible prior to sterilization
• Equipment and utensils should be sterilized in sealed containers (the use of paper and tape is not recommended)
• Equipment and utensils should be introduced in a manner that retains at least one layer of sterilized-protective covering or wrap until entry into the critical zone
• Equipment and utensils should be sterilized/depyrogenated using a just-in-time approach
• Inventories of materials in the aseptic environment should be minimized
• Equipment should be selected for high reliability, ease of changeover, and adjustment
• Remote adjustment of equipment should be utilized where possible
• Tool free change over from one format to another should be possible
• Equipment should be tolerant of container-closure miss-feeds, jams, and other problems to minimize the need for interventions
• Equipment (and to some extent facility) should use process analytical technology and other feedback systems for ease of control, operation, and documentation
• Non-product contact portions of the equipment should be easily decontaminated and non-invasive of the critical zone
• All equipment surfaces should be resistant to the potential corrosive action of sanitizing and decontamination agents.

Containersand closures:

• Containers and closures must be prepared and sterilized/de-pyrogenated using a validated process
• Containers and closures should be introduced in a manner that retains at least one layer of sterilized-protective covering or wrap until entry into the critical zone
• Containers and closures should be selected for reliability of handling in the processing equipment
• Containers and closures should be suitable quality for their intended use because higher acceptable quality levels for defects can result in a reduction in the need for interventions
• Containers and closures should be sterilized/depyrogenated using a just-in-time approach.

Product:

• Product materials must be prepared and sterilized using validated methods
• Product delivery should be made directly into the critical zone
• Where product is supplied to the critical zone in sterile container (e.g., sterile powders), it should be introduced in a manner that retains at least one layer of sterilized-protective covering or wrap until entry into the critical zone.

Personnel:

• Personnel must receive initial and periodic training in current good manufacturing practice, aseptic processing, microbiology, aseptic gowning, and job specific tasks
• Where appropriate, personnel should be initially and, periodically thereafter, assessed for their proficiency in aseptic gowning
• Personnel should be initially and, periodically thereafter, assessed for their proficiency in aseptic technique
• Personnel should be monitored upon each exit from the aseptic core (gloves on enclosures should be monitored at the end of the batch or campaign)
• Gown materials should be cleaned and sterilized using validated methods
• Gloves on enclosures should be replaced periodically, sterilized, and integrity tested
• Personnel should be trained and diligent in their adherence to aseptic techniques
• Manual filling by aseptically-gowned personnel should be recognized as an anachronistic throwback to an earlier time and no longer used for aseptic processing.

Procedures:

• Procedures should be reviewed to eliminate unnecessary work steps and simplify aseptic processes
• Interventions should be designed for minimal risk of contaminating sterile materials
• Interventions performed during aseptic processing must be recognized as increasing the risk of contamination dissemination
• All interventions should be performed using sterilized tools whenever possible
• Intervention procedures should be established in detail for all inherent interventions and, more broadly, for corrective interventions (where some flexibility is necessary due to their greater diversity).

Monitoring:

• Despite the limitations, with respect to its performance noted in the first part of this effort, monitoring of aseptic processing should be performed.
• Monitoring of any type must not subject the product to increased risk of contamination. No monitoring is preferable to monitoring that risks contamination of sterile materials.
• EM must be recognized as interventions and subject to the similar constraints and expectations.
• Monitoring must be recognized as subject to adventitious contamination unrelated to the environment, material, or surface being sampled.
• Viable monitoring should not be considered an in-process sterility test.
• EM results should not be considered as 'proof' of either sterility or non-sterility.
• Microbial monitoring can never recover all microorganisms present in an environment, nor on a surface.
• The absence or presence of microorganisms in an environmental sample is not confirmation of asepsis, nor is it indicative of process inadequacy.
• Significant excursions from the routine microbial prolife should be investigated.
• Detection of low numbers of microorganisms within the critical zones of manned cleanrooms should be considered a rare event. Such a finding does not correlate to a loss of process control, since it is within the normal range of observations.
• Investigations into recoveries of low numbers of microorganisms in manned cleanrooms should be recognized as predominantly make-work exercises.
• Process simulation are indicators of capability, but cannot definitely establish the sterility of any material.
• Process simulations in excess of 5-10,000 units are of relatively limited value; their greatest utility is in the evaluation of aseptic set-up practices.

Conclusion
The first section of this work addresses the limitations of monitoring tools used for aseptic processing. The current methods cannot prove sterility (or its absence). It is the authors' contention that to achieve success with aseptic processing, the practitioner must properly address the relevant issues outlined in the latter half of this work. There is nothing industry can do to provide proof of sterility. The authors believe, however, that adherence to the recommendations herein will make aseptically-produced products as safe as currently possible.
The methods proposed are largely incompatible with existing aseptic processing guidance, regulatory, and pharmacopeial doctrine because the authors have, essentially, deconstructed monitoring as a means for defining or accepting aseptic-processing activities and endeavored to outline a comprehensive QbD approach for establishing it more appropriately. If industry is to continue to improve aseptic processing beyond its current capabilities and, even to proper control contemporary aseptic-processing operations, the authors believe that greater attention should be focused on the design elements. We offer this work as an opening statement in what we hope will be a continued dialogue through which sterile products can be manufactured by—and controlled—in the safest means possible.
James Agalloco* is president of Agalloco & Associates and a member of Pharmaceutical Technology's Editorial Advisory Board, 908.874.7558,
. James Akers is president of Akers Kennedy & Associates.
*To whom all correspondence should be addressed.
References
1. J. Agalloco and J. Akers, Pharm. Technol., 29 (11), 74-88 (2005).
2. J. Agalloco and J. Akers, Pharm. Technol., 30 (7), 60-76 (2006).
3. H. Katayama et al., PDA J Pharm Sci and Tech., 62 (4), 235-243 (2008).
4. J. Agalloco and J. Akers, Pharm. Technol., 30 (7) (2006) 60-76.
5. J. Agalloco and J. Akers, supplement to Pharm. Technol., Aseptic Processing, 31, s8-11 (2007).
6. J. Agalloco and J. Akers, supplement to Pharm. Technol., Aseptic Processing, 29, s16-23 (2005).
7. M. Nasr, "Quality by Design (QbD)-A Modern System Approach to Pharmaceutical Development and Manufacturing-FDA Perspective," presentation at FDA Quality Initiative Workshop at ISPE meeting (Bethesda, MD, February 2007).
8. ICH Q8(R2) Pharmaceutical Development (ICH, Geneva, 2009).
9. L. Mestrandrea, presentation at the 4th Annual PDA Global Conference on Pharmaceutical Microbiology (Bethesda, MD, Oct. 2009).

Managing Bioanalytical Cross-Contamination

Min Shuan Chang, Ph.D., Elaine J. Kim, and Tawakol A. El-Shourbagy, Ph.D. Abbott Laboratories

Introduction

Analysis of drug concentration in biological samples is an integral part of the drugdevelopment process [1]. Concentration data from biological samples is required to study the absorption, distribution and elimination properties of a new chemical entity and to understand its dose-response relationship in both clinical and non-clinical studies. A clear understanding of pharmacokinetic variability becomes increasingly important in later stages of clinical studies, especially for pivotal bioequivalent studies such as those required for changes in formulation. Unlike a manufacturing process, contamination in an analytical laboratory does not directly impact the product. However, contamination leads to reporting biased results that
impacts the validity of the derived decisions and increases regulatory risk.
Laboratory contamination is defined as an unintended and undesirable transfer of analyte or interfering compounds into an analytical sample or sample extract before or during the analytical process. The following is a short list of the characteristics of laboratory contamination.
Detection

• Usually observed as a positive bias.
• Blank, placebo or pre-dose (first dose) has detectable analyte(s).
• Results do not fit the trend of the concentration profile.
• May or may not be detected by standards or quality control samples.

Source

• Contaminated animals or subjects.
• Contamination during sampling at the site.
• Contamination during sampling at laboratory.
• Contamination during analysis.

Contamination of test subjects and contamination during sampling at study sites have been discussed previously [2, 3, 4, 5] and are outside the scope of this article. Becausecontamination may not be predictable, detection is not assured by the current quality control program. For a batch containing a blank, a zero standard (blank with internal standard), a set of eight calibration standards, two sets of three quality control samples (QCs) and 80unknowns from the serialbleeding of five subjects or treatments, contamination (from a high concentration sample) may be detected in approximately 16 samples, i.e. blanks, pre dose samples, the sample at the end of elimination phase, two of the lowest standards and the low QC. Therefore, a single incidence of laboratory cross-contamination may be detected only 17 percent of the time. Therefore, occurrence of contamination may only be observed through assay statistics including a positive bias or residue for the low standards and QCs.
Laboratory contamination during the sample analysis process may be classified into two categories, carryover and cross-contamination. Carryover is the result of transferring an analyte from an earlier sample to later samples, usually due to the sharing of a common
container or transferring device. Carryover is serial in nature and occurs in both sample preparation and the analytical process. Carryover is generally distributed in a narrow zone (Figure 1). The effect of HPLC autosampler carryover may be estimated from the
results of a few samples and that the relative effect of carryover on concentration results may be calculated [6, 7, 8].

Cross-contamination is the transfer of an analyte from a sample to another that is processed with it. Cross-contamination is parallel in nature and may not involve a medium. For a bioanalytical assay, the major sources of cross-contamination are spills, aerosols and drips
during transfer. Because both the occurrence and magnitude are random, cross-contamination is difficult to estimate and manage. The term contamination will be used to describe both carryover and crosscontamination.

Recognize the contamination incident

Unlike accuracy and precision, contamination may not be detectable by the generally accepted QC program, but positive bias in low QC or low standards (more data points exhibit positive bias than negative bias or observation of large positive bias) are clues. A critical review of historical data would give good estimate for contamination potential of a method. If the results justify an investigation, performing experiments to understand the root cause will minimize
future risks.

cgmp

1. Introduction

This guide is intended for those involved in the storage, transportation and distribution of pharmaceuticals. It is closely linked to other existing guides recommended by the WHO Expert Committee on Specifications for Pharmaceutical Preparations, such as:

• Good trade and distribution practice (GTDP) of pharmaceutical starting materials (1);
• The stability testing of pharmaceutical products containing well-established drug substances in conventional dosage forms (information given in connection with regulation for marketing authorization) (2);
• Good manufacturing practices (GMP) (3);
• The cold chain, especially for vaccines and biologicals;
• The International Pharmacopoeia (4).

The objective of this guide is to supplement the above-mentioned documents by describing the special measures considered appropriate for the storage and transportation of pharmaceuticals. However, they may be adapted to meet individual needs where necessary, provided that the desired standards of quality are still achieved.
The guidelines are applicable not only to manufacturers of medicinal products but also to pharmaceutical importers, contractors and wholesalers, and community and hospital pharmacies. They should be adjusted in line with the type of activity where the storage of pharmaceuticals is taking place. National or regional regulations should be followed for all related activities.

2. Glossary

The definitions given below of some of the terms used in this document take into account the terminology of current regulations and recommendations.
active pharmaceutical ingredient (API)
Any substance or mixture of substances intended to be used in the manufacture of a pharmaceutical dosage form and that, when used in the production of a drug, becomes an active ingredient of that drug. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect the structure and function of the body.
contamination
The undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter, into or onto a starting material, or intermediate or finished product during production, sampling, packaging or repackaging, storage or transport.
cross-contamination
Contamination of a starting material, intermediate product or finished product with another starting material or product during production.
excipient
A substance, other than the active ingredient, which has been appropriately evaluated for safety and is included in a drug delivery system to:

- aid in the processing of the drug delivery system during its manufacture;
- protect, support or enhance stability, bioavailability, or patient acceptability;
- assist in product identification; or
- enhance any other attribute of the overall safety and effectiveness of the drug during storage or use.

expiry date
The date given on the individual container (usually on the label) of a drug product up to and including which the product is expected to remain within specifications, if stored correctly. It is established for each batch by adding the shelf-life to the date of manufacture.
labelling
The action involving the selection of the correct label, with the required information, followed by line clearance and application of the label.
manufacture
All operations of purchase of materials and products, production, quality control, release, storage and distribution of finished products, and the related controls.
material
A general term used to denote starting materials (active pharmaceutical ingredients and excipients), reagents, solvents, process aids, intermediates, packaging materials and labelling materials.
packaging material
Any material, including printed material, employed in the packaging of a pharmaceutical product, but excluding any outer packaging used for transportation or shipment. Packaging materials are referred to as primary or secondary according to whether or not they are intended to be in direct contact with the product.
pharmaceutical product
Any medicine intended for human use or veterinary product administered to food-producing animals, presented in its finished dosage form or as a starting material for use in such a dosage form, that is subject to control by pharmaceutical legislation in both the exporting state and the importing state.
production
All operations involved in the preparation of a pharmaceutical product, from receipt of materials, through processing, packaging and repackaging, labelling and relabelling, to completion of the finished product.
retest date
The date when a material should be re-examined to ensure that it is still suitable for use.
storage
The storing of pharmaceutical products and materials up to their point of use.
supplier
A person providing pharmaceutical products and materials on request. Suppliers may be agents, brokers, distributors, manufacturers or traders. Where possible, suppliers should be authorized by a competent authority.

3. Personnel

3.1 At each storage site (e.g. that of a manufacturer, distributor, wholesaler, community or hospital pharmacy) there should be an adequate number of qualified personnel to achieve pharmaceutical quality assurance objectives. National regulations on qualifications should be followed.
3.2 All personnel should receive proper training in relation to good storage practice, regulations, procedures and safety.
3.3 All members of staff should be trained in, and observe high levels of, personal hygiene and sanitation.
3.4 Personnel employed in storage areas should wear suitable protective or working garments appropriate for the activities they perform.

Prevention of cross-contamination and bacterial contamination during production

16.10 When dry materials and products are used in production, special precautions should be taken to prevent the generation and dissemination of dust. Provision should be made for proper air control (e.g. supply and extraction of air of suitable quality).
16.11 Contamination of a starting material or of a product by another material or product must be avoided. This risk of accidental cross-contamination arises from the uncontrolled release of dust, gases, particles, vapours, sprays or organisms from materials and products in process, from residues on equipment, from intruding insects, and from operators’ clothing, skin, etc. The significance of this risk varies with the type of contaminant and of the product being contaminated. Among the most hazardous contaminants are highly sensitizing materials, biological preparations such as living organisms, certain hormones, cytotoxic substances, and other highly active materials. Products in which contamination is likely to be most significant are those administered by injection or applied to open wounds and those given in large doses and/or over a long time.
16.12 Cross-contamination should be avoided by taking appropriate technical or organizational measures, for example:

(a) carrying out production in dedicated and self-contained areas (which may be required for products such as penicillins, live vaccines, live bacterial preparations and certain other biologicals);
(b) conducting campaign production (separation in time) followed by appropriate cleaning in accordance with a validated cleaning procedure;
(c) providing appropriately designed airlocks, pressure differentials, and air supply and extraction systems;
(d) minimizing the risk of contamination caused by recirculation or re-entry of untreated or insufficiently treated air;
(e) wearing protective clothing where products or materials are handled;
(f) using cleaning and decontamination procedures of known effectiveness;
(g) using a “closed system” in production;
(h) testing for residues;
(i) using cleanliness status labels on equipment.

16.13 Measures to prevent cross-contamination and their effectiveness should be checked periodically according to standard operating procedures.
16.14 Production areas where susceptible products are processed should undergo periodic environmental monitoring (e.g. for microbiological monitoring and particulate matter where appropriate).

The Importance of Microbiology in the Contamination Control Plan for Aseptic, Terminally Sterilized and Non-sterile Manufacturing

Introduction

The development of a contamination control program is critical to the effort to get a new facility qualified, and to maintain the facility in a state of control once qualified.   The design and successful execution of a contamination control program requires a plan. The creation of a specific document allows the company philosophy, goals, and expectations to be formalized and agreed to by all parties. It also provides the goals and metrics by which the state of control for the facility can be measured in the annual review. The business reasons for this are obvious in terms of reduced regulatory risk and reduction of rejected/recalled batches (Lowry 2001).
This plan is important no matter what type of facility is being developed. Although it is most frequently used in the Quality plan for commissioning an aseptic facility, this is also important and should be used for commissioning and controlling facilities using terminal sterilization, and for non-sterile manufacturing facilities.
Why be concerned with contamination control in a nonsterile manufacturing facility? In many ways contamination control is more of a concern in a non-sterile facility than in sterile product production facilities. The sterile production facility knows there is a problem with contamination and cross-contamination of batches, the non-sterile facility has a great temptation to belief they are not touched by these issues. This can lead to an extremely cavalier attitude about contamination control by the operators and management.
The non-sterile manufacturer is responsible for all aspects of his product, including any objectionable organisms present (Sutton, 2006) as described in a recent newsletter (PMF Newsletter v12 n7).
The API manufacturer is also concerned with contamination control. The FDA has explicit instruction on this score (FDA 1998) out of CBER. The EMEA guidance on API manufacture also includes guidance on control of bioburden and cross-contamination of batches (EMEA 2000).
This essay will not be able to provide more than an overview of issues in the space available this month. However, it is hoped that the need for an adequate contamination control plan for a facility will be made clear, and the beginnings of the content of such a plan explained. The interested reader is referred to the articles listed in the “References” and the “Further Readings” sections.

Scope

The Contamination Control Plan should be developed as part of the facility commissioning effort. As such, there will be four distinct phases of the facility operations that will need to be addressed:

1. 1. Commissioning and initial start-up
   2. Ongoing Operations
   3. Shut-down for regular maintenance
   4. Start-up after scheduled shut-down

These phases will not have the same level of contamination control. In fact, the third and fourth phases may well have different levels of control to be addressed. A good plan will discuss the concerns specific to each of these phases.
This program, and the protocol governing the program, are essential documents useful in documenting the rationale and methods used to accomplish three tasks:

• Minimizing the bioburden throughout the manufacturing processes
• Minimizing the level of batch residual cross-over contamination
• Minimizing the level of cleaning material residual contamination

As the SME (Subject Matter Expert) in microbiology, we will be most heavily involved in the first of these three tasks, minimizing bioburden. However, all three will be discussed (at least briefly) in this essay for context.

Minimizing Bioburden

Validated methods

All measures of bioburden in a facility will be indirect. We cannot count bacterial cells on a surface or in the air. We must transfer the microorganisms to an agar plate (or some other mechanism) and count colony forming units. If we make the assumption that the transfer of microorganisms from the air or from a surface to agar is consistent, then we can use these numbers to estimate trends over time. This assumes that the nutrient agar is capable of growing the microorganisms to visible colonies. As residual disinfectant on
a surface may impede the growth of microorganisms, neutralizers are frequently incorporated into the growth media (Dey-Engley agar, MCTA, etc.). All sampling methods must be validated for the conditions of use.
The facility should be disinfected regularly using validated sanitizers and sporicides. The contamination control plan should describe the methods for testing and rationale for acceptance of materials to be used in the ongoing program of disinfection. The plan should ideally describe the in vitro or laboratory tests to evaluate the sanitizers, including the identification of the most resistant microorganisms found in the facility as well as the most difficult-to-disinfect materials in the facility. This is also where the method for on-going evaluation of the sanitizers based on environmental monitoring data will be recorded. The choice of disinfection regimens should be reevaluated annually, and the contamination control plan should describe how this evaluation will occur.

Know the enemy

A successful contamination control program is geared to providing the most useful information on the microorganisms present while at the same time showing some fiscal responsibility. The FDA aseptic processing guidance document recommends genetic identification of all organisms isolated from the manufacturing environment on a regular basis. (FDA, 2004) This is a laudable goal, but few of us have anything near the required budget to accomplish this task, and in all honesty it is reasonable to wonder if it is really necessary. The numbers of CFU from validated sites (viable air and surface, non-viable) is sufficient to provide a measure of the state of control of the facility. However, periodic cataloging of the resident microflora will provide you with a good check on the continued effectiveness of the disinfectants in use. Shifts of bioburden to spore forming microorganisms will be strong evidence of the need for use of a sporicidal agent. Occasionally, this effort will also pick up shifts among non-spore-forming organisms – this is not due to “resistance” but rather ecological shifts towards species more naturally resistant to the disinfectant in use.

Control incoming bioburden

The first step in any control program is to control contamination at the very beginning of the process. This includes raw materials (excipients, API, water, etc) and the primary containers. All materials should be tested for incoming bioburden against documented acceptance criteria. Part of the incoming bioburden will also be any water used as an excipient to the process. A good guide for the water bioburden is the EMEA guidance on the subject (EMEA 2002).

Appropriate gowning

The gowning methods and materials are of critical importance to minimization of contamination. Although most attention is placed on aseptic gowning procedures, the appropriate use of gowning precautions will be a great boon to most non-sterile manufacturing facilities as well.   All personnel should be well-trained in appropriate gowning practice and behavior. The contamination control plan should describe the rationale for the level of gowning chosen, the frequency of gown cleaning, behavior and the acceptable gown materials for the type of manufacturing process.

Training

Operator training is critical to contamination control. No supervisor can be present at all locations at all times. Each operator must be aware of his or her role in contamination control and how to minimize the risk to batch integrity. The PDA has published a technical report that speaks to some of these training requirements from the microbiological perspective (PDA 2001).

Controlled Environments

Control and monitoring of the environment is another critical element of the contamination  control plan. Large portions of this can be addressed by the corporate Environmental Monitoring Master Plan (which provides rationale and consistency for a single EM  philosophy across the different facilities of the corporation) or the site Environmental Master Plan (which provides consistency and detailed instruction for the various manufacturing buildings at a given site).  However, the Contamination Control Plan should cite the relevant documents and their role in contamination control. Those interested in more on environmental monitoring should refer to the PDA’s treatment of the subject for a good overview (PDA 2001).
The appropriate Environmental Monitoring (EM) plan for non-sterile manufactures and for API manufacturers is not well-defined from a regulatory sense. There are no strong recommendations such as those seen for the environmental monitoring of aseptic facilities; however the absence of regulatory guidance is not the same thing as the absence of need for the activity. EM is useful for determining the state of control of the facility and so is an important part of the monitoring program for all manufacturers.

Well-defined and Understood Manufacturing Processes

The manufacturing process should be evaluated for its potential to limit or eliminate bioburden. The two common methods for performing this is either a HACCP-type (Jahnke and Kuhn 2003) or a FMEA approach. The use of organic solvents, heat, or other inhospitable activities can greatly reduce bioburden of a process. The contribution of compression (and associated shear), for example, should be evaluated for a potential reduction in risk of excessive microbial contamination (Blair 1991). The contribution of the finished product water activity should also contribute to this analysis (USP 2007).
Of particular importance in this evaluation for the potential for microbial contamination of the process are cleaning steps, equipment hold times, HVAC, control level of environments for critical tasks, open-system vs closed-system operations, and bioburden monitoring (among others specific to your process). As an example of the importance of the bioburden control point issue, there is a strong regulatory expectation in Europe that products sterilized by filtration should have a pre-filtration bioburden of not more than 10 CFU/100 mL immediately before the sterilizing filter (or be subjected to dual filtration in series).
Finally the Contamination Control Plan should cite the need clear SOPs on all aspects of manufacturing, monitoring and control. These SOPs are critical for training, documentation and batch release.

Minimization of Batch Residual Cross-over Contamination.

The contamination control plan should also address the potential for a batch to be contaminated by material from the previous batch manufactured using that equipment. Obviously, the contamination control plan should describe the methods by which this likelihood is minimized.
The concern over batch residual cross-over is most relevant when there is more than one product manufactured at a site. This concern has little to do with the sterility of the finished
product, and is relevant to sterile and non-sterile manufacture alike.

Minimization of Cleaning Material Residual Contamination

Validation of cleaning procedures is essential to demonstrate not only that the cleaning procedure effectively cleans and sanitizes the manufacturing equipment, but also that residual cleaning material is removed to prevent contamination of the next batch manufactured.

Conclusions

The Contamination Control Plan is an important document designed to formalize the rationale, methods and validation of contamination control procedures in a manufacturing facility. This plan is a valuable tool for pharmaceutical, medical device and personal product manufactures and should be written to address all phases of the facilities life cycle. The Contamination Control Plan should specifically address:

• Minimizing the bioburden throughout the manufacturing processes
• Minimizing the level of batch residual cross-over contamination
• Minimizing the level of cleaning material residual contamination

The microbiologist, as SME, has a critical role to play in the first of these three primary goals, and this essay has therefore been directed at that first topic. Minimization of bioburden in the manufacturing process occurs through (but is not limited to):

• Minimizing bioburden in the process
• Control incoming bioburden
• Appropriate Gowning
• Controlled Environments
• Well-defined Standard Operating Procedures; and
• Well-defined and understood manufacturing processes.

References

1. Blair, TC et al. 1991. On the Mechanism of Kill of Microbial Contaminants During Tablet Compression. Intl J Pharmaceutics. 72:111-115.
2. EMEA 2002. Note for Guidance on Quality of Water for Pharmaceutical Use. http://www.emea.europa.eu/pdfs/human/qwp/015801en.pdf.
3. EMEA 1996. CPMP/QWP/486/95 Note for Guidance on Manufacture of the Finished Dosage Form. http://www.emea.europa.eu/pdfs/human/qwp/048695en.pdf.
4. EMEA. 2000. CPMP/ICH.4106/00 Note for Guidance onGood Manufacturing Practice for Active Pharmaceutical Ingredients. (ICH Q7).   http://www.emea.europa.eu/pdfs/human/ich/410600en.pdf.
5. FDA. 1998. Guidance for Industry – Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients.  http://www.fda.gov/cber/gdlns/active.pdf.
6. FDA. 2004. Guidance for Industry – Sterile Drugs Products Produced by Aseptic Processing – Current Good  Manufacturing Practice.   http://www.fda.gov/cder/guidance/5882fnl.pdf.
7. Jahnke, M and K-D Kuhn. 2003. Use of the Hazard Analysis and Critical Control Points (HACCP) Risk Assessment on a Medical Device for Parenteral Application. PDA J Pharm Sci Tech. 57(1):32-42.
8. Lowry, S. 2001. Designing a Contamination Control Program.  IN Microbiology in Pharmaceutical Manufacturing R. Prince (ed) DHI/PDA Publ.   pp. 203-266.
9. PDA. 2001. PDA Tech Report #13 (Revised): Fundamentals of an Environmental Monitoring Program.
10. PDA. 2001. PDA Tech Report #35: A Proposed Training Model for the Microbiological Function In the Pharmaceutical Industry.
11. PIC/s. 2004 PI 006-2 Recommendations on Validation Master Plan: Installation and Operational Qualification – Non-sterile Process Validation, Cleaning Validation.
12. Sutton, S. 2006. The Harmonization of the Microbial Limits Tests. Pharm Technol. 30(12):66-73.
13. USP. 2007. <1112> Application of Water Activity Determination to Nonsterile Pharmaceutical Products.

Cleanroom Particle Counting: The 5 Micron Issue

By Tim Sandle, Ph.D, M.A., BSc (Hons), CBiol, MSBiol., MIScT
The IEST Journal has an interesting article on cleanroom metrology by Lothar Gail. Within the article i an exploration of the 5 micron particle size issue. AS those involved with cleanrooms will know there are two particle count sizes looked for within cleanrooms: 0.5 and 5.0 micron.
The FDA emphasise in the Guide to Aseptic Filling that the 0.5 micron size is te important one for determining if the environment is below or above the accepted evel of particles and in doing so draws upon the ISO 14644 cleanroom standard. However, more controversially with Europe, the EU GMP Guide states that both particle sizes are important.
In arguing against the need to measure 5.0 microns, Gail states:

EC GMP requiring the detection of 5-µm particles with a sample volume of at least 1 m³ for ISO Class 5 classification and monitoring, overlooks some essential facts:

• 5-µm particle counts in an ISO Class 5 environment should be avoided in principle due to background noise level and poor resolution. The poor reliability of 5-µm particle counts cannot be fully compensated by increasing the measuring time.
• 5-µm particle determination proves to be about 10 times more expensive and timeconsuming than 0.5-µm particle counts.
• Currently there is no scientific evidence that 5-µm particle detection offers any improvement for cleanroom hygiene control. EC GMP regulation impedes international harmonization of cleanroom qualification and monitoring procedures.

Even with the latest development of particle counters that offer substantially higher sampling flow rates, the situation does not improve: Areas of ISO Class 5 normally are as small as possible. A particle counter with high sample flow rates cannot be placed in that area since the high sample flow is withdrawn from a small volume. In small areas such as pass-throughs, when the sample flow air is returned into the environment, the pressure differential may be affected; when the sample flow air is returned into the measured area, the air change rate may be affected.

Major Area Of Concern For Pharmaceutical Plants - Waste Treatment

Pharmaceutical manufacturing undergoes various steps, starting from identification of raw drug materials to their conversion into appropriate medicines. Proper waste management is very much essential for all pharmaceutical manufacturing plants because there are huge chances for production of liquid and solid wastes, and hazardous air emissions during each step of drugs development.
To prevent the workers engaged in producing different drugs from being exposed to perilous air emissions, numerous Environmental Assessment (EA) programs and Good Management Practices (GMP) are very effective. These practices assure the complete safety of Pharmaceutical engineers working in Pharmaceutical manufacturing plants.
The EA program includes the study of biodegradable, physical and chemical aspects of various toxic drug byproducts, it mainly deals with the parent drug and not its derivative. Various tests based on aqueous toxicity and photolysis process are also performed by EA program. Waste treatment and management are also taken care of by Pharmaceutical engineers.
Several reports are also prepared by different drug development plants for the complete knowledge of waste and byproducts characteristics. The key components of drug pollutants are the particulate matter and volatile organic compounds. From the cleaning of machineries and equipments used in the drug development industries, numerous hazardous and highly toxic aqueous exhausts are produced. Different types of materials and production processes gives rise to different liquid effluents.
The remnants of containers include solid wastes which can be very lethal and contains injurious solvents.
Finding the alternatives for noxious drug ingredients is the major area of concern for all manufacturing experts and skilled Pharmaceutical engineers. They are planning to replace these lethal drug intermediates with bio-friendly and bio-degradable elements. These byproducts affect the atmosphere very badly by creating air and water pollution so the major area of concern for renowned healthcare sectors is to provide remedies for its control.

Do I Really Have To Remove My Aquarium?

Fumigation is a means to control pests by enclosing a structure within a 'tent', injecting a gaseous pesticide and allowing the poison time to infiltrate nooks and crannies, thus killing targeted vermin. In Hawaii, using the pesticide Vikane™ (Dow AgroScience's trade name for sulfuryl fluoride - F₂O₂S) is most often used to eliminate drywood termites. It is also used on the mainland to control other drywood termite species. Fortunately, drywood termites do not occur in all states and are restricted to warmer climates. But they can be a real problem in coastal North and South Carolina, south Georgia, Florida, south Alabama, coastal Mississippi, Louisiana, Texas, New Mexico, Arizona and southern California.

Licensed pest control specialists generally recommend removal of aquaria from the structure but might allow an aquarium to remain inside during treatment (using, of course, aeration from an air pump situated well away from and outside the building). They are doing what they are trained to do - recommend to the customer the best options for their pets. In fact, little is known about the effects of this pesticide on many animals. Indeed, Kollman (date unknown) states that effects of Vikane on fish, wildlife and other non-target organisms are not known.
Hawaii is a land of eternal summer where killing frosts don't occur (unless you're living on the peaks of the Big Island's Mauna Loa, Mauna Kea or Maui's Haleakala). Hence, invertebrates such as corals thrive, but less desirable inverts such as termites and wood-boring beetles also enjoy the sub-tropical climate, and these pests aren't particular - they live in humble, ramshackle coffee shacks all the way up to multi-million dollar homes. While my home is decidedly somewhere-in-between, several termite colonies were quite content to dine on its wooden frame. Professional help was needed.

Figure 1. "Tenting" a house for drywood termites. The tent contains the toxic gas within the structure.

My fears were confirmed when the inspector recommended I remove 4 aquaria from the house. This would be a major project! I considered leaving the tanks in the house and simply supplying 'clean' air from outside, but rejected this notion. Instead, at almost the last minute, I decided to conduct a few experiments to determine the effects of the pesticide on a few selected invertebrates. Although this may sound cruel, I knew that moving the animals to an outside home and back again also involved risks to the health and lives of the captive animals. Perhaps something could be learned from this ordeal.
The evening before the scheduled fumigation, I removed a few invertebrates from aquaria and randomly placed them in ten Mason jars containing 750 ml of aquarium water (see Figure 2). Five jars would be left uncovered and aerated from an air pump within the house. This would be the worst case scenario, where nothing was done to prevent the pesticide from making contact with the water and its inhabitants. Another five jars would be covered with two pieces cut from nylon polymer bags (NyloFume™, Dow AgroSiences) which are impermeable to Vikane. These were supplied by the exterminator to bag food, medicine and other goods from exposure. Aeration to these five containers was supplied by an air pump situated well away from the tented house.

Figure 2. The experiment's set up. Air temperature, water temperatures, photosynthetically active radiation (PAR) and pH were monitored.

Since the air conditioner would have to be turned off during fumigation, I had concerns about the temperature of the jars' contents getting too high. I monitored air temperature and water temperature in one of the covered jars with a datalogger (WatchDog™ model 425, Spectrum Technologies) as well as light intensity (using a Spectrum PAR sensor modified for 60 Hz light). pH and temperature were monitored in an uncovered jar with a separate datalogger (Hach HQ40d™ multi-meter). Fluoride (as F^-) was measured using the SPADNS method and a Hach DR890 colorimeter (chloride concentrations exceeding 7,000 mg/l and sulfate exceeding 200 mg/l will cause high results, and distillation is recommended. This was not done, however it is assumed that there was no difference in the aliquots since they were originally from the same source. Hence the measurements should be valid for comparative purposes).

Results

None of the inhabitants of the covered jars suffered any apparent harm during fumigation. Results were different for some of the invertebrates exposed to the gas. Woven Topsnails (Trochus intextus) seemed particularly susceptible to the effects of fumigation and succumbed within 24 hours. Vikane was also deadly to Spiny Brittle Stars (Ophiocoma erinaceus), Ten-lined Sea Urchins (Eucidaris metularia), and Rock-boring Sea Urchins (Echinometra mathaei), but the effects were not immediate and the animals perished over the course of several days. Rock Anemones (Aiptasia pulchella) and an unidentified zoanthid (Protopalythoa sp.), were 'burned' during the fumigation event but survived (see Figures 3 and 4) and recovered in about 1 week. A green alga (Ulva) and unidentified red algae also survived exposure with no apparent harm or loss of photopigments.

Figure 3. One of the Aiptasia anemones before fumigation with sulfuryl fluoride.

Figure 4. The typical appearance of Aiptasia anemones after exposure to sulfuryl fluoride and chlorocipin. They appear to be 'burned'.

Discussion

When examining the possible effects of sulfuryl fluoride on invertebrates, we must consider that another agent is also used during fumigation - chloropicrin. This is a warning agent (a 'tear gas') released in trace amounts into the structure to drive out people or animals the inspector might have missed (there's a scary thought).
Sulfuryl fluoride is soluble in water (solubility = 750 ppm), and in alkaline water (including seawater) it undergoes rapid hydrolysis and forms fluorosulfuric acid (HSO₃ F) and fluoride. Hence we would expect to see a drop in pH when Vikane dissolved into the water - and this was noted in the open jar monitored for pH. See Figure 5.

Figure 5. Water pH fell sharply when chlorocipin and sulfuryl fluoride were released into the structure. The green line marks the beginning of fumigation, and the red line is when the 'tent' was removed and structure ventilation began.

Additionally, we would expect to see an increase in fluoride in the 'exposed' water. This, too, was noted - several days after fumigation, elevated fluoride was found in the water of the jars exposed to the fumigation gases. Natural seawater is used and the covered jars contained ~1 mg/l fluoride while the 'exposed' jars contained an average of 2.2 mg/l fluoride.
Air temperature and hence water temperatures stayed within an acceptable range during the experiment. See Figure 6.

Figure 6

Photosynthetically active radiation stayed at low values during the 12 hour photoperiod. Inadvertently, PAR records indicated exact times the tent was placed on and removed from the structure (the jars were situated near a window; data not shown).
Dissolved oxygen was not measured in the jars but aeration was probably sufficient. Further, decaying matter exerts an oxygen demand and none of the containers with mortalities generated any signs of anoxic or anaerobic activity (judged visually and by smell).
The results from this brief experiment suggest that temperature and pH modulations were not severe enough to cause distress or death in the affected animals. However, swings in these parameters correlated exactly with the release of the pesticide and its warning agent. Further, elevated fluoride levels found in the 'open' containers several days after exposure suggest sulfuryl fluoride did contribute to the demise of the marine invertebrates.
On a happier note, the specimens in the covered and aerated containers suffered no mortalities. This suggests that covering an aquarium with NyloFume™ bags and providing aeration from a source outside of the affected structure is sufficient to prevent contact with either the warning agent or pesticide.
Based on this evidence, I'll elect to keep the aquaria inside the house and exercise all due precautions next time fumigation is needed. I lost a captive-bred Flame Angel due to stresses of moving him about (and not due to any effects of the pesticide). In retrospect, I should have simply covered the tanks and maintained good aeration and water circulation. If you find yourself in the same situation, where sulfuryl fluoride is the fumigant, perhaps you should consider this too. Discuss this with a licensed professional and reach an understanding first. My limited experiences suggest you and your aquarium will make it through just fine.

References

1. American Public Health Association, 1998. Standard Methods for the Examination of Water and Wastewater. Washington, DC.
2. Environmental Protection Agency, 2008. Structural fumigation using sulfuryl fluoride: DowElanco's Vikane gas fumigant. http://www.epa.gov/ozone/mbr/casestudies/volume2/sulffury2.html
3. Hach Company, 1997. DR2010 Spectrometer Handbook. Loveland, Co.
4. Kollman, W., date unknown. Environmental fate of sulfuryl fluoride. Environmental Monitoring Branch, Sacramento, Ca.

Termite Fumigation Issues

Have you recently found out that you have a serious termite infestation? Have you just been told that you will have to use gas on them because it is the fastest method of termite control and you do not have any time to lose? If so, poisonous gas probably is the only answer.
However no one would condemn you for being a little concerned about having your house filled with poisonous gas. It does not sound a very healthy environment to have to live, eat and sleep in afterwards, does it? The good news is that there is little cause for concern, especially if you use a reputable firm with a history of using gas on termites.
Vikane is one of the most commonly used gases for the fumigation of termites. It is usually used with a practice called tenting. Tenting means quite literally erecting a tent over the whole structure involved, say your house.
The tent is then sealed as much as possible, the Vikane gas is pumped in and fans are utilized to make sure that it is circulated throughout your house, including your attic and basement. The gas is left to do its deadly work for a day within the sealed up tent and within your house.
On the second day, the tent is taken off and the house is aired using the fans again. Delicate instruments are used to determine the levels of gas in all parts of your home and when the pest controller is convinced that the levels of gas have dropped to where your house is safe for human occupancy, you will be permitted to move back in. That will typically be on the third day.
Vikane does not leave a sticky deposit, so it will not leave a film on your furnishings which you will have to clean off later. When the house has been thoroughly ventilated, all the gas will have disappeared, although there may still be a few innocuous pockets left behind rafters and joists in the attic and basement.
Tenting your house may give you grounds to think that the gas must be dangerous for surrounding wildlife or your neighbours, but this is not the reason for tenting. The tent is erected in order to retain the gas against the outside of the exterior walls of your house as well, so that it is treated from inside and out, although it does help stop wasting gas also.
This tenting method of fumigation with Vikane is a very successful method of eliminating an infestation of termites from a building. In fact, it is so efficient that your contractor should issue you with a warranty, although you may have to have the process repeated every year or two in order to maintain the warranty.
Vikane is aimed solely at termites, so it will not eradicate any other eco-system that has established itself within your house. It will not kill spiders, ants, bed bugs or cockroaches. More's the pity, I can hear you saying.

The Facts About Fumigation

Subjecting a home to fumigation is one of the easiest and fastest ways to rid a home of an insect infestation.The chemicals that are used in the process are very effective and can get into areas that other types of home pest control products would not be able to reach. Whether or not to use fumigation to rid your home is a personal decision that has several pros and cons associated with it.
How Fumigation Is Done
Fumigation is a process that can be done by either the homeowner or a trained professional. If the homeowner would like to fumigate the home on their own, they will need to purchase the poison fog that will be used to kill all of the insects that are present in the home. Typically sold as foggers or bug bombs, these products have specific instructions on the label as to how to activate the poison and how many of the units should be used for an area of a particular size.
If the fumigation is being done by professionals, then they will usually place a plastic tent over the home to hold in the poisonous fumes. Then they will pump enough of the poisonous gases into the home to fill every nook, cranny, and hiding places where there may be an insect to be killed. The chemicals used in fumigation are very strong, so it is important that nothing living is in the home except for the insects that the homeowner wants to kill.
Issues Associated With Fumigation
There are a number of different issues that are associated with the fumigation of a home. One of the biggest issues is that the poisonous fumes permeate everything in the home and will take a couple of days to clear out of the home completely. Homeowners that enter the home before it is properly ventilated and breathe in the fumes may become ill from the exposure to the chemicals.
Furniture, fabrics, and curtains that are exposed to the fumigation fumes can hold these chemicals for weeks if not properly cleaned after the treatment. Sometimes the furniture will need to be exposed to the fumes of the fumigation to kill any insects that are lurking within, but when people resume the use of these furniture items, they can become sick from the residue from the poison. Many people hire a cleaning agency to come and detail their home after they have had a fumigation done to clean up any carcasses from the insects as well as wash all of the fabric items in the home to remove the fumes and residue from the treatment.

If A Pest Infestation Has Occurred, Pest Fumigation May Be Necessary!

Pest problems can be annoying and dangerous. Whether its ants in your cupboards, or rats in the roof of your house, you may need to call a pest control services company to eliminate the problem. When pests take over business premises such as restaurants or food storage companies, they can be a health hazard. In such cases, pest fumigation may be the only solution.
Cockroaches are common culprits, and they are not fussy about what habitat they encroach upon. Apparently, there is only one type of food that a cockroach will not eat. It's cucumber! Everything else is on the menu. Cockroaches are found in homes and businesses, and they are a real menace. They crawl in, fly in, eat anything and everything they can find and, of course, they breed.
Cockroaches, if left unchecked, can cause health problems to humans. Food poisoning has also been linked to pest infestations, particularly cockroaches. They secrete allergens which can be very dangerous for people who suffer with respiratory problems.
There are however other pests that cause destruction in a home or business premises. These include fleas, bees, wasps, bed bugs, spiders, rodents and termites. If the pest control company cannot solve the problem with chemical sprays, pest fumigation may be recommended.
Pest fumigation is a pest control method that fills an entire building with fumigants that will either poison or suffocate the pests inside. It is often the only way to get rid of termites and wood boring insects that are causing extensive damage to wooden areas in a home or factory.
The building to be fumigated is first completely covered with large tarpaulins or 'tents'. The fumigant is then released inside the building. The building will remain covered for a certain period of time. This allows the fumigant to penetrate all areas and kill the pests.
After this, the building is ventilated so that the poison can disperse. It will then be safe for humans to re-enter the premises. The reason for the tarpaulins is to prevent the fumigant escaping and causing potential harm to neighbouring people / buildings. The pest fumigation process can take up to a week to complete, depending on the level of infestation and the size of the building.
Methyl bromide was the most commonly used fumigant until it was banned because it harms the ozone layer. Present day fumigants include phosphine, chloropicrin, hydrogen cyanide, methyl isocyanate, iodoform, sulfuryl fluoride, and iodoform. A popular choice among many pest control services is sulfuryl fluoride.
Sulfuryl fluoride has the ability to kill pests at any stage of their lives, including eggs. It does not harm the ozone layer and it is not associated with the dangers of phosphine. Sulfuryl fluoride is used widely as a pest fumigant to control dry wood termites that thrive in warm climates. It is also effective for the eradication of bark beetles, powder post beetles, rodents and bed bugs.
Pest fumigation is a dangerous operation. It must be carried out by competent personnel or registered pest control companies that are in possession of the correct certification that allows them to perform pest fumigation operations.

Basics of Ultrasonics

By Controlled Environments

Created 2010-12-28 01:41

Barbara Kanegsberg

Ed Kanegsberg

You don’t clean without energy. It takes energy to overcome the forces binding contaminants to the substrate. In most cleaning systems, a liquid cleaning agent is used; and energy, beyond the innate solvency properties of the cleaning agent, is required. This energy can come from the motion of atoms and molecules, such as from the kinetic energy associated with high temperatures. The motion associated with liquid spray is another source of kinetic energy widely used in critical cleaning. Another method for providing this motion is from sound waves in the ultrasonic frequency range.
Ultrasonics have proven to be an effective tool for many critical cleaning applications, ranging from initial cleaning after machining to final assembly in controlled environments. The forces associated with ultrasonics are very powerful; the local atoms have kinetic motions equivalent to temperatures as hot as the surface of the sun. The phenomenon is instantaneous and transient, so that successful cleaning with ultrasonics can be achieved without damage to fragile surfaces. Ultrasonics include omni-directional action. In contrast with line-of-sight processes, this allows the cleaning energy to reach complex surfaces, in some cases including blind holes. Both particulates and thin films can be removed from surfaces by ultrasonic action.
HOW ULTRASONICS WORKS
Generation of sound waves in a liquid in an ultrasonic tank is analogous to generation of sound waves in air by an audio system. A transducer converts electrical signals to mechanical vibrations that generate sinusoidal sound waves in the liquid. The sine wave has a positive or compressive phase during which liquid molecules move toward one another, and a negative or rarefaction phase during which the molecules move away from each other. The instantaneous pressure, P, in the fluid at time, t, can be expressed as

When Ps > Po, the pressure during the rarefaction phase is reduced to less than the vapor pressure of the liquid. During this time of “negative” pressure, a tear or vacuum “bubble” will form and grow. During the subsequent compression, the bubbles suddenly collapse, creating shock waves and microjets of fluid (Figure 1).¹ It is these shock waves or microjets, not the transducer generated sound, that provides the energy to dislodge unwanted soils. The creation and collapse of vapor bubbles is called “cavitation.”

MORE IS NOT NECESSARILY BETTER
The frequency and amplitude of the ultrasonic sound waves determine the energy created by the collapsing cavitation bubbles. The energy increases with increasing amplitude but decreases with increasing frequency. As the frequency increases, the positive and negative phases of the sine wave become shorter. As a result, smaller, “gentler” bubbles are produced.
Any force, including ultrasonic forces used in cleaning, has the potential for both positive and negative effects. The shock waves and jets that dislodge soil can also dislodge (erode) the underlying surface, the substrate that is being cleaned. On a macro level, cavitation also occurs with ship propellers creating vacuum tears in the liquid. This causes erosion that is a major cause of ship and boat propeller failure. Therefore a balancing act, a compromise, must be reached—sufficient energy to dislodge the soils but not so much as to damage the substrate. Substrates from softer metals, like aluminum and copper, are more easily damaged. This does not mean that one can not use ultrasonics to clean them, but rather that the process must be appropriately controlled. In fact, it is important to consider potential damage issues when considering any cleaning force. For example, many critical cleaning processes use high-pressure spray in air. When miniature components are cleaned using inline systems, longer exposure to high-pressure spray may be recommended. Excessively high impingement spray can damage delicate components; just as, on a macro level, wind-driven rain can damage property.
Commercially available ultrasonic systems have frequencies that range from 20kHz to over 400kHz. The lower end (20kHz-40kHz) are effective for hard metals, such as steel or titanium, and for removal of larger particles. Higher frequency units, because the duration of negative pressure is shorter, create cavitation with smaller bubbles and “gentler” implosions and are less likely to damage the surface. The higher frequencies can also be more effective at reaching small particles. This is because, as cavitation energy decreases at high frequency, a fluid flow effect called “acoustic streaming” dominates and can penetrate a fluid surface boundary layer to reach the smaller particles. At even higher frequencies, above about 500kHz, the cleaning process, essentially entirely from acoustic streaming, is referred to as megasonics. Acoustic streaming is unidirectional as are classic megasonic systems; and megasonics is traditionally used in microelectronics where surfaces are flat.
Some ultrasonics systems feature multiple frequencies in the same tank to address both large and small particles.² There are many other parameters that affect the efficacy of an ultrasonic system.³ One of those parameters is the liquid medium in the tank. Bubble collapse is a function of viscosity, surface tension, and temperature. For instance, adding a surfactant to water lowers its surface tension, and makes the creation of cavitation bubbles easier. At low temperatures, viscosity impedes cavitation; at temperatures close to the boiling point, a high vapor pressure causes vapor filled or “squishy” bubbles, reducing the impact of the collapse. For water, there is an optimal temperature at about 55°C.⁴
References

1. J. Fuchs, “The Fundamental Theory and Application of Ultrasonics for Cleaning,” Handbook for Critical Cleaning, B. Kanegsberg and E. Kanegsberg, editors; CRC Press (2001).
2. K. Gopi & S. Awad, “Ultrasonic Cleaning with Two Frequencies,” Handbook for Critical Cleaning, Second Edition, B. Kanegsberg and E. Kanegsberg, editors; CRC Press (expected 2011).
3. B. Kanegsberg & E. Kanegsberg, “Parameters in Ultrasonic Cleaning for Implants and other Critical Devices,” Journal of ASTM International, April 2006, Vol. 3, No.
4. 4. L.D. Rosenberg, “On the Physics of Ultrasonic Cleaning,” Ultrasonic News, 4, p. 16 (1960).

Estimating Hydrochloric Acid and Ammonium Hydroxide Loss

Mark Caulfield

C. W. Extrand

Sung In Moon

Calculations suggest break-through from semiconductor bulk chemical distribution systems occurs in a matter of days and steady state permeation accounts for several milliliters of chemical loss each day.
Permeability (P) and diffusion (D) coefficients were measured for hydrogen chloride and ammonia gas transport through a polytetrafluoroethylene copolymer, perfluoroalkoxy (PFA), using standard manometric techniques. These data were subsequently used to estimate the performance characteristics, such as break-through times and permeation rates, of a representative chemical distribution system that might be found inside a semiconductor wafer fabrication facility. Our findings suggest that break-through occurs in a matter of days and that steady state permeation can account for the loss of several grams of hydrochloric acid or ammonium hydroxide each day. This loss rate for hydrogen chloride would be equivalent to dumping five milliliters of concentrated hydrochloric acid on to the floor of a fabrication facility each day, or more likely into the secondary containment sub-system, and allowing the acid to dissipate over the course of a day. This equates to two liters per year. Everything else being equal, the loss rate of ammonium hydroxide is expected to be more than two times that of hydrochloric acid. To prevent accumulation of hydrogen chloride or ammonia, the secondary containment sub-system must be purged. The necessary purge rate can be estimated using the mass transport data making this study useful to facility planners and operators.
Among melt-processable thermoplastics, tetrafluoroethylene (TFE) - perfluoroalkoxy copolymers, often abbreviated simply as PFA, have a unique combination of purity, toughness, and nearly universal chemical inertness. Therefore, PFA has been used broadly for the transport and storage of high purity chemicals in semiconductor wafer fabrication facilities or “fabs.”^1,2 Although much is known about the purity, mechanical, and thermal properties of PFA,^3-5 less information is available regarding its permeation characteristics.
Some permeation testing has been performed on PFA,^6-13 but most studies have not addressed two of the most widely used semiconductor process chemicals, hydrochloric acid and ammonium hydroxide. The active ingredient in both of these aqueous chemicals is dissolved gas, hydrogen chloride or ammonia, respectively. Thus, they are quite mobile and have caused concerns about unwanted permeation, cross-contamination, and corrosion.¹³ In this article, we explore breakthrough times and steady-state permeation rates of hydrogen chloride and ammonia for a PFA chemical distribution system.
A REPRESENTATIVE BULK CHEMICAL SYSTEM
In the following examples, we use a representative bulk chemical system that could be used for distributing hydrochloric acid or ammonium hydroxide. It is shown schematically in Figure 1. The distribution system consists of a bulk chemical container, a pump, tubing, pipe, and valves. The various PFA components are tabulated in Table 1. The valves are mounted inside containment boxes. The chemical, hydrochloric acid or ammonium hydroxide, is pumped from a chemical container through a one inch (25 mm) PFA supply line to three tee boxes that each contain two PFA drop valves. The drop valves feed six valve boxes that in turn distribute the chemical to 30 points of use via ¾ inch (19 mm) PFA tubing. Unused chemical is sent back to the storage container through a one inch PFA return line. For simplicity, we assume that all components are constructed from PFA.
Tee and valve boxes would typically be fabricated from polypropylene (PP). The tee boxes shown here have dimensions of 48 cm x 42 cm x 24 cm. The valve boxes are larger, approximately 90 cm x 80 cm x 30 cm. Although not shown, a typical system would also have secondary containment around the runs of pipe and tubing, often two inch (50 mm) poly vinyl chloride (PVC) pipe.
Table 1 also includes quantities and dimensions of the chemical distribution components: length (L), thickness (B), surface area (A), and fractional surface area (fA) relative to the entire system. The total surface area is 660,529 cm², which can inconspicuously allow chemical to escape the PFA via permeation. This system has a large surface area that is approximately equivalent to one side of a volleyball court (66 m² or 710 ft²). The total length of the system is one kilometer, so it is not surprising that most of the surface area is from the tubing and pipe, which accounts for >98% of the total surface area. Almost all of that area (97%) lies outside the tee and valve boxes. The remainder of the wetted surface area listed in Table 1 is from the valve diaphragms. We also estimated the area of the valve bodies, a total sum of 12,600 cm². This is much larger than the area associated with the diaphragms (1,660 cm²).


MASS TRANSPORT PROPERTIES OF PFA
Permeability (P) and diffusion (D) coefficients of PFA for both hydrogen chloride and ammonia gas were measured at 25°C by standard manometric techniques. ¹⁴ Gas pressures for hydrogen chloride ranged between 15 and 25 cmHg or for ammonia, from 42 to 47 cmHg. Values of P and D did not depend on gas pressure in these ranges. Their averages are summarized in Table 2. The diffusion coefficient describes the mobility of a molecule in a material, while the permeability coefficient is an inherent material property that describes the normalized “flow” rate through a material. Greater solubility of ammonia in PFA led to a permeability coefficient (P) that was nearly two times larger than for hydrogen chloride. The measured values agreed with the few published values found in open literature.^9,13

PERFORMANCE OF THE BULK CHEMICAL SYSTEM
Break-through times. If hydrochloric acid or ammonium hydroxide were introduced into our representative distribution system, how much time would pass before hydrogen chloride or ammonia gas would begin to appear at the outer surface of our PFA components? The break-through time (tb) depends on the sample thickness (B) and the diffusion coefficient (D) of the material,¹⁵

Assuming we have a perfectly sealed system, breakthrough of hydrogen chloride or ammonia would occur first in the thinnest wall sections of the valve diaphragms (7-8 hours). These gases would begin to emerge from the tubing in tb = four to five days.
Steady state permeation rates. Once break-through occurs, steady state is generally reached after 3tb.¹⁵ For the tubing in this system, that would happen approximately three weeks after introduction of hydrochloric acid or ammonium hydroxide into the dry system. If we assume the concentration in the surrounding atmosphere (tee boxes, valve boxes, and containment sub-systems, etc.) is effectively zero and is kept there, then volumetric loss rates (Q) due to permeation can be estimated from each component using the following equation,^15,16

where q is the volume of gas at standard temperature and pressure (To = 0°C = 273 K and Po = 1 atm = 76 cmHg) that permeates, t is time, P is the permeability coefficient, B is the component thickness, A is the area (A), and (ph) is the internal partial pressure of the gas. In turn, the volumetric loss rates can be converted into mass loss rates (m˙ ) using the ideal gas law,

where M is the molar mass of the gas in question (36.46 g/mol for HCl and 17.03 g/mol for ammonia) and R is the ideal gas constant (6236.6 cm3cmHg/K•mol). Steady state permeation rates depend on the vapor pressure of hydrogen chloride and ammonia, which are determined by the concentrations of hydrochloric acid and ammonium hydroxide. In the calculations, we used 22.5 cmHg for hydrogen chloride and 47.0 cmHg for ammonia as vapor pressures. These numbers represent 37% hydrochloric acid and 25% ammonium hydroxide, respectively.
Considering one of the components as a scenario— the chemical supply line is comprised of 152 m of one inch PFA tubing. Under steady state conditions, it would be expected to lose 225 standard cm³ of hydrogen chloride gas per day to permeation or 832 standard cm3 per day of ammonia. On a mass basis, this equates to 0.37 g or 0.63 g per day, respectively. Steady state mass loss rates are listed in Table 3 for all components. Since most of the area available for transport is found in the tubing, it accounts for most of the steady state gas loss. The daily totals are 2.1 g/day for hydrogen chloride and 3.6 g/day for ammonia. These loss rates of hydrogen chloride and ammonia can be converted into the amount of hydrochloric acid and ammonium hydroxide using concentration and density. The loss rate for hydrogen chloride would be equivalent to dumping five milliliters of concentrated hydrochloric acid on to the floor of a fab each day, or more likely into the secondary containment sub-system, allowing the acid to dissipate over the course of a day. This equates to two liters per year. Everything else being equal, the loss rate of ammonium hydroxide is expected to be more than two times that of hydrochloric acid.
Removal of permeants from the secondary containment sub-system. If we assume the secondary containment sub-system for a hydrochloric acid or ammonium hydroxide line is sealed and isolated from the ambient fab environment, it should be purged periodically to prevent accumulation of errant hydrogen chloride or ammonia. At the other extreme, if it were required to maintain levels of either gas in the secondary containment below the Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL), then constant purging of the sub-system would be necessary.
Again, let us use hydrogen chloride to make a few estimates. Without purging, the rate of accumulation will vary throughout the system. Hydrogen chloride levels will rise more slowly in the large valve boxes and more quickly in the confines of the tubing secondary containment. Therefore, to minimize hydrogen chloride concentration rise in the secondary containment sub-system, it is sufficient to address the smallest annular volume surrounding the tubing outside the boxes.
The daily hydrogen chloride loss at 25°C from a unit length of one inch tubing is 0.016 cm³ per day, while the annular volume of a unit length of secondary containment is 15 cm³. The OSHA PEL for hydrogen chloride is 5 ppm.¹⁷ In order to dilute the hydrogen chloride gas to this level, the air volume inside the containment sub-system should be turned over roughly 200 times per day. This corresponds to a residence time of seven minutes. Thus, the purge gas flow rate through the containment sub-system (0.8 m3) should be 0.1 m3/min (3.5 ft³/min). The highest purge gas velocities would occur in the PVC conduit containing the one inch PFA tubing. With an annular cross-sectional area of 15 cm², the average velocity in the conduit would be 75 m/min (4.5 km/hour = 3 mi/hour).


CONCLUSIONS
Permeability and diffusion coefficients of hydrogen chloride and ammonia gas were measured for PFA and then used to estimate the performance of a representative bulk chemical distribution system in a semiconductor wafer fab constructed from PFA. Our calculations suggest that for real systems, break-through occurs in a matter of days and steady state permeation accounts for several milliliters of chemical loss each day. Most of that loss comes from the long runs of tubing that transport chemical throughout fabrication facilities. To prevent accumulation and maintain very low levels of hydrogen chloride or ammonia, the secondary containment sub-system must be purged. The purge rate can be estimated using mass transport data.
Acknowledgements
We thank Entegris management, especially D. Brettingen, R. Lindblom, and B. Reichow for supporting this work and allowing publication. Also, thanks to E. Adkins, A. Anderson, B. Arriola, S. Cantor, C. Duston, L. Goedecke, J. Goodman, J. Hennen, T. King, S. Moroney, S. Sirignano, and V. Szpara for their suggestions on the technical content and text.
References

1. Khaladkar, P.R., “Fluoropolymers for Chemical Handling Applications,” Scheirs, J. (Ed.), Modern Fluoropolymers, Wiley, New York, 1997, Chapter 16.
2. Extrand, C.W., “The Use of Fluoropolymers to Protect Semiconductor Materials,” Journal of Fluorine Chemistry, 2003, 122, 121.
3. Goodman, J., Andrews, S., Solid State Technol. 1990, 33, 65–68.
4. Goodman, J., Van Sickle, P.M., Microcontamination. 1991, 9 ,21–25.
5. Kerbow, D.L., Sperati, C.A., “Physical constants of fluoropolymers,” Polymer Handbook, 4th ed.; Brandrup, J., Immergut,E. H., Grulke, E. A., Eds., Wiley: New York, 1999, pp. V31–V58.
6. Giacobbe, F. W. J Appl Polym Sci 1990, 39, 1121–1132.
7. Giacobbe, F. W. J Appl Polym Sci 1991, 42, 2361–2364.
8. Giacobbe, F. W. J Appl Polym Sci 1992, 466, 1113.
9. Pauly, S. Polymer Handbook, 4th ed.; Brandrup, J., Immergut, E. H., Grulke, E. A., Eds., Wiley: New York, 1999.
10. Monson, L., Moon, S.I., Extrand, C.W., “Gas Permeation Resistance of Various Grades of Perfluoroalkoxy-polytetrafluoroethylene Copolymers,” Journal of Applied Polymer Science, 2009, 111, 141- 147.
11. De Angelis, M. G.; Sarti, G. C.; Sanguineti, A.; Maccone, P. J Polym Sci Part B: Polym Phys 2004, 42, 1987–2006.
12. Aminabhavi, T. M.; Naidu, B. V. K. J Appl Polym Sci 2004, 92, 991–996.
13. Grant, D. & Carrieri, D. “The effect of HCl permeaton through PFA on expected component life,” Fabtech, Vol 37, 01 March 2008, 101-105.
14. Standard Test Method for Determining Gas Permeability Characteristics of Plastic Film and Sheeting; American Society for the Testing of Materials: West Conshohocken, PA, 1998; ASTM D1434-82. Test Method for Gas Transmission Rate through Plastic Film and Sheeting; Japanese Industrial Standard: Tokyo, Japan, 1987, JIS K7126.
15. Crank, J. The Mathematics of Diffusion; Oxford University Press: London, 1970.
16. Daynes, H. A., The Process of Diffusion through a Rubber Membrane, Proceedings of the Royal Society of London. Series A, Containing Papers of a Mathematical and Physical Character, 1920, 97, 286.
17. “Occupational Safety and Health Guidelines for Hydrogen Chloride.” United States Department of labor. 22 Oct. 2010. http://www.osha.gov/SLTC/healthguidelines/hydrogenchloride/ recognition.html.