Hard-on-Hard Lubrication in the Artificial Hip under Dynamic Loading Conditions

The tribological performance of an artificial hip joint has a particularly strong influence on its success. The principle causes for failure are adverse short- and long-term reactions to wear debris and high frictional torque in the case of poor lubrication that may cause loosening of the implant. Therefore, using experimental and theoretical approaches models have been developed to evaluate lubrication under standardized conditions. A steady-state numerical model has been extended with dynamic experimental data for hard-on-hard bearings used in total hip replacements to verify the tribological relevance of the ISO 14242-1 gait cycle in comparison to experimental data from the Orthoload database and instrumented gait analysis for three additional loading conditions: normal walking, climbing stairs and descending stairs. Ceramic-on-ceramic bearing partners show superior lubrication potential compared to hard-on-hard bearings that work with at least one articulating metal component. Lubrication regimes during the investigated activities are shown to strongly depend on the kinematics and loading conditions. The outcome from the ISO gait is not fully confirmed by the normal walking data and more challenging conditions show evidence of inferior lubrication. These findings may help to explain the differences between the in vitro predictions using the ISO gait cycle and the clinical outcome of some hard-on-hard bearings, e.g., using metal-on-metal.     

Surface slide track mapping of implants for total disc arthroplasty

Total disc arthroplasty has recently become a potential alternative to spinal arthrodesis. Until recently, there has been no standardized method for evaluating the wear of an artificial disc and myriad testing conditions have been used. The American Society for Testing and Materials (ASTM) and International Organization of Standardization (ISO) recently published guidance documents for the wear assessment of intervertebral spinal disc prostheses; however, various kinematic profiles are suggested, leading to different wear paths between the articulating surfaces of the implants. Since the wear between materials is influenced by the type of relative motion, it is important to select test conditions that lead to clinically realistic results. The purpose of this study was to characterize the slide tracks generated by 7 test conditions allowed for by the ISO and ASTM guidance documents and in Euler sequences consistent with 4 commercially available spine wear simulators. The analysis was performed for a ball-in-socket articulation under both lumbar and cervical motion test conditions. Results were generated analytically using a mathematical algorithm and then validated experimentally. Four tests resulted in elliptical sliding tracks of similar geometries for both the lumbar and cervical conditions. Curvilinear and ribbon-shaped wear paths were generated for 3 tests. With the data normalized for implant diameter, the sliding distance was similar between the lumbar and cervical conditions allowed for in the ASTM guidance. This distance differed compared with the results for the ISO guidance document where the lengths of cervical slide tracks were twice those for the lumbar conditions. Slide tracks were also found to be insensitive to the type of simulator under all testing conditions.     

The New International Standards for Life Cycle Assessment: ISO 14040 and ISO 14044

Background, Aims and Scope The development of the international standards for life cycle assessment (ISO 14040:1997, ISO 14041:1999, ISO 14042:2000, ISO 14043:2000) was an important step to consolidate procedures and methods of LCA. Their contribution to the general acceptance of LCA by all stakeholders and by the international community was crucial. Currently, the process of the revision of this first generation of LCA standards is close to completion. The paper explains the outline as well as formal and technical changes of the coming new international standards of LCA, i.e. the new ISO 14040 and ISO 14044. Methods The paper refers to life cycle assessment based on the international standards for LCA (ISO 14040:1997, ISO 14041:1999, ISO 14042:2000, ISO 14043:2000). The content relates to the Final Draft International Standard (FDIS) versions of the new ISO 14040 and ISO 14044. Results and Discussion With the publication of the two new standards, ISO 14040 and ISO 14044, the existing four standards ISO 14040:1997, ISO 14041:1999, ISO 14042:2000 and ISO 14043:2000 are technically revised, cancelled and replaced. According to the scope of the revision, the core part of the technical contents remains unchanged. Improved readability and the removal of errors and inconsistencies was the focus of the revision. However, despite the fact that the main technical content was confirmed to be still valid, some relevant formal and technical changes were made. On the technical side these include e.g. the addition of principles for LCA, the addition of an annex about applications, the addition of several definitions (e.g. product, process, etc.), clarifications concerning LCA intended to be used in comparative assertions intended to be disclosed to the public, clarifications concerning the critical review panel, clarifications concerning system boundary, etc. On the formal side, changes include the reduced number of standards, a reduced number of annexes, a reduced number of pages that contain requirements, alignment of definitions and clarification of compliance with the standards. Conclusion The two new standards, ISO 14040 and ISO 14044, reconfirm the validity of the main technical content of the previous standards. Errors and inconsistencies were removed and the readability was improved. The added technical content is in line with the previous requirements and serves mainly as a clarification of the technical content. The unanimous vote on the Draft International Standard versions proved that this was achieved on the basis of the broadest possible international consensus. Recommendation and Outlook Currently the national member bodies undertake the final voting on the FDIS-versions of the standards. Based on the voting results at the previous stages of the documents, a positive result is expected. The publication of the new international standards for life cycle assessment (ISO 14040 and ISO 14044) is expected around mid-2006. For the sake of the international and stakeholder acceptance of LCA, it is recommended that the new standards serve as core reference documents for the users and practitioners of LCA.     

In vitro response of the natural cadaver knee to the loading profiles specified in a standard for knee implant wear testing

The purpose of this study was to examine how a natural knee responds to the inputs of a total knee replacement testing standard developed by the International Organization for Standardization (ISO). This load control standard prescribes forces to be used for wear testing of knee replacements independent of implant size or design. A parallel ISO standard provides wear testing inputs that are displacement based instead of force based. Eight fresh frozen cadaveric knees were potted and tested in a 6 degree of freedom knee simulator using the load-control standard. The resulting displacements during load-control testing were compared to the prescribed displacements of the ISO displacement standard. At half the tibial torque prescribed by the load standard there was three times more average internal tibial rotation (20.3°) than is prescribed by the displacement standard (5.7°). The AP motion resulting from load testing was much different than is specified by the displacement standard. All eight knees had anterior tibial translation with respect to the femur during swing phase while the displacement standard specifies posterior tibial displacement. The variation in these motions among knees and their difference from the ISO displacement standard may be one factor that explains why wear results of total knee replacements based on ISO load or displacement testing frequently do not agree with each other or with clinical retrievals.     

Investigation of explanted hip and acetabulum hip prostheses]

Retrieved ceramic femoral heads and acetabular cups were investigated. On the basis of the case studies, the reasons for revision are discussed. Wear patterns and wear rates were found to differ from those observed in hip simulating testing. Monolithic ceramic cups showed a high wear rate. Owing to their limited range of motion, ceramic "mushroom heads" are associated with impingement that leads to a high risk of cup loosening, high wear rates and in vivo fractures. The combination of ceramic "mushroom heads" and cups is not recommended. An evaluation of complications shows that some can be explained by patient behaviour--e.g. Japanese sitting position, horse riding. Designers need to develop new concepts offering a larger range of motion, for example, with head diameters of 32 and 36 mm that reduce the risk of impingement, subluxation and dislocation, while increasing the range of motion. The potential of ceramic/ceramic coupling has been known since the 70s, and ceramic concepts for total hip replacement are currently experiencing a renaissance, although further developments are still possible.     

A direct comparison of patient and force-controlled simulator total knee replacement kinematics

The need to critically evaluate the efficacy of current total knee replacement (TKR) wear testing methodologies is great. Proposed international standards for TKR wear simulation have been drafted, yet their methods continue to be debated. The "gold standard" to which all TKR wear testing methodologies should be compared is measured in vivo TKR performance in patients. The current study compared patient TKR kinematics from fluoroscopic analysis and simulator TKR kinematics from force-controlled wear testing to quantify similarities in clinical ranges of motion and contact bearing kinematics and to evaluate the proposed ISO force-controlled wear testing methodology. The treadmill walking kinematics from eight well-functioning, 13 month average post-op patients were compared to the 2 million cycle interval walking cycle kinematics from a force-controlled (Instron/Stanmore Knee Joint Simulator, Instron, Canton, MA) knee simulator using identical implant designs (Natural Knee II, Standard Congruent, Zimmer, Warsaw, IN). The in vivo and simulator data showed good agreement in kinematic patterns and ranges of clinical motion. Tribologically the data sets showed similar contact pathway ranges of motion and wear travel distances per cycle. Surgical and simulator alignments of the implant systems were determined to be a contributing factor in observed kinematic differences. This study's statistical findings offer supporting evidence that the simulation of in vivo walking cycle wear kinematics can be accurately reproduced with a force controlled testing methodology.     

Usability of national reporting data as a reference for generic unit processes

Background, aim and scope  Renewable energy sources nowadays constitute an increasingly important issue in our society, basically because of the need for alternative sources of energy to fossil fuels that are free of CO₂ emissions and pollution and also because of other problems such as the diminution of the reserves of these fossil fuels, their increasing prices and the economic dependence of non-producers countries on those that produce fossil fuels. One of the renewable energy sources that has experienced a bigger growth over the last years is wind power, with the introduction of new wind farms all over the world and the new advances in wind power technology. Wind power produces electrical energy from the kinetic energy of the wind without producing any pollution or emissions during the conversion process. Although wind power does not produce pollution or emissions during operation, it should be considered that there is an environmental impact due to the manufacturing process of the wind turbine and the disposal process at the end of the wind turbine life cycle, and this environmental impact should be quantified in order to compare the effects of the production of energy and to analyse the possibilities of improvement of the process from that point of view. Thus, the aim of this study is to analyse the environmental impact of wind energy technology, considering the whole life cycle of the wind power system, by means of the application of the ISO 14040 standard [ISO (1998) ISO 14040. Environmental management—life cycle assessment—principles and framework. International Standard Organization, Geneva, Switzerland], which allows quantification of the overall impact of a wind turbine and each of its component parts using a Life Cycle Assessment (LCA) study. Materials and methods  The procedures, details, and results obtained are based on the application of the existing international standards of LCA. In addition, environmental details and indications of materials and energy consumption provided by the various companies related to the production of the component parts are certified by the application of the environmental management system ISO 14001 [ISO (2004) ISO 14001 Environmental management systems—requirements with guidance for use. International Standard Organization, Geneva, Switzerland]. A wind turbine is analysed during all the phases of its life cycle, from cradle to grave, by applying this methodology, taking into account all the processes related to the wind turbine: the production of its main components (through the incorporation of cut-off criteria), the transport to the wind farm, the subsequent installation, the start-up, the maintenance and the final dismantling and stripping down into waste materials and their treatment. The study has been developed in accordance with the ISO 14044 standard [ISO (2006) ISO 14044: Environmental management—life cycle assessment—requirements and guidelines. International Standard Organization, Geneva, Switzerland] currently in force. Results  The application of LCA, according to the corresponding international standards, has made it possible to determine and quantify the environmental impact associated with a wind turbine. On the basis of this data, the final environmental effect of the wind turbine after a lifespan of 20 years and its subsequent decommissioning have been studied. The environmental advantages of the generation of electricity using wind energy, that is, the reduction in emissions and contamination due to the use of a clean energy source, have also been evaluated. Discussion  This study concludes that the environmental pollution resulting from all the phases of the wind turbine (manufacture, start-up, use, and dismantling) during the whole of its lifetime is recovered in less than 1 year. Conclusions  From the developed LCA model, the important levels of contamination of certain materials can be obtained, for instance, the prepreg (a composite made by a mixture of epoxy resin and fibreglass). Furthermore, it has been concluded that it is possible to reduce the environmental effects of manufacturing and recycling processes of wind turbines and their components. Recommendations and perspectives  In order to achieve this goal in a fast and effective way, it is essential to enlist the cooperation of the different manufacturers.     

Wear Testing of Moderate Activities of Daily Living Using In Vivo Measured Knee Joint Loading

Resumption of daily living activities is a basic expectation for patients provided with total knee replacements. However, there is a lack of knowledge regarding the impact of different activities on the wear performance. In this study the wear performance under application of different daily activities has been analyzed. In vivo load data for walking, walking downstairs/upstairs, sitting down/standing up, and cycling (50 W & 120 W) has been standardized for wear testing. Wear testing of each activity was carried out on a knee wear simulator. Additionally, ISO walking was tested for reasons of comparison. Wear was assessed gravimetrically and wear particles were analyzed. In vivo walking produced the highest overall wear rates, which were determined to be three times higher than ISO walking. Moderate wear rates were determined for walking upstairs and downstairs. Low wear rates were determined for standing up/sitting down and cycling at power levels of 50 W and 120 W. The largest wear particles were observed for cycling. Walking based on in vivo data has been shown to be the most wear-relevant activity. Highly demanding activities (stair climbing) produced considerably less wear. Taking into account the expected number of loads, low-impact activities like cycling may have a greater impact on articular wear than highly demanding activities.     

Effect of swing phase load on metal-on-metal hip lubrication, friction and wear

There is renewed interest in metal-on-metal (MOM) total hip replacements (THRs), however, variable wear rates have been observed clinically. It is hypothesised that changes in soft tissue tensioning during surgery may alter loading of THRs during the swing phase of gait leading to changes in fluid film lubrication, friction and wear. This study aimed to assess the effect of swing phase load on the lubrication, friction and wear of MOM hip replacements. Theoretical lubrication modelling was carried out using elastohydrodynamic theory. All the governing equations were solved numerically for the lubricant film thickness between the articulating surfaces under the transient dynamic conditions with low and high swing phase loads. Friction testing was completed using a single axis pendulum simulator, simplified loading cycles were applied with low and high swing phase loads. MOM hip replacements were tested in a hip simulator, modified to provide different swing phase loading regimes; a low (100 N) and a high load (as per ISO 14242-1; 280 N). Results demonstrated that the performance of MOM bearings is highly dependent on swing phase load. Hence, changes in the tension of the tissues at surgery and variations in muscle forces may increase swing phase load, reduce lubrication, increase friction and accelerate wear. This may explain some of the variations that have been observed with clinical wear rates.     

Kinematic evaluation of cruciate-retaining total knee replacement patients during level walking: A comparison with the displacement-controlled ISO standard

Differences between wear-scar features of simulator-tested and retrieved tibial total knee replacement (TKR) liners have been reported. This disagreement may result from differences between in vivo kinematic profiles and those defined by the International Organization for Standardization (ISO). The purpose of this study was to determine the knee kinematics of a TKR subject group during level walking and compare them with the motion profiles defined by the ISO standard for a displacement-controlled knee wear testing simulator. Twenty-nine patients with a posterior cruciate ligament-retaining TKR design were gait tested using the point cluster technique to obtain flexion–extension (FE) rotation, anterior–posterior (AP) translation and internal–external (IE) rotation knee motions during a complete cycle of level walking. Relative ranges of motion and timing of key points within the in vivo motion data were compared against the same ranges and same key points from the input profiles of the displacement-controlled wear testing standard ISO14243-3. The subjects exhibited a FE pattern similar to ISO, with an insignificant difference in range of FE rotation from midstance to terminal stance. However, the subjects had a significantly higher range of knee flexion from terminal stance into swing. The subjects also exhibited a phase delay for the entire gait cycle. For AP translation, the standard profile had statistically significant lower magnitudes than seen in vivo. Opposite pattern of AP motion was also apparent from midstance and swing. Similarly, ISO specified a smaller IE total range of rotation with a motion pattern in complete opposition to that seen in vivo. In conclusion, significant differences were found in both the magnitudes and pattern of in vivo motion compared with ISO.     

A New Simulator for Bio-Tribological Study

A new bio-tribological simulator system was designed and built for basic wear tests on artificial hip joint materials and for common tribological studies applications. The module of hip joint simulator is consisted of Flexion and Extension (FE), Abduction and Adduction (AA) and Internal and External Rotation (IER). Preliminary tests were done with a 28 mm CoCrMo femoral head and a Ultra High Molecular Weight Polyethylene (UHMWPE) cup. Results showed that the wear rate was close to the clinical one. A frequency control system and a heating system were developed to offer a wide range of rotation frequency and temperature so as to provide proper experiments. In the Pin-on-Disk (POD) part, eight precision-made pins were generated and an advanced computer system was built up to measure the friction coefficient of the tests samples.     

Development of computational wear simulation of metal-on-metal hip resurfacing replacements

As one of the alternatives to traditional metal-on-polyethylene total hip replacements, metal-on-metal hip resurfacing prostheses demonstrating lower wear have been introduced for younger and more active patients during the past decade. However, in vitro hip simulator testing for the predicted increased lifetime of these surface replacements is time-consuming and costly. Computational wear modelling based on the Archard wear equation and finite element contact analysis was developed in this study for artificial hip joints and particularly applied to metal-on-metal resurfacing bearings under simulator testing conditions to address this issue. Wear factors associated with the Archard wear equation were experimentally determined and based on the short-term hip simulator wear results. The computational wear simulation was further extended to a long-term evaluation up to 50 million cycles assuming that the wear rate stays constant. The prediction from the computational model shows good agreement with the corresponding simulator study in terms of volumetric wear and the wear geometry. The simulation shows the progression of linear wear penetrations, and the complexity of contact stress distribution on the worn bearing surfaces. After 50 million cycles, the maximum linear wear was predicted to be approximately 6 and 8 microm for the cup and head, respectively, and no edge contact was found.     

Radiological evaluation of polyethyelene wear of cementless total hip endoprosthesis]

During the last years increasingly cementless hip endoprostheses have been implanted. Radiological wear measurement of cemented hip endoprostheses for the material couples polyethylene cup-ceramic- or metal head has been established in the literature. However, for cups encased by metal (screwing or pressfit cups), this method of measurement is not applicable. Therefore, a method has been developed to measure wear on radiographs on cementless spherical implants. The data were compared to those, obtained from conventional wear measurements on cemented hip cups. The results indicate that both techniques generate comparable results, thus validating the new technique as being suited for cementless cup implants.     

The choice of the femoral center of rotation affects material loss in total knee replacement wear testing – A parametric finite element study of ISO 14243-3

A leading cause of long-term failure of total knee replacements (TKRs) is osteolysis caused by polyethylene wear particles. The current gold standard for preclinical wear testing of TKRs is mechanical knee simulators. The definition of the femoral center of flexion-extension rotation (CoR) has been identified as one possible source of variability within TKR wear tests, since the femoral curvature varies from distal to posterior. The magnitude of the influence on wear due to changes in location of femoral CoR has not been investigated in depth. During this study, a computational framework utilizing finite element analysis for modelling wear of TKRs was developed and used to investigate the influence of the location of femoral CoR on TKR polyethylene wear during standardized displacement controlled testing (ISO 14243-3:2014). The study was carried out using a 40-point Latin Hypercube Design of Experiments approach. Volumetric wear was highly correlated to femoral CoR in both the superior/inferior and anterior/posterior directions, with a stronger relationship in the superior/inferior direction. In addition, wear scars showing linear penetration were examined, with large differences in simulations at the extreme ends of the sampling region. In this study, it was found that variations in the location of the femoral center of rotation can represent a large source of variability in the preclinical testing and evaluation of the wear performance of total knee replacements. This study represents the first attempt at quantifying the effect on wear of different femoral center of rotations across a large sampling space.     

New compounds for improving wear behavior of a tumor knee endoprosthesis]

Wear of the central bushing made of ultra-high molecular weight polyethylene (PE-UHMW) of the hinged knee endoprosthesis of a tumour-resection system is the leading reason for revision. The aim of the study was to optimize the wear characteristics of the endoprosthesis on the basis of the tribological properties of new materials and an additional finite element (FE) calculation taking account of the given design. In screening tests the reference combination of PE-UHMW bushing and CoCr axis--used in the clinical setting--was first tested. The PE-UHMW bushing was then replaced by one made of each of the materials reinforced high-density polyethylene (PE-HD) and carbon fibre-reinforced epoxy resin (CFRP). In addition, a new material combination with an alumina ceramic bushing and a CFRP axis was investigated. In comparison with the reference combination PE-UHMW/metal, the combination of ceramic bushing and CFRP axis showed less wear. However, with the particular design of the prosthesis studied here, high mechanical loading applied experimentally resulted in mechanical failure. FE calculations confirmed these experimental results. Improvement of the wear characteristics of this specific implant caused therefore be achieved only by optimizing the bearing design.     

A comparative study of the characteristics of femoral hip prosthesis heads--study and results ceramic-coated hip joint heads of titanium]

Today, only hard/soft cup and femoral head combinations are employed for hip joint prostheses. Highly polished ceramic is a material with very good tribological properties for femoral heads, being highly resistant to mechanical wear and tear, and highly resistant to chemical reactions in the biological environment. The advantage of metal heads, in contrast, undoubtedly lies in their resistance to breakage and the ease with which their geometry can be modified with respect, for example, to antirotation angle and neck length. The ideal material for femoral heads is a combination of the two materials. The new multi-layer combination of titanium-niobium oxide/nitride ceramic coating applied to a prehardened titanium head combines the positive material properties in an ideal manner. Femoral heads made of CoCrMo, oxide-hardened titanium, aluminium oxide or multilayer titanium-niobium ceramic were compared by means of friction an wear and tear tests. The TiNb-ceramic-metal heads showed similar abrasion at the surface as the ceramic heads. At the high loads of more than 400 kp, which may also be reached under physiological conditions, the specially coated titanium-ceramic heads proved to be superior in terms of resistance to fracture and tribological properties.     

Association between contact hip stress and RSA-measured wear rates in total hip arthroplasties of 31 patients

BACKGROUND: The main concern in the long run of total hip replacements is aseptic loosening of the prosthesis. Optimization of the biomechanics of the hip joint is necessary for optimization of long-term success. A widely implementable tool to predict biomechanical consequences of preoperatively planned reconstructions still has to be developed. A potentially useful model to this purpose has been developed previously. The aim of this study is to quantify the association between the estimated hip joint contact force by this biomechanical model and RSA-measured wear rates in a clinical setting. METHODS: Thirty-one patients with a total hip replacement were measured with RSA, the gold standard for clinical wear measurements. The reference examination was done within 1 week of the operation and the follow-up examinations were done at 1, 2 and 5 years. Conventional pelvic X-rays were taken on the same day. The contact stress distribution in the hip joint was determined by the computer program HIPSTRESS. The procedure for the determination of the hip joint contact stress distribution is based on the mathematical model of the resultant hip force in the one-legged stance and the mathematical model of the contact stress distribution. The model for the force requires as input data, several geometrical parameters of the hip and the body weight, while the model for stress requires as input data, the magnitude and direction of the resultant hip force. The stress distribution is presented by the peak stress-the maximal value of stress on the weight-bearing area (p(max)) and also by the peak stress calculated with respect to the body weight (p(max)/W(B)) which gives the effect of hip geometry. Visualization of the relations between predicted values by the model and the wear at different points in the follow-up was done using scatterplots. Correlations were expressed as Pearson r values. RESULTS: The predicted p(max) and wear were clearly correlated in the first year post-operatively (r = 0.58, p = 0.002), while this correlation is weaker after 2 years (r = 0.19, p = 0.337) and 5 years (r = 0.24, p = 0.235). The wear values at 1, 2 and 5 years post-operatively correlate with each other in the way that is expected considering the wear velocity curve of the whole group. The correlation between the predicted p(max) values of two observers who were blinded for each other's results was very good (r = 0.93, p < 0.001). CONCLUSION: We conclude that the biomechanical model used in this paper provides a scientific foundation for the development of a new way of constructing preoperative biomechanical plans for total hip replacements.     

ICH-harmonised guidances on genotoxicity testing of pharmaceuticals: evolution, reasoning and impact.

The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) has convened an expert working group which consisted of the authors of this paper and their respective committees, consulting groups and task forces. Two ICH guidances regarding genotoxicity testing have been issued: S2A, 'Guidance on Specific Aspects of Regulatory Genotoxicity Tests' and S2B, 'Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals.' Together, these guidance documents now form the regulatory backbone for genotoxicity testing and assessment of pharmaceuticals in the European Union, Japan, and the USA. These guidances do not constitute a revolutionary new approach to genotoxicity testing and assessment, instead they are an evolution from preexisting regional guidelines, guidances and technical approaches. Both guidances describe a number of specific criteria as well as a general test philosophy in genotoxicity testing. Although these guidances were previously released within the participating regions in their respective regulatory communiqués, to ensure their wider distribution and better understanding, the texts of the guidances are reproduced here in their entirety (see Appendix A) and the background for the recommendations are described. The establishment of a standard battery for genotoxicity testing of pharmaceuticals was one of the most important issues of the harmonisation effort. This battery currently consists of: (i) a test for gene mutation in bacteria, (ii) an in vitro test with cytogenetic evaluation of chromosomal damage with mammalian cells or an in vitro mouse lymphoma tk assay, (iii) an in vivo test for chromosomal damage using rodent hematopoietic cells. A major change in testing philosophy is the acceptance of the interchangeability of testing for chromosomal aberrations in mammalian cells and the mouse lymphoma tk assay. This agreement was reached on the basis of the extensive review of databases and newly generated experimental data which are in part described in this publication. The authors are fully aware of the fact that some of the recommendations given in these ICH guidances are transient in nature and that the dynamic qualities and ongoing evolution of genetic toxicology makes necessary a continuous maintenance process that would serve to update the guidance as necessary.     

The Second International Standard for somatropin (recombinant DNA-derived human growth hormone): preparation and calibration in an international collaborative study.

A preparation of somatropin (recombinant DNA-derived human growth hormone) was prepared as lyophilised ampoules according to WHO procedures for international biological standards. The candidate preparation (98/574) was evaluated in an international collaborative study (16 laboratories, nine countries), with the following aims: (i) to determine the suitability of the preparation to serve as the International Standard for somatropin by studying its performance in the current range of physico-chemical and biological assay methods employed for somatropin; (ii) to assign a content in terms of the existing (first) International Standard for somatropin, using the currently recognised assay procedure (Size Exclusion High Performance Liquid Chromatography, SE HPLC); (iii) to confirm the specific biological activity of the candidate preparation; (iv) to confirm the stability of the candidate preparation. On the basis of the collaborative study WHO agreed that: the preparation in ampoules coded 98/574 is suitable to serve as the next WHO International Standard for somatropin; the preparation in ampoules coded 98/574 should be established as the second International Standard for somatropin, with a defined ampoule content of 1.95 mg total somatropin plus somatropin-related proteins per ampoule; the specific activity of the preparation should be defined as 3.0 IU/mg somatropin.