Sterility Assurance Level Research Articles

A Histological and Biomechanical Analysis of Human Acellular Dermis (HAD) Created Using a Novel Processing and Preservation Technique.

Large and complex defects requiring reconstruction are challenging for orthopaedic surgeons. The use of human acellular dermal (HAD) matrices to augment large soft tissue defects such as those seen in massive rotator cuff tears, knee extensor mechanism failures and neglected Tendo-Achilles tears has proven to be a valuable tool in surgeons reconstructive armamentarium. Different methods for allograft decellularization and preservation alter the native properties of the scaffold. Traditional processing and preservation methods have shown to have drawbacks that preclude its widespread use. Some of the common issues include inferior biomechanical properties, the risk of rejection, limited customization, difficulty in storing and transporting, the requirement of pre-operative preparation, and last but not the least increased cost. We describe a novel processing and preservation method utilizing a two-step non-denaturing decellularization method coupled with preservation using a water-sequestering agent (glycerol) to remove immunogenic components while retaining biomechanical properties. The efficiency of this novel process was compared with the traditional freeze-drying method and verified by histological evaluation and biomechanical strength analysis. The absence of cellular components and matrix integrity in hematoxylin and eosin-stained glycerol-preserved HAD (gly-HAD) samples compared to freeze-dried HAD (FD-HAD) demonstrated effective yet gentle decellularization. Biomechanical strength analysis revealed that gly-HADs are stronger with an ultimate tensile load to the failure strength of 210 N compared to FD-HAD (124N). The gly-HADs were found to have an optimal suture-retention strength of 126 N. Finally, sterility testing of the resultant grafts was checked to ensure a sterility assurance level of 10-6 to establish implantability. The novel processing and preservation technique is described in this paper to create a Human Acellular Dermis with higher biomechanical strength and superior histological characteristics. The processing and preservation technique ensured high sterility assurance levels to establish implantability.

Sterilization effects on nitric oxide-releasing glucose sensors

Nitric oxide (NO) release from S-nitrosothiol-modified mesoporous silica nanoparticles imbedded in the diffusion limiting layer of a glucose sensor has been demonstrated as an effective strategy for mitigating the foreign body response common to sensor implantation, resulting in improved analytical performance. With respect to potential clinical translation of this approach, the effects of sterilization on NO-releasing biosensors require careful evaluation, as NO donor chemistry is sensitive to temperature and environment. Herein, we evaluated the influence of multiple sterilization methods on 1) sterilization success; 2) NO payload; and 3) sensor performance to establish the commercialization potential of NO-releasing glucose sensors. Sensors were treated with ethylene oxide gas, the most common sterilization method for intricate medical devices, which led to undesirable (i.e., premature) release of NO. To reduce NO loss, alternative sterilization methods that were studied included exposure to ultraviolet (UV) light and immersion in 70 % ethanol (EtOH). Sterilization cycle times required to reach a 10−6 sterility assurance level were determined for both UV light and 70 % EtOH against Gram-negative and -positive bacteria. The longest sterilization cycle times (258 s and 628 s for 70 % EtOH and UV light, respectively) resulted in a negligible impact on benchtop sensor performance. However, sterilization with 70 % ethanol resulted in a reduced NO-release duration. Ultraviolet light exposure for ∼10 min proved successful at eliminating bacteria without compromising NO payloads or durations and presents as the most promising method for sterilization of these sensors. In addition, storage of NO-releasing sensor membranes at –20 and –80 °C resulted in preservation of NO release for 6 and 12 months, respectively.

Development and optimization of a one step process for the production and sterilization of liposomes using supercritical CO2

Liposomes are very interesting drug delivery systems for pharmaceutical and therapeutic purposes. However, liposome sterilization as well as their industrial manufacturing remain challenging. Supercritical carbon dioxide is an innovative technology that can potentially overcome these limitations. The aim of this study was to optimize a one-step process for producing and sterilizing liposomes using supercritical CO2. For this purpose, a design of experiment was conducted. The analysis of the experimental design showed that the temperature is the most influential parameter to achieve the sterility assurance level (SAL) required for liposomes (≤10−6). Optimal conditions (80 °C, 240 bar, 30 min) were identified to obtain the fixed critical quality attributes of liposomes. The conditions for preparing and sterilizing empty liposomes of various compositions, as well as liposomes containing the poorly water-soluble drug budesonide, were validated. The results indicate that the liposomes have appropriate physicochemical characteristics for drug delivery, with a size of 200 nm or less and a PdI of 0.35 or less. Additionally, all liposome formulations demonstrated the required SAL and sterility at concentrations of 5 and 45 mM, with high encapsulation efficiency.

UV Reflectance of Spacecraft Materials and Analog Soils: Implications for Bioburden Reductions on the Undersides of Mars Rovers

AbstractThe Mars Sample Return mission architecture will utilize three spacecraft to collect, cache, recover, launch, and return to Earth a diversity of regolith and rock samples. However, no comprehensive Mars Microbial Survival (MMS) model currently exists. As an initial effort in building an MMS model, we examined the UV reflectance of 15 spacecraft materials and seven Mars analog soils within the context of the Perseverance mission. Data were used to predict the times required to achieve one lethal dose (syn., Sterility Assurance Level [SAL]; def. as a bioburden reduction of −12 logs). Results suggest that a single SAL dosage of UVC was achieved on exposed surfaces on the upper deck of Perseverance within a few hours to a few sols post‐landing at Jezero Crater. The overall average for UVC reflectance from spacecraft materials was approximately 10%. The overall UVC reflectance from Mars analog soils was measured at 1.3%. The Adaptive Caching Assembly (ACA) on Perseverance is located on the forward edge of the underbelly of the spacecraft. Modeling of the accumulated UVC dosage for the ACA yielded a prediction of reaching one SAL for downward facing surfaces at 93 sols that receive “single‐bounce” UVC photons from the local terrain. The SAL increases to 930 sols if an additional “bounce” of the solar UV irradiation is required to reach a partially protected site in the ACA hardware. The current study is the first to report the UVC reflectance from a diversity of spacecraft materials.

Determination of the Sterilization Dose of Gamma-Ray Irradiation for Polyvinyl Alcohol-Collagen-Chitosan Composite Membrane as a Material for Periodontal Regenerative Surgery.

Membrane sterility is very necessary considering its function as an implant material. Therefore, this research aims to determine the dose of gamma-ray irradiation for the sterilization of polyvinyl alcohol (PVA)-collagen-chitosan composite membranes used as regenerative surgery materials. A total of 100 pieces of the composite membranes were prepared in a size of 2.0 × 1.5 cm by mixing 7.5% PVA, 3% collagen, and 2% chitosan using the film casting method in three batches. Furthermore, the bioburden test was performed to determine the initial microbial count in the sample by following ISO 11737-1. The results were used to ascertain the dose of gamma-ray irradiation on the sample according to ISO 11137-2. The dose verification test was then performed at the sterility assurance level 10-6. The average result of the bioburden test from three batches was 6.6 colony forming unit; hence, the verification dose was 4.8 kGy. In the verification dose test, since there was only one contaminated sample, the sterility dose test was continued. The sterile gamma-ray irradiation dose for PVA-collagen-chitosan composite membrane was 17.1 kGy.

Behavior and linkage mechanism of extracellular polymers, cell membrane peroxides and intracellular peroxidases during high concentration vaporized hydrogen peroxide sterilization

Vaporized hydrogen peroxide (VHP) sterilization has been widely used in the fields of medical care and pharmaceuticals. Extracellular polymeric substances (EPS) connected tightly to the cell membrane is first barrier that must be broken through, and less is known about direct change of cell membrane peroxides, and the linkage mechanism among EPS, cell membrane and intracellular damages is still unclear during high concentration VHP sterilization. After optimizing the VHP sterilization process of specific drug-packaging equipment based on the sterility assurance level of 10−6 cfu, we studied the degradation kinetics of exopolysaccharide, exoprotein, extracellular DNA, and investigated the changes of cell membrane lipid/protein peroxides and intracellular peroxidases, and discussed the linkage mechanism of microbial EPS, cell membrane and intracellular damages during high concentration VHP sterilization. The results indicated: (1) The order of degradation kinetics of microbial EPS was exopolysaccharide > exoprotein > extracellular DNA, it was the key to achieve fast and effective VHP sterilization that sufficient high concentration VHP (>400 ppm) was adopted to rapidly destroy EPS (>20 min), resulting in the serious destruction of proteins and lipids of cell membrane; (2) The key mechanism of short time sterilization using high concentration VHP was that the serious loss of the structure/function of cell membrane was the most fatal but the damage of intracellular enzymes and DNA was limited for bacterial cell living.

Use of supercritical CO2 for the sterilization of liposomes: Study of the influence of sterilization conditions on the chemical and physical stability of phospholipids and liposomes

The effects of four potential supercritical carbon dioxide (ScCO2) sterilization conditions on the chemical stability of 9 phospholipids and on the physicochemical characteristics of liposomes consisting of stable phospholipids, as well as their sterilization efficiency were evaluated. These conditions were : C1 (ScCO2/70 °C/150 bar/240 min), C2 (ScCO2/0.25 % water/ 0.15% H2O2/ 0.5% acetic anhydride/38° C/85 bar/45 min), C3 (ScCO2/0.08 % peracetic acid/35° C/104 bar/180 min) and C4 (ScCO2/200 ppm H2O2/40 °C/270 bar/90 min). The results showed for phospholipids, a significant increase in hydrolysis products of 3.77 to 14.50 % and an increase in oxidation index of 6.10 to 430.50 % with unsaturated phospholipids for all tested conditions while with saturated phospholipids, no significant degradation was observed. Concerning the liposome formulation, no change in dispersion color and no phospholipid degradation were observed. However, a decrease in liposome size from 126.90 nm to 111.80 nm, 96.27 nm, 99.60 nm and 109.13 nm and an increase in the PdI from 0.208 to 0.271, 0.233, 0.285, and 0.298 were found with conditions C1, C2, C3 and C4 respectively. For the sterilization efficiency, conditions C1, C2 and C3 achieved the required sterility assurance level (SAL) of 10-6 for liposomes.

Interventions Risk Evaluation and Management in Aseptic Manufacturing.

Interventions performed by personnel during an aseptic process can be a key source of microbiological contamination of sterile biopharmaceutical products, irrespective of the type of manufacturing system used. Understanding the relative risk of this source of contamination provides valuable information to help make decisions for the design, qualification, validation, operation, monitoring, and evaluation of the aseptic process. These decisions can be used to improve the aseptic process and provide assurance of the sterility of the products. To achieve these goals, an assessment of the contamination risk is needed. This risk assessment should be objective, accurate, and useful. This article presents an Intervention Risk Evaluation Model (IREM) philosophy and an objective, accurate, and useful method for intervention risk determination. The IREM uses a key word approach to identify, obtain, measure, and evaluate intervention risk factors. This article presents a general discussion of the method with the help of a case study to illustrate the development of the model, whereas subsequent parts would focus on application of this model with practical examples. This not only attempts to create objectivity of the entire process, but it develops awareness of the associated risks among shop floor operators, which can lead to a reduction of the overall risk level of the process and an improvement in the sterility assurance level.

Quick and environmentally friendly sterilization process of dental instruments by radical vapor reactor

Dental instruments such as dental burs, endodontic files, scalers, and dental vacuum tips require complete sterilization to protect patients from infection. Generally, these instruments are sterilized by autoclaving or using ethylene oxide gas. However, these sterilization methods require a long time, high energy, and the production of hazardous waste. Therefore, a quick, low-energy, and high-sterilization method that generates no hazardous waste is required in the dental field. A radical vapor reactor (RVR) can sterilize bacteria by producing high concentrations of reactive oxygen species. In this study, we found that RVR can sterilize dental instruments effectively (i.e., under 10 min with green technology), and that packed dental instruments can be completely sterilized in 10 min using RVR treatment. Furthermore, we demonstrated that RVR treatment can meet the sterility assurance level. Thus, we propose the use of RVR technology to perform quick sterilization with a low environmental load.

Enhanced Immunogenicity of a Whole-Inactivated Influenza A Virus Vaccine Using Optimised Irradiation Conditions.

Influenza A virus presents a constant pandemic threat due to the mutagenic nature of the virus and the inadequacy of current vaccines to protect against emerging strains. We have developed a whole-inactivated influenza vaccine using γ-irradiation (γ-Flu) that can protect against both vaccine-included strains as well as emerging pandemic strains. γ-irradiation is a widely used inactivation method and several γ-irradiated vaccines are currently in clinical or pre-clinical testing. To enhance vaccine efficacy, irradiation conditions should be carefully considered, particularly irradiation temperature. Specifically, while more damage to virus structure is expected when using higher irradiation temperatures, reduced radiation doses will be required to achieve sterility. In this study, we compared immunogenicity of γ-Flu irradiated at room temperature, chilled on ice or frozen on dry ice using different doses of γ-irradiation to meet internationally accepted sterility assurance levels. We found that, when irradiating at sterilising doses, the structural integrity and vaccine efficacy were well maintained in all preparations regardless of irradiation temperature. In fact, using a higher temperature and lower radiation dose appeared to induce higher neutralising antibody responses and more effective cytotoxic T cell responses. This outcome is expected to simplify irradiation protocols for manufacturing of highly effective irradiated vaccines.

From Salvage to Prevention: A Single-Surgeon Experience with Acellular Dermal Matrix and Infection in Prepectoral Breast Reconstruction.

Increasing amounts of acellular dermal matrix are being used with the adoption of prepectoral breast reconstruction. Postoperative infection remains a challenge in breast reconstruction, and the contribution of acellular dermal matrix type, processing, and sterility assurance level to risk of complications in prepectoral reconstruction is not well studied. The authors performed a retrospective review of patients who underwent immediate prepectoral breast reconstruction from February of 2017 to July of 2020. Because of an increase in the rate of infection, the drain protocol was changed and acellular dermal matrix type was switched from AlloDerm (sterility assurance level, 10-3) to DermACELL (sterility assurance level, 10-6) in January of 2019. Demographic and surgical variables were collected, in addition to details regarding development and management of infection. Despite higher rates of direct-to-implant reconstruction and bilateral procedures and increased implant volumes, the rate of infection was significantly lower in patients who received DermACELL instead of AlloDerm [two of 38 (5.3 percent) versus 11 of 41 (26.8 percent); p = 0.014]. Drain duration was slightly longer in the DermACELL group, consistent with the change in drain protocol. Baseline demographic and clinical characteristics remained similar between the two groups. With increased reliance on large amounts of acellular dermal matrix for prepectoral breast reconstruction, it directly follows that the properties of acellular dermal matrix with respect to incorporation, sterility, and implant support are that much more important to consider. There have been few studies comparing different types of acellular dermal matrix in prepectoral breast reconstruction, and further research is required to determine the contribution of acellular dermal matrix type and processing techniques to development of postoperative infection. Therapeutic, III.

Effects of radiation dose and nitrogen purge on collagen scaffold properties.

Sterilization of medical devices is commonly performed using radiation methods. However, collagen materials can be damaged when using standard radiation doses (25kGy). Small increases of radiation dose can allow for increases in the acceptable initial bioburden load of aseptically manufactured devices while maintaining required sterility assurance levels, which is often critical in early stage translational settings. In this study, we hypothesized that small increases in radiation dose from 15 to 20kGy would result in significant changes to several key characteristics of collagen scaffolds. Scaffolds were manufactured by lyophilizing the pepsin digest of dense bovine connective tissue in cylindrical molds and were irradiated at either 0, 15, 17.5, or 20kGy with an additional group packaged in nitrogen and irradiated at 17.5 kGy. Groups were evaluated for changes to the soluble collagen and glycosaminoglycan mass fractions, protein banding patterns in electrophoresis, a collagen fragmentation assay, and resistance to enzymatic degradation. All parameters were statistically analyzed using one-way analysis of variance with Tukey's correction for multiple comparisons. The soluble collagen mass fraction was significantly decreased in the 20kGy group; however, there was no significant effect of radiation dose or a nitrogen-rich environment on the other measured parameters, including protein banding patterns, fragmented collagen content, and resistance to enzymatic degradation.Statement of Clinical Significance: Collagen scaffolds have proven useful in clinical applications but can be damaged by standard radiation doses. Low-dose sterilization may be a viable alternative that minimally impacts key properties of these scaffolds.

Sterilization of sealed PVDF pouches containing decellularized scaffold by electrical stimulation.

A terminal sterilization process for tissue engineering products, such as allografts and biomaterials is necessary to ensure complete removal of pathogenic microorganisms such as the bacteria, fungi, and viruses. However, it can be difficult to sterilize allografts and artificial tissue models packaged in wet conditions without deformation. In this study, we investigated the sterilization effects of electrical stimulation (ES) and assessed its suitability by evaluating sterility assurance levels in pouches at a constant current. Stability of polyvinylidene fluoride pouches was determined by a sterility test performed after exposure to five microorganisms (Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, Escherichia coli, and Candida albicans) for 5 days; the sterility test was also performed with decellularized human dermal tissues inoculated with the five microorganisms. Sterilization using ES inactivated microorganisms both inside and outside of sealed pouches and caused no damage to the packaged tissue. Our results support the development of a novel system that involves ES sterilization for packaging of implantable biomaterials and human derived materials.

Gamma sterilization of collagen/hydroxyapatite composites: Validation and radiation effects

In this work, gamma sterilization was validated, and the impact of this sterilization process on collagen/hydroxyapatite (Col/HAp) composites was investigated. It has been already recognized that the improper sterilization of healthcare products may lead to infection and mortality/morbidity issues in patients. Gamma sterilization has emerged as a promising sterilization method because it shows advantages such as low cost, a small increase in temperature of irradiated materials, and no production of toxic residues. Moreover, gamma rays can reach the products even when contained in sealed packages. The dose of gamma radiation applied in this study ranged from 17.5 to 50 kGy. The studied samples were examined by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), thermogravimetry (TG), and differential scanning calorimetry (DSC). No apparent effect of gamma radiation on HAp was observed even when doses as high as 50 kGy were applied. On the other hand, Col was greatly affected by gamma radiation, displaying cross-linking and degradation after sterilization. These structural changes may alter Col's properties, which could, in turn, impact its medical use. As a consequence, it is strongly recommended that the irradiation dose used to sterilize the Col/HAp composites shall be kept as low as possible to mitigate the structural changes induced in Col. It was noticed that a radiation dose of 17.5 kGy was sufficient to sterilize the examined samples because a sterility assurance level (SAL) below 10−6 was detected. Although dramatic structural changes were observed in Col when this dose was applied, the sterilized samples showed no toxicity to human mesenchymal stem cells. Based on these results, we established a VDMax of 17.5 kGy for Col/HAp-based healthcare products.

Flexible gastrointestinal endoscope processing challenges, current issues and future perspectives

At present, the most frequent method for processing flexible gastrointestinal (GI) endoscopes is cleaning followed by high-level disinfection as terminal sterilization is often not practicable. Post-processing monitoring studies consistently show high levels of positive cultures remaining on endoscopes, which can lead to patient infection and even fatality. The processing deficiency is attributed to the complex design of endoscopes, incomplete cleaning, formation of biofilms and lack of margin of safety with high-level disinfection. To demonstrate that flexible GI endoscopes can be practicably terminally sterilized. An endoscope sterilization cycle was developed in a vaporized hydrogen peroxide sterilization system. The cycle was used to study the sterilization of flexible GI endoscopes which included colonoscopes and duodenoscope and material compatibility for both original flexible GI endoscopes and those experimentally modified endoscopes using compatible materials. Testing demonstrated that the vaporized hydrogen peroxide can sterilize flexible GI endoscopes (colonoscopes, duodenoscope) with a sterility assurance level of 10-6. Additionally, no recoverable survivors were detected when devices were artificially soiled with hard water and serum. Material compatibility test results demonstrated that replacing molybdenum disulphide lubricant with a graphite-based inert lubricant can make them compatible with vaporized hydrogen peroxide sterilizers. Flexible GI endoscopes can be practicably terminally sterilized using vaporized hydrogen peroxide sterilization technologies if their materials are revised to become compatible.

Advancing the Sustainable Use of Ethylene Oxide through Process Validation.

Based on excellent material compatibility and ability for scale, ethylene oxide (EO) sterilization constitutes approximately 50% of single-use medical device sterilization globally. Epidemiological considerations have elevated focus toward optimization of EO processes, whereby only necessary amounts of sterilant are used in routine processing. EO sterilization of medical devices is validated in accordance with AAMI/ANSI/ISO 11135:2014 via a manner in which a sterility assurance level (SAL) of 10-6 is typically achieved, with multiple layers of conservativeness delivered, using "overkill" approaches to validation. Various optimization strategies are being used throughout the medical device industry to deliver the required SAL while utilizing only necessary amounts of sterilant. This article presents relevant experiences and describes challenges and considerations encountered in delivering EO process optimization. Thus far, the results observed by the authors are encouraging in demonstrating how EO processing can be optimized in the delivery of critical single-use medical devices for patient care.

Opportunities for the application of real-time bacterial cell analysis using flow cytometry for the advancement of sterilization microbiology.

Medical devices provide critical care and diagnostic applications through patient contact. Sterility assurance level (SAL) may be defined as the probability of a single viable micro-organism occurring on an item after a sterilization process. Sterilization microbiology often relies upon using an overkill validation method where a 12-log reduction in recalcitrant bacterial endospore population occurs during the process that exploits conventional laboratory-based culture media for enumeration. This timely review explores key assumptions underpinning use of conventional culture-based methods in sterilization microbiology. Consideration is given to how such methods may limit the ability to fully appreciate the inactivation kinetics of a sterilization process such as vaporized hydrogen peroxide (VH2O2) sterilization, and consequently design efficient sterilization processes. Specific use of the real-time flow cytometry (FCM) is described by way of elucidating the practical relevance of these limitation factors with implications and opportunities for the sterilization industry discussed. Application of FCM to address these culture-based limitation factors will inform real-time kinetic inactivation modelling and unlock potential to embrace emerging opportunities for pharma, medical device and sterilization industries including potentially disruptive applications that may involve reduced usage of sterilant.

Sterility of gamma-irradiated pathogens: a new mathematical formula to calculate sterilizing doses.

In recent years there has been increasing advocacy for highly immunogenic gamma-irradiated vaccines, several of which are currently in clinical or pre-clinical trials. Importantly, various methods of mathematical modelling and sterility testing are employed to ensure sterility. However, these methods are designed for materials with a low bioburden, such as food and pharmaceuticals. Consequently, current methods may not be reliable or applicable to estimate the irradiation dose required to sterilize microbiological preparations for vaccine purposes, where bioburden is deliberately high. In this study we investigated the applicability of current methods to calculate the sterilizing doses for different microbes. We generated inactivation curves that demonstrate single-hit and multiple-hit kinetics under different irradiation temperatures for high-titre preparations of pathogens with different genomic structures. Our data demonstrate that inactivation of viruses such as Influenza A virus, Zika virus, Semliki Forest virus and Newcastle Disease virus show single-hit kinetics following exposure to gamma-irradiation. In contrast, rotavirus inactivation shows multiple-hit kinetics and the sterilizing dose could not be calculated using current mathematical methods. Similarly, Streptococcus pneumoniae demonstrates multiple-hit kinetics. These variations in killing curves reveal an important gap in current mathematical formulae to determine sterility assurance levels. Here we propose a simple method to calculate the irradiation dose required for a single log10 reduction in bioburden (D10) value and sterilizing doses, incorporating both single- and multiple-hit kinetics, and taking into account the possible existence of a resistance shoulder for some pathogens following exposure to gamma-irradiation.

Disinfection Methods and Survival of SARS-CoV-2 in the Environment and Contaminated Materials: A Bibliometric Analysis

The presence of SARS-CoV-2 in sewage and water resources has been used as an indication for the possible occurrence of the virus among communities and for its potential of transmission among humans through the surrounding environment or water resources. In order to reduce the transmission of SARS-CoV-2, contaminated surfaces should be disinfected frequently by using an effective disinfectant. The present review discusses a bibliometric analysis of the global SARS-CoV-2 research and focuses mainly on reviewing the efficiency of the most traditional disinfection technologies. The disinfection methods reviewed include those for hospitals’ or medical facilities’ wastewater, contaminated surfaces, and contaminated masks. The elimination of the virus based on the concept of sterility assurance level (SAL) is also discussed. In addition, the chemical disinfectants that are currently used, as well as their temporary efficiency, are also reviewed. The different technologies that are globally used for disinfection processes during the COVID-19 pandemic are shown. However, more advanced technologies, such as nanotechnology, might have more potential for higher inactivation effectiveness against SARS-CoV-2.

Radiation Process Control: Product Dose vs. Process Dose.

The requirements for the irradiation of healthcare products have been well established and implemented across the globe for several decades. The ISO 11137 series of standards gives the user the road map for designing a radiation process that will routinely deliver the required sterility assurance level so that product consistently meets specifications. The latest addition to the ISO 11137 series of standards should provide much-needed guidance around establishing a highly reproducible process based on a statistical analysis of the validated state of control. Most industries refer to this as "process control."