text:
INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE Q3D. Current Step 4 version
- Kelly Parrish
- 3 years ago
- Views:
1 INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE ICH HARMONISED GUIDELINE GUIDELINE FOR ELEMENTAL IMPURITIES Q3D Current Step 4 version dated 16 December 2014 This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the European Union, Switzerland, Japan, USA and Canada.
2 Q3D Document History Code History Date Q3D Approval by the Steering Committee under Step 2a. 6 June 2013 Q3D Q3D Q3D Q3D Q3D Approval by the Steering Committee under Step 2b and release for public consultation. Post sign-off corrigendum in: Table 4.1 W and Al were removed from the list of included elemental impurities in Class 2B and 3 respectively. Table A.2.1 the Class for Ni was changed to read 3 instead of 2. Post sign-off minor editorial corrections including: removal of references to Appendix 5 (pgs i & 13); deletion of redundant text (pg 4); change of Option 2 to Option 2a (pg 10); insertion of omitted text under Safety Limiting Toxicity (pg 35); removal of duplicated redundant text (pg 41); replacing references to metals in text and metal in Table A.4.7 title with elementals and elements (pg 73); and deletion of header Table A.4.10 (pg 75). Addition of line numbers to facilitate the provision of comments by stakeholders. Approval by the Steering Committee under Step 4 and recommendation for adoption to the ICH regulatory bodies. 6 June June July September November 2014 Current Step 4 version Code History Date Q3D Corrigendum to correct: the modifying factor in the text of the safety assessment for Selenium (changed to 2 instead of 10 consistent with Section 3.1); and two references for consistency in the safety assessments for Barium (deleted reference) and Vanadium (revised reference). 16 December 2014 Legal notice: This document is protected by copyright and may be used, reproduced, incorporated into other works, adapted, modified, translated or distributed under a public license provided that ICH's copyright in the document is acknowledged at all times. In case of any adaption, modification or translation of the document, reasonable steps must be taken to clearly label, demarcate or otherwise identify that changes were made to or based on the original document. Any impression that the adaption, modification or translation of the original document is endorsed or sponsored by the ICH must be avoided. The document is provided "as is" without warranty of any kind. In no event shall the ICH or the authors of the original document be liable for any claim, damages or other liability arising from the use of the document. The above-mentioned permissions do not apply to content supplied by third parties. Therefore, for documents where the copyright vests in a third party, permission for reproduction must be obtained from this copyright holder.
3 GUIDELINE FOR ELEMENTAL IMPURITIES ICH Harmonised Guideline Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting on 12 November 2014, this guideline is recommended for adoption to the regulatory parties to ICH. TABLE OF CONTENTS 1. INTRODUCTION SCOPE SAFETY ASSESSMENT OF POTENTIAL ELEMENTAL IMPURITIES Principles of the Safety Assessment of Elemental Impurities for Oral, Parenteral and Inhalation Routes of Administration Other Routes of Administration Justification for Elemental Impurity Levels Higher than an Established PDE Parenteral Products ELEMENT CLASSIFICATION RISK ASSESSMENT AND CONTROL OF ELEMENTAL IMPURITIES General Principles Potential Sources of Elemental Impurities Identification of Potential Elemental Impurities Recommendations for Elements to be Considered in the Risk Assessment Evaluation Summary of Risk Assessment Process Special Considerations for Biotechnologically-Derived Products CONTROL OF ELEMENTAL IMPURITIES CONVERTING BETWEEN PDES AND CONCENTRATION LIMITS SPECIATION AND OTHER CONSIDERATIONS ANALYTICAL PROCEDURES LIFECYCLE MANAGEMENT GLOSSARY REFERENCES Appendix 1: Method for Establishing Exposure Limits Appendix 2: Established PDEs for Elemental Impurities Appendix 3: Individual Safety Assessments Appendix 4: Illustrative Examples... 68
5 GUIDELINE FOR ELEMENTAL IMPURITIES Q3D 1. INTRODUCTION Elemental impurities in drug products may arise from several sources; they may be residual catalysts that were added intentionally in synthesis or may be present as impurities (e.g., through interactions with processing equipment or container/closure systems or by being present in components of the drug product). Because elemental impurities do not provide any therapeutic benefit to the patient, their levels in the drug product should be controlled within acceptable limits. There are three parts of this guideline: the evaluation of the toxicity data for potential elemental impurities; the establishment of a Permitted Daily Exposure (PDE) for each element of toxicological concern; and application of a riskbased approach to control elemental impurities in drug products. An applicant is not expected to tighten the limits based on process capability, provided that the elemental impurities in drug products do not exceed the PDEs. The PDEs established in this guideline are considered to be protective of public health for all patient populations. In some cases, lower levels of elemental impurities may be warranted when levels below toxicity thresholds have been shown to have an impact on other quality attributes of the drug product (e.g., element catalyzed degradation of drug substances). In addition, for elements with high PDEs, other limits may have to be considered from a pharmaceutical quality perspective and other guidelines should be consulted (e.g., ICH Q3A). This guideline presents a process to assess and control elemental impurities in the drug product using the principles of risk management as described in ICH Q9. This process provides a platform for developing a risk-based control strategy to limit elemental impurities in the drug product. 2. SCOPE The guideline applies to new finished drug products (as defined in ICH Q6A and Q6B) and new drug products containing existing drug substances. The drug products containing purified proteins and polypeptides (including proteins and polypeptides produced from recombinant or non-recombinant origins), their derivatives, and products of which they are components (e.g., conjugates) are within the scope of this guideline, as are drug products containing synthetically produced polypeptides, polynucleotides, and oligosaccharides. This guideline does not apply to herbal products, radiopharmaceuticals, vaccines, cell metabolites, DNA products, allergenic extracts, cells, whole blood, cellular blood components or blood derivatives including plasma and plasma derivatives, dialysate solutions not intended for systemic circulation, and elements that are intentionally included in the drug product for therapeutic benefit. This guideline does not apply to products based on genes (gene therapy), cells (cell therapy) and tissue (tissue engineering). In some regions, these products are known as advanced therapy medicinal products. This guideline does not apply to drug products used during clinical research stages of development. As the commercial process is developed, the principles contained in this guideline can be useful in evaluating elemental impurities that may be present in a new drug product. Application of Q3D to existing products is not expected prior to 36 months after publication of the guideline by ICH. 3. SAFETY ASSESSMENT OF POTENTIAL ELEMENTAL IMPURITIES 3.1 Principles of the Safety Assessment of Elemental Impurities for Oral, Parenteral and Inhalation Routes of Administration The method used for establishing the PDE for each elemental impurity is discussed in detail in Appendix 1. Elements evaluated in this guideline were assessed by reviewing the publicly available data contained in scientific journals, government research reports and studies, international regulatory 1
6 standards (applicable to drug products) and guidance, and regulatory authority research and assessment reports. This process follows the principles described in ICH Q3C: Residual Solvents. The available information was reviewed to establish the oral, parenteral and inhalation PDEs. For practical purposes, the PDEs to be applied to the drug product that are presented in Appendix 2 Table A.2.1 have been rounded to 1 or 2 significant figures. A summary safety assessment identifying the critical study for setting a PDE for each element is included in Appendix 3. There are insufficient data to set PDEs by any route of administration for iridium, osmium, rhodium, and ruthenium. The PDEs for these elements were established on the basis of their similarity to palladium. The factors considered in the safety assessment for establishing the PDE are listed below in approximate order of relevance: The likely oxidation state of the element in the drug product; Human exposure and safety data when it provided applicable information; The most relevant animal study; Route of administration; The relevant endpoint(s). Standards for daily intake for some of the elemental impurities discussed in this guideline exist for food, water, air, and occupational exposure. Where appropriate, these standards were considered in the safety assessment and establishment of the PDEs. The longest duration animal study was generally used to establish the PDE. When a shorter duration animal study was considered the most relevant, the rationale was provided in the individual safety assessment. Inhalation studies using soluble salts (when available) were preferred over studies using particulates for inhalation safety assessment and derivation of inhalation PDEs. Depending on available data, inhalation PDEs were based on either local (respiratory system) or systemic toxicity. For PDEs established for inhalation (and oral or parenteral routes as applicable), doses were normalized to a 24- hour, 7-day exposure. In the absence of data and/or where data are available but not considered sufficient for a safety assessment for the parenteral and or inhalation route of administration, modifying factors based on oral bioavailability were used to derive the PDE from the oral PDE: Oral bioavailability <1%: divide by a modifying factor of 100; Oral bioavailability 1% and <50%: divide by a modifying factor of 10; Oral bioavailability 50% and <90%: divide by a modifying factor of 2; and Oral bioavailability 90%: divide by a modifying factor of 1. Where oral bioavailability data or occupational inhalation exposure limits were not available, a calculated PDE was used based on the oral PDE divided by a modifying factor of 100 (Ref. 1). 3.2 Other Routes of Administration PDEs were established for oral, parenteral and inhalation routes of administration. When PDEs are necessary for other routes of administration, the concepts described in this guideline may be used to derive PDEs. An assessment may either increase or decrease an established PDE. The process of derivation of the PDE for another route of administration may include the following: Consider the oral PDE in Appendix 3 as a starting point in developing a route-specific PDE. Based on a scientific evaluation, the parenteral and inhalation PDEs may be a more appropriate starting point. Assess if the elemental impurity is expected to have local effects when administered by the intended route of administration: 2
7 o o o If local effects are expected, assess whether a modification to an established PDE is necessary. Consider the doses/exposures at which these effects can be expected relative to the adverse effect that was used to set an established PDE. If local effects are not expected, no adjustment to an established PDE is necessary. If available, evaluate the bioavailability of the element via the intended route of administration and compare this to the bioavailability of the element by the route with an established PDE: o When a difference is observed, a correction factor may be applied to an established PDE. For example, when no local effects are expected, if the oral bioavailability of an element is 50% and the bioavailability of an element by the intended route is 10%, a correction factor of 5 may be applied. If a PDE proposed for the new route is increased relative to an established PDE, quality attributes may need to be considered. 3.3 Justification for Elemental Impurity Levels Higher than an Established PDE Levels of elemental impurities higher than an established PDE (see Table A.2.1) may be acceptable in certain cases. These cases could include, but are not limited to, the following situations: Intermittent dosing; Short term dosing (i.e., 30 days or less); Specific indications (e.g., life-threatening, unmet medical needs, rare diseases). Examples of justifying an increased level of an elemental impurity using a subfactor approach of a modifying factor (Ref. 2,3) are provided below. Other approaches may also be used to justify an increased level. Any proposed level higher than an established PDE should be justified on a case-bycase basis. Example 1: element X is present in an oral drug product. From the element X monograph in Appendix 3, a No-Observed-Adverse-Effect Level (NOAEL) of 1.1 mg/kg/day was identified. Modifying factors F1-F5 have been established as 5, 10, 5, 1 and 1, respectively. Using the standard approach for modifying factors as described in Appendix 1, the PDE is calculated as follows: PDE = 1.1 mg/kg/d x 50 kg / 5 x 10 x 5 x 1 x 1 = 220 µg/day Modifying factor F2 (default = 10) can be subdivided into two subfactors, one for toxicokinetics (TK) and one for toxicodynamics, each with a range from 1 to Using the plasma half-life of 5 days, the TK adjustment factor could be decreased to 1.58 for once weekly administration (~1 half-life), and to 1 for administration once a month (~5 half-lives). Using the subfactor approach for F2, the proposed level for element X administered once weekly can be calculated as follows: Proposed level = 1.1 mg/kg/d x 50 kg / 5 x (1.6 x 3.16) x 5 x 1 x 1 = 440 µg/day For practical purposes, this value is rounded to 400 µg/day. Example 2: The TK adjustment factor approach may also be appropriate for elemental impurities that were not developed using the modifying factor approach. For element Z, a Minimal Risk Level (MRL) of 0.02 mg/kg/day was used to derive the oral PDE. From literature sources, the plasma halflife was reported to be 4 days. This element is an impurity in an oral drug product administered once every 3 weeks (~ 5 half-lives). Using first-order kinetics, the established PDE of 1000 µg/day is modified as follows: Proposed level = 0.02 mg/kg/d x 50 kg / 1/3.16 = 3.16 mg/day For practical purposes, this value is rounded to 3000 µg/day. 3
8 3.4 Parenteral Products Parenteral drug products with maximum daily volumes up to 2 liters may use the maximum daily volume to calculate permissible concentrations from PDEs. For products whose daily volumes, as specified by labeling and/or established by clinical practice, may exceed 2 liters (e.g., saline, dextrose, total parenteral nutrition, solutions for irrigation), a 2-liter volume may be used to calculate permissible concentrations from PDEs. (Ref. 4) 4. ELEMENT CLASSIFICATION The elements included in this guideline have been placed into three classes based on their toxicity (PDE) and likelihood of occurrence in the drug product. The likelihood of occurrence is derived from several factors including: probability of use in pharmaceutical processes, probability of being a coisolated impurity with other elemental impurities in materials used in pharmaceutical processes, and the observed natural abundance and environmental distribution of the element. For the purposes of this guideline, an element with low natural abundance refers to an element with a reported natural abundance of < 1 atom/10 6 atoms of silicon (Ref. 5). The classification scheme is intended to focus the risk assessment on those elements that are the most toxic but also have a reasonable probability of inclusion in the drug product (see Table 5.1). The elemental impurity classes are: Class 1: The elements, As, Cd, Hg, and Pb, are human toxicants that have limited or no use in the manufacture of pharmaceuticals. Their presence in drug products typically comes from commonly used materials (e.g., mined excipients). Because of their unique nature, these four elements require evaluation during the risk assessment, across all potential sources of elemental impurities and routes of administration. The outcome of the risk assessment will determine those components that may require additional controls which may in some cases include testing for Class 1 elements. It is not expected that all components will require testing for Class 1 elemental impurities; testing should only be applied when the risk assessment identifies it as the appropriate control to ensure that the PDE will be met. Class 2: Elements in this class are generally considered as route-dependent human toxicants. Class 2 elements are further divided in sub-classes 2A and 2B based on their relative likelihood of occurrence in the drug product. Class 2A elements have relatively high probability of occurrence in the drug product and thus require risk assessment across all potential sources of elemental impurities and routes of administration (as indicated). The class 2A elements are: Co, Ni and V. Class 2B elements have a reduced probability of occurrence in the drug product related to their low abundance and low potential to be co-isolated with other materials. As a result, they may be excluded from the risk assessment unless they are intentionally added during the manufacture of drug substances, excipients or other components of the drug product. The elemental impurities in class 2B include: Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se and Tl. Class 3: The elements in this class have relatively low toxicities by the oral route of administration (high PDEs, generally > 500 µg/day) but may require consideration in the risk assessment for inhalation and parenteral routes. For oral routes of administration, unless these elements are intentionally added, they do not need to be considered during the risk assessment. For parenteral and inhalation products, the potential for inclusion of these elemental impurities should be evaluated during the risk assessment, unless the route specific PDE is above 500 µg/day. The elements in this class include: Ba, Cr, Cu, Li, Mo, Sb, and Sn. Other elements: Some elemental impurities for which PDEs have not been established due to their low inherent toxicity and/or differences in regional regulations are not addressed in this guideline. If these elemental impurities are present or included in the drug product they are addressed by other guidelines and/or regional regulations and practices that may be applicable for particular elements (e.g., Al for compromised renal function; Mn and Zn for patients with compromised hepatic function), or quality considerations (e.g., presence of W impurities in therapeutic proteins) for the final drug product. Some of the elements considered include: Al, B, Ca, Fe, K, Mg, Mn, Na, W and Zn. 4
9 5. RISK ASSESSMENT AND CONTROL OF ELEMENTAL IMPURITIES In developing controls for elemental impurities in drug products, the principles of quality risk management, described in ICH Q9, should be considered. The risk assessment should be based on scientific knowledge and principles. It should link to safety considerations for patients with an understanding of the product and its manufacturing process (ICH Q8 and Q11). In the case of elemental impurities, the product risk assessment would therefore be focused on assessing the levels of elemental impurities in a drug product in relation to the PDEs presented in this guidance. Information for this risk assessment includes but is not limited to: data generated by the applicant, information supplied by drug substance and/or excipient manufacturers and/or data available in published literature. The applicant should document the risk assessment and control approaches in an appropriate manner. The level of effort and formality of the risk assessment should be proportional to the level of risk. It is neither always appropriate nor always necessary to use a formal risk management process (using recognized tools and/or formal procedures, e.g., standard operating procedures.) The use of informal risk management processes (using empirical tools and/or internal procedures) may also be considered acceptable. Tools to assist in the risk assessment are described in ICH Q8 and Q9 and will not be presented in this guideline. 5.1 General Principles For the purposes of this guideline, the risk assessment process can be described in three steps: Identify known and potential sources of elemental impurities that may find their way into the drug product. Evaluate the presence of a particular elemental impurity in the drug product by determining the observed or predicted level of the impurity and comparing with the established PDE. Summarize and document the risk assessment. Identify if controls built into the process are sufficient or identify additional controls to be considered to limit elemental impurities in the drug product. In many cases, the steps are considered simultaneously. The outcome of the risk assessment may be the result of iterations to develop a final approach to ensure the potential elemental impurities do not exceed the PDE. 5.2 Potential Sources of Elemental Impurities In considering the production of a drug product, there are broad categories of potential sources of elemental impurities. Residual impurities resulting from elements intentionally added (e.g., catalysts) in the formation of the drug substance, excipients or other drug product components. The risk assessment of the drug substance should address the potential for inclusion of elemental impurities in the drug product. Elemental impurities that are not intentionally added and are potentially present in the drug substance, water or excipients used in the preparation of the drug product. Elemental impurities that are potentially introduced into the drug substance and/or drug product from manufacturing equipment. Elemental impurities that have the potential to be leached into the drug substance and drug product from container closure systems. The following diagram shows an example of typical materials, equipment and components used in the production of a drug product. Each of these sources may contribute elemental impurities to the drug product, through any individual or any combination of the potential sources listed above. During the risk assessment, the potential contributions from each of these sources should be considered to determine the overall contribution of elemental impurities to the drug product. 5
10 Manufacturing equipment * Drug Substance Elemental impurities in drug Product Water ** Container Closure System Excipients * The risk of inclusion of elemental impurities can be reduced through process understanding, equipment selection, equipment qualification and Good Manufacturing Practice (GMP) processes. ** The risk of inclusion of elemental impurities from water can be reduced by complying with compendial (e.g., European Pharmacopoeia, Japanese Pharmacopoeia, US Pharmacopeial Convention) water quality requirements, if purified water or water for injection is used in the manufacturing process(es). 5.3 Identification of Potential Elemental Impurities Potential elemental impurities derived from intentionally added catalysts and inorganic reagents: If any element listed in Table 5.1 is intentionally added, it should be considered in the risk assessment. For this category, the identity of the potential impurities is known and techniques for controlling the elemental impurities are easily characterized and defined. Potential elemental impurities that may be present in drug substances and/or excipients: While not intentionally added, some elemental impurities may be present in some drug substances and/or excipients. The possibility for inclusion of these elements in the drug product should be reflected in the risk assessment. For the oral route of administration, the risk assessment should evaluate the possibility for inclusion of Class 1 and Class 2A elemental impurities in the drug product. For parenteral and inhalation routes of administration, the risk assessment should evaluate the possibility for inclusion of the Class 1, Class 2A and Class 3 elemental impurities as shown in Table 5.1. Potential elemental impurities derived from manufacturing equipment: The contribution of elemental impurities from this source may be limited and the subset of elemental impurities that should be considered in the risk assessment will depend on the manufacturing equipment used in the production of the drug product. Application of process knowledge, selection of equipment, equipment qualification and GMP controls ensure a low contribution from manufacturing equipment. The specific elemental impurities of concern should be assessed based on knowledge of the composition of the components of the manufacturing equipment that come in contact with components of the drug product. The risk assessment of this source of elemental impurities is one that can potentially be utilized for many drug products using similar process trains and processes. In general, the processes used to prepare a given drug substance are considerably more aggressive than processes used in preparing the drug product when assessed relative to the potential to leach or remove elemental impurities from manufacturing equipment. Contributions of elemental impurities from drug product processing equipment would be expected to be lower than contributions observed for the drug substance. However, when this is not the case based on process knowledge or understanding, the 6
11 applicant should consider the potential for incorporation of elemental impurities from the drug product manufacturing equipment in the risk assessment (e.g., hot melt extrusion). Elemental impurities leached from container closure systems: The identification of potential elemental impurities that may be introduced from container closure systems should be based on a scientific understanding of likely interactions between a particular drug product type and its packaging. When a review of the materials of construction demonstrates that the container closure system does not contain elemental impurities, no additional risk assessment needs to be performed. It is recognized that the probability of elemental leaching into solid dosage forms is minimal and does not require further consideration in the risk assessment. For liquid and semi-solid dosage forms there is a higher probability that elemental impurities could leach from the container closure system during the shelflife of the product. Studies to understand potential leachables from the container closure system (after washing, sterilization, irradiation, etc.) should be performed. This source of elemental impurities will typically be addressed during evaluation of the container closure system for the drug product. Factors that should be considered (for liquid and semi-solid dosage forms) include but are not limited to: Hydrophilicity/hydrophobicity; Ionic content; ph; Temperature (cold chain vs room temperature and processing conditions); Contact surface area; Container/component composition; Terminal sterilization; Packaging process; Component sterilization; Duration of storage. 5.4 Recommendations for Elements to be Considered in the Risk Assessment The following table provides recommendations for inclusion of elemental impurities in the risk assessment. This table can be applied to all sources of elemental impurities in the drug product. Table 5.1: Elements to be Considered in the Risk Assessment Element Class If intentionally added (all routes) If not intentionally added Oral Parenteral Inhalation Cd 1 yes yes yes yes Pb 1 yes yes yes yes As 1 yes yes yes yes Hg 1 yes yes yes yes Co 2A yes yes yes yes V 2A yes yes yes yes Ni 2A yes yes yes yes Tl 2B yes no no no Au 2B yes no no no Pd 2B yes no no no Ir 2B yes no no no Os 2B yes no no no Rh 2B yes no no no Ru 2B yes no no no Se 2B yes no no no 7
12 Ag 2B yes no no no Pt 2B yes no no no Li 3 yes no yes yes Sb 3 yes no yes yes Ba 3 yes no no yes Mo 3 yes no no yes Cu 3 yes no yes yes Sn 3 yes no no yes Cr 3 yes no no yes 5.5 Evaluation As the potential elemental impurity identification process is concluded, there are two possible outcomes: 1) The risk assessment process does not identify any potential elemental impurities. The conclusion of the risk assessment and supporting information and data should be documented. 2) The risk assessment process identifies one or more potential elemental impurities. For any elemental impurities identified in the process, the risk assessment should consider if there are multiple sources of the identified elemental impurity or impurities and document the conclusion of the assessment and supporting information. The applicant s risk assessment can be facilitated with information about the potential elemental impurities provided by suppliers of drug substances, excipients, container closure systems, and manufacturing equipment. The data that support this risk assessment can come from a number of sources that include, but are not limited to: Prior knowledge; Published literature; Data generated from similar processes; Supplier information or data; Testing of the components of the drug product; Testing of the drug product. During the risk assessment, a number of factors that can influence the level of the potential impurity in the drug product and should also have been considered in the risk assessment. These include but are not limited to: Efficiency of removal of elemental impurities during further processing; Natural abundance of elements (especially important for the categories of elements which are not intentionally added); Prior knowledge of elemental impurity concentration ranges from specific sources; The composition of the drug product. 5.6 Summary of Risk Assessment Process The risk assessment is summarized by reviewing relevant product or component specific data combined with information and knowledge gained across products or processes to identify the significant probable elemental impurities that may be observed in the drug product. The summary should consider the significance of the observed or predicted level of the elemental impurity relative to the PDE of the elemental impurity. As a measure of the significance of the observed elemental impurity level, a control threshold is defined as a level that is 30% of the established PDE in the drug product. The control threshold may be used to determine if additional controls may be required. 8
13 If the total elemental impurity level from all sources in the drug product is expected to be consistently less than 30% of the PDE, then additional controls are not required, provided the applicant has appropriately assessed the data and demonstrated adequate controls on elemental impurities. If the risk assessment fails to demonstrate that an elemental impurity level is consistently less than the control threshold, controls should be established to ensure that the elemental impurity level does not exceed the PDE in the drug product. (See Section 6) The variability of the level of an elemental impurity should be factored into the application of the control threshold to drug products. Sources of variability may include: Variability of the analytical method; Variability of the elemental impurity level in the specific sources; Variability of the elemental impurity level in the drug product. At the time of submission, in the absence of other justification, the level and variability of an elemental impurity can be established by providing the data from three (3) representative production scale lots or six (6) representative pilot scale lots of the component or components or drug product. For some components that have inherent variability (e.g., mined excipients), additional data may be needed to apply the control threshold. There are many acceptable approaches to summarizing and documenting the risk assessment that may include: tables, written summaries of considerations and conclusions of the assessment. The summary should identify the elemental impurities, their sources, and the controls and acceptance criteria as needed. 5.7 Special Considerations for Biotechnologically-Derived Products For biotechnology-derived products, the risks of elemental impurities being present at levels that raise safety concerns at the drug substance stage are considered low. This is largely because: a) elements are not typically used as catalysts or reagents in the manufacturing of biotech products; b) elements are added at trace levels in media feeds during cell culture processes, without accumulation and with significant dilution/removal during further processing; c) typical purification schemes used in biotech manufacturing such as extraction, chromatography steps and dialysis or Ultrafiltration-Diafiltration (UF/DF) have the capacity to clear elements introduced in cell culture/fermentation steps or from contact with manufacturing equipment to negligible levels. As such, specific controls on elemental impurities up to the biotech drug substance are generally not needed. In cases where the biotechnology-derived drug substance contains synthetic structures (such as antibody-drug conjugates), appropriate controls on the small molecule component for elemental impurities should be evaluated. However, potential elemental impurity sources included in drug product manufacturing (e.g., excipients) and other environmental sources should be considered for biotechnologically-derived drug products. The contribution of these sources to the finished product should be assessed because they are typically introduced in the drug product manufacture at a step in the process where subsequent elemental impurity removal is not generally performed. Risk factors that should be considered in this assessment should include the type of excipients used, the processing conditions and their susceptibility to contamination by environmental factors (e.g., controlled areas for sterile manufacturing and use of purified water) and overall dosing frequency. 6. CONTROL OF ELEMENTAL IMPURITIES Control of elemental impurities is one part of the overall control strategy for a drug product that assures that elemental impurities do not exceed the PDEs. When the level of an elemental impurity may exceed the control threshold, additional measures should be implemented to assure that the level does not exceed the PDE. Approaches that an applicant can pursue include but are not limited to: Modification of the steps in the manufacturing process that result in the reduction of elemental impurities below the control threshold through specific or non-specific purification steps; 9
14 Implementation of in-process or upstream controls, designed to limit the concentration of the elemental impurity below the control threshold in the drug product; Establishment of specification limits for excipients or materials (e.g., synthetic intermediates); Establishment of specification limits for the drug substance; Establishment of specification limits for the drug product; Selection of appropriate container closure systems. Periodic testing may be applied to elemental impurities according to the principles described in ICH Q6A. The information on the control of elemental impurities that is provided in a regulatory submission includes, but is not limited to, a summary of the risk assessment, appropriate data as necessary, and a description of the controls established to limit elemental impurities. 7. CONVERTING BETWEEN PDES AND CONCENTRATION LIMITS The PDEs, reported in micrograms per day (µg/day) provided in this document give the maximum permitted quantity of each element that may be contained in the maximum daily intake of a drug product. Because the PDE reflects only total exposure from the drug product, it is useful to convert the PDE, into concentrations as a tool in evaluating elemental impurities in drug products or their components. The options listed in this section describe some acceptable approaches to establishing concentrations of elemental impurities in drug products or components that would assure that the drug product does not exceed the PDEs. The applicant may select any of these options as long as the resulting permitted concentrations assure that the drug product does not exceed the PDEs. In the choice of a specific option the applicant must have knowledge of, or make assumptions about, the daily intake of the drug product. The permitted concentration limits may be used: As a tool in the risk assessment to compare the observed or predicted levels to the PDE; In discussions with suppliers to help establish upstream controls that would assure that the product does not exceed the PDE; To establish concentration targets when developing in-process controls on elemental impurities; To convey information regarding the controls on elemental impurities in regulatory submissions. As discussed in Section 5.2, there are multiple sources of elemental impurities in drug products. When applying any of the options described below, elemental impurities from container closure systems and manufacturing equipment should be taken into account before calculating the maximum permitted concentration in the remaining components (excipients and drug substance). If it is determined during the risk assessment that the container closure systems and manufacturing equipment do not contribute to the elemental impurity level in the drug product, they do not need to be considered. Where contributions from container closure systems and manufacturing equipment exist, these contributions may be accounted for by subtracting the estimated daily intake from these sources from the PDE before calculation of the allowed concentration in the excipients and drug substance. Option 1: Common permitted concentration limits of elements across drug product components for drug products with daily intakes of not more than 10 grams: This option is not intended to imply that all elements are present at the same concentration, but rather provides a simplified approach to the calculations. The option assumes the daily intake (amount) of the drug product is 10 grams or less, and that elemental impurities identified in the risk assessment (the target elements) are present in all components of the drug product. Using Equation 1 below, and a daily intake of 10 grams of drug product, this option calculates a common permissible target elemental concentration for each component in the drug. This approach, for each target element, allows determination of a fixed common maximum concentration in micrograms per gram in each component. The permitted concentrations are provided in Appendix 2, Table A
15 PDE( g / day) Concentration ( g / g) (1) daily amount of drug product ( g / day) If all the components in a drug product do not exceed the Option 1 concentrations for all target elements identified in the risk assessment, then all these components may be used in any proportion in the drug product. An example using this option is shown in Appendix 4, Table A.4.2. If the permitted concentrations in Appendix 2, Table A.2.2 are not applied, Options 2a, 2b, or 3 should be followed. Option 2a: Common permitted concentration limits across drug product components for a drug product with a specified daily intake: This option is similar to Option 1, except that the drug daily intake is not assumed to be 10 grams. The common permitted concentration of each element is determined using Equation 1 and the actual maximum daily intake. This approach, for each target element, allows determination of a fixed common maximum concentration in micrograms per gram in each component based on the actual daily intake provided. An example using this option is provided in Appendix 4, Table A.4.3. If all components in a drug product do not exceed the Option 2a concentrations for all target elements identified in the risk assessment, then all these components may be used in any proportion in the drug product. Option 2b: Permitted concentration limits of elements in individual components of a product with a specified daily intake: This option requires additional information that the applicant may assemble regarding the potential for specific elemental impurities to be present in specific drug product components. The applicant may set permitted concentrations based on the distribution of elements in the components (e.g., higher concentrations in components with the presence of an element in question). For each element identified as potentially present in the components of the drug product, the maximum expected mass of the elemental impurity in the final drug product can be calculated by multiplying the mass of each component material times the permitted concentration established by the applicant in each material and summing over all components in the drug product, as described in Equation 2. The total mass of the elemental impurity in the drug product should comply with the PDEs given in Appendix 2, Table A.2.1. unless justified according to other relevant sections of this guideline. If the risk assessment has determined that a specific element is not a potential impurity in a specific component, there is no need to establish a quantitative result for that element in that component. This approach allows that the maximum permitted concentration of an element in certain components of the drug product may be higher than the Option 1 or Option 2a limit, but this should then be compensated by lower allowable concentrations in the other components of the drug product. Equation 2 may be used to demonstrate that component-specific limits for each element in each component of a drug product assure that the PDE will be met. k = C k = M k = N g day PDE C k M k (2) k 1 an index for each of N components in the drug product permitted concentration of the elemental impurity in component k (µg/g) mass of component k in the maximum daily intake of the drug product (g) An example using this option is provided in Appendix 4 Tables A.4.4 A.4.5. Option 3: Finished Product Analysis: The concentration of each element may be measured in the final drug product. Equation 1 may be used with the maximum total daily dose of the drug product to calculate a maximum permitted concentration of the elemental impurity. An example using this option is provided in Appendix 4, Table A
16 8. SPECIATION AND OTHER CONSIDERATIONS Speciation is defined as the distribution of elements among chemical species including isotopic composition, electronic or oxidation state, and/or complex or molecular structure. When the toxicities of different species of the same element are known, the PDE has been established using the toxicity information on the species expected to be in the drug product. When elemental impurity measurements are used in the risk assessment, total elemental impurity levels in drug products may be used to assess compliance with the PDEs. The applicant is not expected to provide speciation information; however, such information could be used to justify lower or higher levels when the identified species is more or less toxic, respectively, than the species used in the monographs in Appendix 3. When total elemental impurity levels in components are used in the risk assessment, the applicant is not expected to provide information on release of an elemental impurity from the component in which it is found. However, such information could be used to justify levels higher than those based on the total elemental impurity content of the drug product. 9. ANALYTICAL PROCEDURES The determination of elemental impurities should be conducted using appropriate procedures suitable for their intended purposes. Unless otherwise justified, the test should be specific for each elemental impurity identified for control during the risk assessment. Pharmacopoeial procedures or suitable alternative procedures for determining levels of elemental impurities should be used. 10. LIFECYCLE MANAGEMENT The quality systems and management responsibilities described in ICH Q10 are intended to encourage the use of science-based and risk-based approaches at each lifecycle stage, thereby promoting continual improvement across the entire product lifecycle. Product and process knowledge should be managed from development through the commercial life of the product up to and including product discontinuation. Knowledge gained from development combined with commercial manufacturing experience and data can be used to further improve process understanding and process performance. Such improvements can enhance controls on elemental impurities. It is recognized that the elemental impurity data available for some components is somewhat limited at the date of publication of this guideline, which may direct the applicant to a specific set of controls. Additional data, if developed, may lead to modifications of the controls. If changes to the drug product or components have the potential to change the elemental impurity content of the drug product, the risk assessment, including established controls for elemental impurities, should be re-evaluated. Such changes could include, but are not limited to: changes in synthetic routes, excipient suppliers, raw materials, processes, equipment, container closure systems or facilities. All changes are subject to internal change management process (ICH Q10) and if needed appropriate regional regulatory requirements. 12
17 GLOSSARY ACGIH: American Conference of Governmental Industrial Hygienists. ATSDR: Agency for Toxic Substances and Disease Registry. CEC: Commission of the European Community. CFR: Code of Federal Regulations. (USA) Change Management: A systematic approach to proposing, evaluating, approving, implementing and reviewing changes. (ICH Q10) CICAD: Concise International Chemical Assessment Documents. (WHO) Container Closure System: The sum of packaging components that together contain and protect the dosage form. This includes primary packaging components and secondary packaging components, if the latter are intended to provide additional protection to the drug product. A packaging system is equivalent to a container closure system. (ICH Q1A) Control Strategy: A planned set of controls, derived from current product and process understanding, that assures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control. (ICH Q10) Control Threshold: A limit that is applied during the assessment of elemental impurities to determine if additional control elements may be required to ensure that the PDE is not exceeded in the drug product. The limit is defined as 30% of the PDE of the specific elemental impurity under consideration. Daily Dose: The total mass of drug product that is consumed by a patient on a daily basis. EFSA: European Food Safety Agency. EHC: Environmental Health Criteria. (IPCS, WHO) EU SCOEL: European Scientific Committee on Occupational Exposure Limits. EU SEG: European Union Scientific Expert Group. Herbal Products: Medicinal products containing, exclusively, plant material and/or vegetable drug preparations as active ingredients. In some traditions, materials of inorganic or animal origin can also be present. 13
18 IARC: International Agency for Research on Cancer. Inhalation Unit Risk: The upper-bound excess lifetime cancer risk estimated to result from continuous exposure to an agent at a concentration of 1 µg/l in water, or 1 µg/m 3 in air. The interpretation of inhalation unit risk would be as follows: if unit risk = 2 x 10-6 per µg/l, 2 excess cancer cases (upper bound estimate) are expected to develop per 1,000,000 people if exposed daily for a lifetime to 1 µg of the chemical in 1 liter of drinking water. (US EPA) IPCS: International Programme for Chemical Safety. IUPAC: International Union of Pure and Applied Chemistry. IRIS: Integrated Risk Identification System, United States Environmental Protection Agency. LOAEL: Lowest-Observed-Adverse-Effect Level: Lowest concentration or amount of a substance (dose), found by experiment or observation, that causes an adverse effect on morphology, functional capacity, growth, development, or life span of a target organism distinguishable from normal (control) organisms of the same species and strain under defined conditions of exposure. (IUPAC) LoQ: Limit of Quantitation: The quantitation limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be quantitatively determined with suitable precision and accuracy. The quantitation limit is a parameter of quantitative assays for low levels of compounds in sample matrices, and is used particularly for the determination of impurities and/or degradation products. (ICH Q2) LOEL: Lowest-Observed-Effect Level: The lowest dose of substance in a study or group of studies that produces biologically significant increases in frequency or severity of any effects in the exposed humans or animals. Modifying Factor: An individual factor determined by professional judgment of a toxicologist and applied to bioassay data to relate that data to human safety. (ICH Q3C) (See related term Safety Factor) MRL: Minimal Risk Level: An estimate of the daily human exposure to a hazardous substance that is likely to be without appreciable risk. (ATSDR) NAS: National Academy of Science. (USA) NOAEL: No-Observed-Adverse-Effect Level: Greatest concentration or amount of a substance, found by experiment or observation, that causes no detectable adverse alteration of morphology, functional capacity, growth, development, or life span of the target organism under defined conditions of exposure. 14
19 NOEL: No-Observed-Effect Level: The highest dose of substance at which there are no biologically significant increases in frequency or severity of any effects in the exposed humans or animals. NTP: National Toxicology Program. (USA) OEHHA: Office of Environmental Health Hazard Assessment. (California, USA) OELV: Occupational Exposure Limit Value. OSHA: Occupational Safety and Health Administration. (USA) PEL: Permitted Exposure Limit. PDE: Permitted Daily Exposure: The maximum acceptable intake of elemental impurity in pharmaceutical products per day. Product Lifecycle: All phases in the life of the product from the initial development through marketing until the product s discontinuation. (ICH Q9) Quality: The degree to which a set of inherent properties of a product, system, or process fulfills requirements (see ICH Q6A definition specifically for quality of drug substance and drug products). (ICH Q9) Quality Risk Management: A systematic process for the assessment, control, communication, and review of risks to the quality of the drug product across the product lifecycle. (ICH Q9) Quality System: The sum of all aspects of a system that implements quality policy and ensures that quality objectives are met. (ICH Q10) Risk: The combination of the probability of occurrence of harm and the severity of that harm. (ISO/IEC Guide 51, ICH Q9) Risk Acceptance: The decision to accept risk. (ISO Guide 73) Risk Analysis: The estimation of the risk associated with the identified hazards. (ICH Q9) Risk Assessment: A systematic process of organizing information to support a risk decision to be made within a risk management process. It consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards. (ICH Q9) Risk Control: Actions implementing risk management decisions. (ISO Guide 73) 15
20 Risk Identification: The systematic use of information to identify potential sources of harm (hazards) referring to the risk question or problem description. (ICH Q9) Risk Management: The systematic application of quality management policies, procedures, and practices to the tasks of assessing, controlling, communicating, and reviewing risk. (ICH Q9) Safety: Practical certainty that adverse effects will not result from exposure to an agent under defined circumstances. (Ref. 2) Safety Assessment: An approach that focuses on the scientific understanding and measurement of chemical hazards as well as chemical exposures, and ultimately the risks associated with them. This term is often (and in this guideline) used synonymously with risk assessment. (Ref. 2) Safety Factor: A composite (reductive) factor applied by the risk assessment experts to the NOAEL or other reference point, such as the benchmark dose or benchmark dose lower confidence limit, to derive a reference dose that is considered safe or without appreciable risk, such as an acceptable daily intake or tolerable daily intake (the NOAEL or other reference point is divided by the safety factor to calculate the reference dose). The value of the safety factor depends on the nature of the toxic effect, the size and type of population to be protected, and the quality of the toxicological information available. See related terms: Assessment factor, Uncertainty factor. (Ref. 2) Severity: A measure of the possible consequences of a hazard. (ICH Q9) TLV: Threshold Limit Value: The concentration in air to which it is believed that most workers can be exposed daily without an adverse effect (i.e., effectively, the threshold between safe and dangerous concentrations). The values were established (and are revised annually) by the ACGIH and are timeweighted concentrations (TWA) for a 7- or 8-hour workday and 40-hour workweek, and thus related to chronic effects. (IUPAC) TWA: Time Weighted Average: As defined by ACGIH, time-weighted average concentration for a conventional 8-hour workday and a 40-hour workweek. (IUPAC) URF: Unit Risk Factor. US DoL: United States Department of Labor. US EPA: United States Environmental Protection Agency. WHO: World Health Organization. 16
Guidance for Industry
Guidance for Industry Process Validation: General Principles and Practices U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) CenterMore information
INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE ICH HARMONISED TRIPARTITE GUIDELINE PHARMACEUTICAL QUALITY SYSTEM Q10 Current StepMore information
Guidance for Industry. Q10 Pharmaceutical Quality System
Guidance for Industry Q10 Pharmaceutical Quality System U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics EvaluationMore information
INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE ICH HARMONISED TRIPARTITE GUIDELINE VIRAL SAFETY EVALUATION OF BIOTECHNOLOGY PRODUCTSMore information
Air Quality Guidelines
World Health Organization Regional Office for Europe Copenhagen Air Quality Guidelines for Europe Second Edition WHO Regional Publications, European Series, No. 91 The World Health Organization was establishedMore information
Abuse-Deterrent Opioids Evaluation and Labeling
Abuse-Deterrent Opioids Evaluation and Labeling Guidance for Industry U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Clinical MedicalMore information
Guidance on Cumulative Risk Assessment of Pesticide Chemicals That Have a Common Mechanism of Toxicity
Guidance on Cumulative Risk Assessment of Pesticide Chemicals That Have a Common Mechanism of Toxicity Office of Pesticide Programs U.S. Environmental Protection Agency Washington, D.C. 20460 January 14,More information
A Guide to The Globally Harmonized System of Classification and Labeling of Chemicals (GHS)
A Guide to The Globally Harmonized System of Classification and Labeling of Chemicals (GHS) Acronyms/Abbreviations The following list presents some acronyms and abbreviations used in this document. TheMore information
Biologics and biosimilars. An overview
Biologics and biosimilars An overview Contents An introduction to biotechnology... 3 A brief history of medicine development... 4 What are biologic medicines?... 5 How are biologic medicines developed?...More information
General Principles of Software Validation; Final Guidance for Industry and FDA Staff
General Principles of Software Validation; Final Guidance for Industry and FDA Staff Document issued on: January 11, 2002 This document supersedes the draft document, "General Principles of Software Validation,More information
Guidance for Industry
Guidance for Industry Changes to an Approved NDA or ANDA U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) April 2004 CMC RevisionMore information
Reflection paper for laboratories that perform the analysis or evaluation of clinical trial samples
28 February 2012 EMA/INS/GCP/532137/2010 GCP Inspectors Working Group Reflection paper for laboratories that perform the analysis or evaluation of clinical trial Draft agreed by GCP Inspectors WorkingMore information
Report. The Use of Microbiological Risk Assessment Outputs to Develop Practical Risk Management Strategies: A JOINT FAO/WHO EXPERT MEETING
The Use of Microbiological Risk Assessment Outputs to Develop Practical Risk Management Strategies: Metrics to improve food safety Report Kiel, Germany 3 7 April 2006 A JOINT FAO/WHO EXPERT MEETING FederalMore information
(Question No EFSA-Q-2007-080) Adopted after public consultation and discussion in the Panel:
The EFSA Journal (2009) xxx, 1-22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Guidance of the Scientific Panel of Food Contact Material, Enzymes, Flavourings and Processing Aids (CEF) on the Submission of a DossierMore information
INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE S1A. Current Step 4 version
INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE ICH HARMONISED TRIPARTITE GUIDELINE GUIDELINE ON THE NEED FOR CARCINOGENICITY STUDIESMore information
Official Journal of the European Union. (Acts whose publication is obligatory)
27.12.2006 L 378/1 I (Acts whose publication is obligatory) REGULATION (EC) No 1901/2006 OF THE EUROPEAN PARLIAMT AND OF THE COUNCIL of 12 December 2006 on medicinal products for paediatric use and amendingMore information
"How to do"- Document ACTIVE PHARMACEUTICAL INGREDIENTS COMMITTEE
Cefic/APIC "How to do" Document ACTIVE PHARMACEUTICAL INGREDIENTS COMMITTEE GDP for APIs: How to do Document Interpretation of the WHO Guideline GOOD TRADE AND DISTRIBUTION PRACTICES FOR PHARMACEUTICALMore information
Occupational Safety and Health Guidance Manual for Hazardous Waste Site Activities
Occupational Safety and Health Guidance Manual for Hazardous Waste Site Activities Prepared by: National Institute for Occupational Safety and Health (NIOSH) Occupational Safety and Health AdministrationMore information
Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues
18 December 2014 EMEA/CHMP/BMWP/42832/2005 Rev1 Committee for Medicinal Products for Human Use (CHMP) Guideline on similar biological medicinal products containing biotechnology-derived proteins as activeMore information
ISO/IEC Directives Part 2
ISO/IEC DIR 2 ISO/IEC Directives Part 2 Edition 6.0 2011-04 Rules for the structure and drafting of International Standards ISO/IEC DIR 2:2011(E) THIS PUBLICATION IS COPYRIGHT PROTECTED Copyright 2011More information
Choices in Methods for Economic Evaluation
Choices in Methods for Economic Evaluation A METHODOLOGICAL GUIDE Choices in Methods for Economic Evaluation October 2012 Department of Economics and Public Health Assessment 1 Choices in Methods for EconomicMore information
Environmental Management System Tool
Environmental Management System Tool How to use this Tool The Department of the Environment, Water, Heritage and the Arts (DEWHA) has developed the EMS Tool to assist office based organisation who areMore information
HAZARD COMMUNICATION Small Entity Compliance Guide for Employers That Use Hazardous Chemicals
HAZARD COMMUNICATION Small Entity Compliance Guide for Employers That Use Hazardous Chemicals OSHA 3695-03 2014 Occupational Safety and Health Act of 1970 To assure safe and healthful working conditionsMore information
COUNCIL ON ENVIRONMENTAL QUALITY Executive Office of the President
46 Fed. Reg. 18026 (March 23, 1981) As amended COUNCIL ON ENVIRONMENTAL QUALITY Executive Office of the President Memorandum to Agencies: Forty Most Asked Questions Concerning CEQ's National EnvironmentalMore information
Introduction to the Position Classification Standards
Introduction to the Position Classification Standards (Also See The Classifier s Handbook) TABLE OF CONTENTS SECTION I. BACKGROUND... 2 A. Statutory Basis...2 B. Classification Standards Issuances... 2More information
Statement on Standards for Continuing Professional Education (CPE) Programs
Statement on Standards for Continuing Professional Education (CPE) Programs Revised January 2012 Table of Contents Introduction... i Preamble... ii Article I - Definitions... 1 Article II General GuidelinesMore information
Adoption by CHMP for release for consultation November 2010. End of consultation (deadline for comments) 31 March 2011
1 2 3 November 2010 EMA/759784/2010 Committee for Medicinal Products for Human Use 4 5 6 7 Reflection paper on the need for active control in therapeutic areas where use of placebo is deemed ethical andMore information
Guidance for Industry Time and Extent Applications for Nonprescription Drug Products
Guidance for Industry Time and Extent Applications for Nonprescription Drug Products U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER)More information
STOCKHOLM CONVENTION ON PERSISTENT ORGANIC POLLUTANTS. Conscious of the need for global action on persistent organic pollutants,
STOCKHOLM CONVENTION ON PERSISTENT ORGANIC POLLUTANTS The Parties to this Convention, Recognizing that persistent organic pollutants possess toxic properties, resist degradation, bioaccumulate and areMore information
CHAPTER ONE TABLE OF CONTENTS Section Page 1.0 INTRODUCTION... 1 2.0 QA PROJECT PLAN... 1 2.1 DATA QUALITY OBJECTIVES... 2 2.2 PROJECT OBJECTIVES... 2 2.3 SAMPLE COLLECTION... 3 2.4 ANALYSIS AND TESTING...More information


text:
Even though I'm mostly a Gnome user, my LaTeX editor of choice is Kile. Unfortunately, it can become a bit sluggish, especially when dealing with long lines. (I hate artificial line breaks, so I just type one line per paragraph and turn on dynamic word wrapping.)
This seems to have something to do with rendering. To make Kile considerably faster, start it like this:
kile --graphicssystem raster
Instead of
raster, you can also try
opengl, which is supposed to be even faster, but not considered stable yet. YMMV.

subset: commoncrawl


text:
Chandler Champion, a 20-year-old from Leeds studying dance and broadcast journalism at the University of Alabama, was crowned Miss Alabama 2013 at Samford University's Wright Center Saturday night.
"I'm completely in shock," she told AL.com. "I can't wait to see what this year has in store."
Champion, who danced a ballet en pointe for her talent, promotes literacy through "Chandler's Challenge," her pageant platform.
Champion was competing as Miss Leeds area. First runner-up was Miss Rocket City Caitlin Brunell, second runner-up was Miss Smiths Station Haley Bagwell, third runner-up was Miss Cullman Area Kelsey Richter and fourth runner-up was Miss Jefferson County Hayley Barber.
"I was leaving it up to God," she said of her win. "Whatever he had planned for me I was happy with. I could have never expected this. I'm beyond blessed, absolutely."
The rest of the 11 semi-finalists announced Saturday night were: Miss Center Point Jordan Dailey, Miss Wiregrass Area Katherine Fuller, Miss Marble Valley Megan Smith, Miss North Jefferson Area Katie Malone, Miss Chattahoochee Valley Emilee Williams and Miss Lake City Callie Boyd.
The pageant began with 51 contestants.
The top 11 competed in the swimsuit, talent and evening wear competitions during the final night of the pageant. Saturday's final show - which followed three nights of preliminary competition -- was hosted by Miss Alabama 1993 Kalyn Chapman James.
Barber, Brunell and Champion all won their talent preliminaries. Champion and Bagwell won preliminary swimsuit competitions.
The new Miss Alabama will replace Anna Laura Bryan, a Samford graduate from Decatur who made it to the top 12 of Miss America.
In addition, Champion wins a $10,000 cash scholarship. She will represent the state at the Miss America competition on Sunday, Sept. 15, in Atlantic City.
She said she's excited to represent Alabama in September.
"It's something I've dreamed about for as long as I can remember," she said. "When I was little, I didn't dress up as a geisha for Around The World day. I dressed up as Miss America."


text:
There were mixed views for iPad. Some were of the view that iPad is a great product with advantages of being light and easy to carry. One can carry it along for presentations or on travel to read. Many others were of the view that a laptop can do much more than just presentations and reading. Finally, a general consensus was formed that probably "an iPad is a rich man's second laptop"!
Not long ago, we had termed laptops as "rich man's second computer", I didn't even realize when we moved ahead of that era, now I rarely see those big Personal Computers being purchased with as much vigor. Everyone seems to get Laptop or even better a Netbook. So, the confusion gets even worse.
Some more points to be pondered on.
- The smartphones are becoming smarter. I think by the end of 2011 we will have smart phones with 3D projection capabilities, connectivity to all sort of networks and of course a processing power that can bring a laptop of today to shame!
- Do we recall a device called "Pager"? It was a sort of "Twitter" on the go! Wasn't it revolutionary? Where did it go?
- How many devices can a person carry without getting pissed off? One of my teachers once told me that a person can't manage more than 2 activities at a time: home and office, office and personal relationship, personal relationship and studies, studies and office. I think that time has been a proof for that statement, and I firmly believe in it. Extending the same theory, I am of the opinion that a person can't manage more than 2 devices successfully. Most of us must be having a laptop and a phone. If I bring in a iPad along, then one of the 2 former devices have to go! Either a laptop or the phone.
- It is unlikely that we will go away with a phone. What else can we put in our pockets, hold in our hands and talk for hours on? Surely not an ipad! Until and unless we have custom designed clothes to hold them :)
There is no conclusion to this post. Rather, I am still confused on where we are heading to. Conclusively, I can only say that out of Laptops, Netbooks, Leaptops, iPads, phones, smart phones, smarter phones, Kindles, Adams and ... we will have to choose only 2 devices at a time. Most of the devices will converge into others and new devices will evolve over time. More fads will come, some will stay some will not even be mentioned in history.....


text:
On the other hand, for those who notice almost every other weird indications with Your entire body you should head to a physician quickly. Almost never eye twitching generally is a indication of serious neurological troubles. I'm confident it's practically nothing nevertheless.
2012 observed the most expensive political strategies and a few of the most Excessive temperature situations in human historical past, from floods in Australia to cyclones in China to Hurricane Sandy and lots of Other individuals.
We needed to commence what We've begun, and for the current time we have been speaking about the keeping playable modes inside of. We possess the PVP manner, after you will interface on the net to fight distinct players from just about everywhere through the entire planet.
This really is regarded as the #one capturing diversion within the versatile group, we're not by any extend with the creativity beyond any question from this data.
June 24, 2012 at seven:43 am I've worked with Botox and feel it truly is unsafe under the eyes. And will only be applied around the confront higher than eyes. During the neck you die When your muscles paralyze and you will't breathe or swallow. I suppose armpits for sweating are distinctive but fatal from heat exhaustion when you stop People glands from perspiring. How else will One's body amazing itself Normally like cutting a pet dogs tongue out as that is definitely how they interesting their bodies.
Thanks to the newest gears and instructions which will be flooding your account without cost. Also Alternatively, the Raids mode is accessible too. Learn more over it on the subsequent phase.
Indicator me up! No many thanks By default you might get a daily digest made up of check here any guides which were revealed by authors inside your membership listing. If you want, you'll be able to alter the digest interval below. every day
Which style of Enjoy may well not suit Absolutely everyone, so we had to tell our audience with what on earth is expecting them up forward, obtain the Hero Hunters cheats at no cost.
I predicted the A7s to blow the A9 out of your water, as the A7s has about 50 % the pixels on the same-sized sensor, so that they're more substantial plus much more light sensitive. But yeah, the A9 Unquestionably holds its personal listed here.
• Choose to gain as lots of Bucks as possible in your next Gauntlet run? There are several nuances that can help you get even further in the method if you utilize them to the advantage. Skills retain their cost in between their missions. Pretty much wiped out the enemy crew? Maybe you ought to maintain off on making use of Butter's Defender Protect right until the start of the following mission. Choose sensibly nevertheless, since the AI will vehicle-deploy abilities.
Have you ever at any time tried to have an adult dialogue with an individual but couldn't concentrate since your eyelid was twitching?
In the meantime, quite a few People proceed to facial area improve inside their properties, lender accounts and Positions. Only time will notify if the most recent wave of modify Us residents voted for during the midterm elections will end in a destructive or good final result.
I've experienced a twitching remaining upper eyelid for that earlier seven months. I've absent to an ophthalmologist, he ran each of the exams and found nothing at all. Went to your medical doctor, he tells me its most likely Bells Palsy. Its aggravating.
Welcome for the Hero Hunters Cheats and Codes page exactly where our staff of contributors can help you having a list of cheats, codes, hints, hacks, guidelines and unlockables.
Details, Fiction and Hero Hunters mod apk
On the other hand, for those who notice almost every other weird indications with Your entire body you should head to a physician quickly. Almost never eye twitching generally is a indication of serious neurological troubles. I'm confident it's practically nothing nevertheless.


text:
Vintage-inspired Wedding Stationery, greeting cards, prints, homewares and gifts
Handcrafted in our studio in Belfast, Northern Ireland
Shop online anytime for arbee* range of cards & stationery. Our original designs are handcrafted with love from the finest artists' materials. Custom orders very welcome – contact us any time!
Check out what our lovely customers have to say about us
Florence M.
Emer & Rory
Ciara & Padraig
Therese & Neil
Gillian & Ian
Carole J.
Dawn R.
Hannah L.
Rozalyn H.
Christina G.
Follow arbee* on instagram


text:
Hancocks Wine, Spirit & Beer Brand Portfolio
Listed below is the large selection of wine, spirit and beer brands Hancocks Wine, Spirit and Beer Merchants has to offer you
Hancocks Licensed Trade Customers Only. All prices are for the supply of items in New Zealand and are stated in New
Zealand dollars exclusive of goods & services tax (GST). In order to purchase alcohol you must be legally
entitled to do so. All transactions are subject to this and all our other Terms and Conditions, which can be
viewed here.
this website, including online ordering.
Copyright ©2006 - 2019
Hancocks Wine, Spirit and Beer Merchants Limited


text:
First Australian ISPs launch Interpol internet filter
CyberOne, Telstra lock the gates
While debate rages over Telstra and Optus announcing their filtering plans, CyberOne in Canberra has jumped the industry. On Friday, it started filtering its TransACT-connected clients against the Interpol blacklist.
A voluntary industry code of practice for ISPs in Australia aims to disrupt the activities of child pornographers and will rely on a blocklist compiled and supplied by Interpol, in cooperation with the Australian Federal Police (AFP).
CyberOne founder Maciej Mikrut said the company was "very happy that we can do something to disrupt the activities of child pornographers and we believe that the enormous amount of work that Interpol has put into creating this very accurate worst-of-the-worst filter list is a great step forward."
ContentKeeper Technologies, an Australian filtering specialist, has worked with Interpol since last year to launch the filter into the country.
Unlike other filtering proposals, the Interpol approach addresses filtering at the domain level. The aim is to keep ISPs active in the self regulation of their own clients. "There is a big incentive to big hosting providers to keep them honest and to get that stuff off their hosting site," ContentKeeper CTO Mark Riley told The Register.
"We have been pretty vocal in opposition to mandatory filtering. At a political level we don't think it's a good idea due to things like bracket creep and external influence on what would be put on the list from special interest groups. But voluntary filtering makes the whole thing more attractive and turns it into something that is beyond corruption in terms of political interest."
ContentKeeper has created a package for ISPs internationally who want to join the voluntary filtering initiative. ContentKeeper provides the appliance hardware which implements the Interpol database and also supplies the required Interpol block page. ISPs can then activate the full range of filtering facilities at any time on a subscription-based model.
Last Monday the Internet Industry Association revealed details of the framework behind the code relating to child abuse materials.
"We anticipate that we will have ISPs representing between 80-90 per cent of the Australian user base complying with the scheme this year," said IIA's chief executive Peter Coroneos.
"We have considered the alternatives and have come to the view that a voluntary industry code by which ISPs agree to block child pornography sites once notified by the police is the best way forward. This move will bring Australia into alignment with Scandinavia and Europe."
Telstra also reported to have activated its filter over the weekend, according to this report. ®


text:
PAYE operation: double taxation claims submitted by non resident individuals: royalties
For information on what is a royalty, see the International Manual at INTM342510.
The relief available depends upon the terms of each double taxation agreement and HMRC decides whether a claim is allowable by referring to theDT Digest (PDF 184KB) (HMRC website) (external users can find the guidance at http://www.hmrc.gov.uk/taxtreaties/dtdigest.pdf). If it is, relief at source is allowed on future payments of the income. HMRC directs the payer to pay the income without tax deducted or deduct tax at the rate dictated by the double taxation agreement.
Claims for double taxation relief can be made by the originator of the work or someone who is not the originator of the work, see INTM342550.
Claims can be made with respect to either specific works, for example royalties relating to a particular book; or in respect of all royalties paid by a particular payer, for example royalties paid by a publishing company for a number of books.
If full double taxation relief is not available for claims from the originator, consider whether the individual can be classed as a professional author, see INTM342590. This cannot be applied where the individual is not the originator of the work.
Access to COTAX is essential where claims for double taxation relief are received in respect of royalty income. See Action guide tax40170 and tax40181


text:
More manageable monthly payments, better interest rates, and a chance to improve your credit history, these are the three goals of acquiring a bad credit mortgage loan. Do you have a poor credit history? Bad credit mortgage loans can assist you in purchasing a new home or refinancing the one you already live in. Taking a bad credit mortgage loans can help you re-establish your creditworthiness and give you some financial stability.
Generally, if you have been holding a high-interest home loan for twelve consecutive months and have made your payments in a timely manner, you will be able to apply, and probably approved, for a bad credit mortgage loan. Lenders are out there to accommodate your financial aspirations. Your twelve months of on-time payments will have given your credit history quite a nice boost as well. You can choose one of three types of bad credit mortgages.
Type One: New Home
Even though you may have a pretty poor credit history you probably can still get the financing to buy a new home. If you are a first time buyer or you are looking for a second home, this is probably a good solution for you. Bad credit loan mortgages have rather high interest rates, but once you get your credit scores back on track, you will be able to refinance at more reasonable interest rates. With each timely payment you make your credit scores inch up a little higher.
Type Two: Refinance Mortgage
This may sound tricky, but it is not really. A bad credit mortgage refinance allows you to pay off the existing mortgage on the home with the funds gleaned from a second bad credit mortgage loan while keeping the home on the second mortgage as collateral. As noted above, this can happen after twelve months of regularly scheduled payments. You will have a lower interest rate, which means you can build equity faster. Also, your monthly payments should be more manageable.
Type Three: Home Equity
At some point you will have built some substantial equity in your home. That is, a significant portion of the principle on your bad credit mortgage loan will have been paid. You can request a second mortgage loan, also called a home equity loan, in the amount of that sum of equity. The same home can be the collateral. This bad credit second mortgage will have better interest rates and reasonable repayment terms as well.
Many home buyers have such a second mortgage loan, or home equity loan, and have used it for any number of good financial reasons. Often they are used to consolidate a bunch of pesky little debts. Some have used it for home improvements which increases the value of the property. Sometimes the funds are used for emergencies such as unexpected medical expenses or trips necessary for distant family obligations. Paying this on this mortgage is much cheaper than using credit cards. Once again, timely payments will boost your credit scores.
Pulling It All Together
As you can see, taking on a bad credit mortgage loan or a bad credit mortgage refinance can do a lot to boost your credit scores, to make your finances more manageable, and bring your interest rates down. Home buyers with poor credit benefit greatly using these loans.


text:
Having problems with your Bissell ProHeat Turbo Deep Cleaner Upright Steam Vacuum ?
I have a Bissell steam shampoorer..I'm not sure where the water goes. I assume in the bladder (soap & water)..there is a little red plastic piece that I don't know where it goes..somewhere in the bladder?..Anyway, no solution is coming out and of course no vacumming up. Cannot find my manual or instructions. I've had it working before..thanks
Answers :
Here is a tip that will give you all the information you need to fix your BissellProheat Vacuum Problem.
Bissell Proheat Upright Wet/Dry Vacuum Problems
heatman101 \012
Here is a tip that will give you all the information you need to fix your BissellProheat Vacuum Problem.
Bissell Proheat Upright Wet/Dry Vacuum Problems
heatman101 \012
Repair Help & Product Troubleshooting for Bissell ProHeat Turbo Deep Cleaner Upright Steam Vacuum
Tips for a great answer:- Provide details, support with references or personal experience .
- If you need clarification, ask it in the comment box .
- It's 100% free, no registration required.
Suggested Questions/Answers :
I have a Bissell steam shampoorer..I'm not sure where the water goes. I assume in the bladder (soap & water)..there is a little red plastic piece that I don't know where it goes..somewhere in the bladder?..Anyway, no solution is coming out and of course no vacumming up. Cannot find my manual or instructions. I've had it working before..thanks
Hi,Here is a tip that will give you all the information you need to fix your BissellProheat Vacuum Problem.Bissell Proheat Upright Wet/ ... Bissell ProHeat Turbo Deep Cleaner Upright Steam Vacuum
I have Model 9400-3 Bissell Pro heat select 2X microban. I cannot get the solution to come out to shampoo the carbet. I cannot find my instructions that came with the shapooer. Please help.
... Bissell 9500 ProHeat 2X CleanShot Upright Deep Cleaner, Red Berends Vacuum
On off switch stopped working 3rd one to do so this one cannot be returned to old ? model QPV10.5b nothing on shop vac site and nothing comes up on Digi-key site really do not want to buy 150.00 vac again but cannot find on off switch! thanks for your help
Use a higher amp rated switch. If this is not available, then solder and insulate the wires where switch should be, then install an aftermarket in-line switch. ... Vacuums
Vacum I need to check the brushes in the motor smells have removed four screws but the cover is not coming off. I dont want to damage this by forcing it but cannot find any other screws Thanks fairweather
Hi there!\015\012\015\012It would certainly help if you said which model it was.\015\012\015\012I can only give generic help now, and do the best I can for you.\015\012\015\012Most plastic products rely heavily on ... Vacuums
Suction Hose The suction hose has cracked so the suction feature no longer works. I would like to replace it, but cannot find that it is a replaceable part. Hopefully someone else has a solution.
Go to0 http://www.thehooverstore.com/h3000.html there also is a parts break down. You can email them at ... Hoover Floormate H3000 Upright Wet/Dry Vacuum
I have a Kenmore vacum model 11622612200 and it has been working wonderful, however the belt has broken and I cannot get the cover off, I need to look at a manuel to find out how to replace the belt.
... Kenmore Vacuums
Vacuum filter I bought a vacuum from Walmart that works really well, but I cannot find a replacement filter for it. The lable on the bottom of the vacuum reads "Excellent Solutions LTD" Model C 2006B also has 31CX E306773 numbers on it. 120V-60Hz 10Amps I have searched the internet but no luck so far....any suggestions?
We bought one a couple years ago too, no filters. Now, WalMart carries replacement filters for other vacuums that will fit. Go back to WalMart and pick up the Durabrand CF2006 - it's in an orange box, works like a champ, I think it was around $5. ... Vacuums
Cannot find out where to buy the cleaning solution that comes with the Hoover steam vac. Live in Bend, OR.
You dont have to use the hoover stuff,run down to your local home depot and by the zep brand it cost cheaper cleans better and youll get more for your money ... Hoover Vacuums
Bissell Powerease Lighweight Deep Cleaner. (Shampooer) After I fill the solution tank with the solution and water, I put it in it's slot, but all of the contents just come flowing out. I have only used this machine twice and it worked ok. You are supposed to press the trigger and the solution sprays out and then release the trigger when you want it to stop. But like I said, now I just put the tank on and all the contents come flowing out. I don't know what's wrong or how to stop it.
... Vacuums
Bissell Quicksteamer I have a Bissell Quicksteamer that is about 5 years old. I went to use it today and hardly any solution was coming out. I could see it suctioning up what little came out, so I took it apart and cleaned it thoroughly. I tried to use again and no solution is coming out. Everything seems to being working just fine. Thanks
Here's a kinda kick yourself quick fix that might be helpful, I took my whole machine apart all the way to the motor to come to realize that the small rubber piece that cover the tip of the water container was jammed in the hole you sli ... Bissell 1770 Quicksteamer II Upright Vacuum
I have a Electrolux , EL6988 Canister Vacum, howeveer the brushes and motor will not run when turned on. I have take the plates and cleaned around the brushes, but it will not come one. The vacum comes on but the motorized bushes do not activate. Thanks I have lost my owners manual, and have looked for the reset button and can't find or know where it is located. Any suggestions.
I need the molded wire harness inside the plastic wand ( one of the prongs is broke off) What is the part # or where can I buy it? Model EL6988 ... Electrolux UltraLux 2000 Bagged Canister Vacuum
I have a hoover steamvac dual v and is leaking, bristels not working very food only two are speaning and is not sucking any water Very little solution comes out, or comes out in streaks when pressing the solution dispenser button on the handle. I think the lines may be stopped upped.
Http://geeksquad.fixya.com/ThreadView.aspx?prdid=41020&thid=634728\015\012I have a Hoover SteamVac\015\012Posted by albazo on May 30, 2008\015\012I have a Hoover ... Hoover F5866-900 SteamVac Deluxe Wet/Dry Vacuum
Have DC07 that won't come on. Wife said this started happening a few weeks ago. Would come on and then other times would not come on. Now will not come on at all. Believe I have a lose wire. Have taken off star screw by on off switch, but cannot find how to get plastic parts apart to get into electrical connections. How do I do this? I am sure I am missing something simple?
... Dyson DC07 Bagless Upright Cyclonic Vacuum
My carpet cleaner is not spraying out water or solution. motor is working, heater is working but nothing coming out when i press the button
Check if bottom of solution tank and/or lines are gummed up. Clean and blow out lines and inspect check ball assembly.\015\012Hope this helps. Could use more info.\015\012Bob ... Bissell 1699 ProHeat Clear View Upright Steam Vacuum
I have a powerbase 1050W mitre saw and am trying to cahnge the blade. There seems to be no way of reoving the blade, How do you remove the blade? Ther eis a guard over the blade which stops the blade coming out when not in use, and when you lower the blade to cut, which pull sback the guard, you cannot remove the blade as he blade is touching the base. I have tried to find a copy of the manual on line but cannot.
... Vacuums
My B50 Keurig single cup Brewer works great but this am, I find that the bottom Sharp Needle is gone and I cannot find it. It is the needle that punctures the bottom of the K-Cup. Needle and little rubber piece is gone - DO YOU SELL THIS.
Herein Fixya we don't sell anything, we just give some guidance how to find thepart you need. Also Keurig makes it next to impossible to get parts unless youhave sent in your warranty and even then they want you to send the ... Vacuums
My Dirt Devil M082476 Full Bag indicator light keeps coming on when I turn my vacum up to full intensity. I have tried changing the bag and checked that all hose is clear. If I leave the vacum on low intensity the suction is minimal and does not increas when I turn up the suction. Is there a solution to this? I look forward to your response
... Dirt Devil M084105 Jaguar Vacuum
My steam pocket mop seems clogged. Steam does not come out of the mop head. The clog appears to be in the rectangular mop head. The triangular head still works fine. I've tried soaking it in hot water and soaking it with cleaning solutions. They have not worked. If I blow into the connection piece, no air goes through. That's what leads me to believe there is a clog. If you can help, please do. I like the product and haven't been able to use it for awhile because of this. Thanks.
I had the same issue with the rectangular mop and corrected it by disassembling the tube from the rectangular piece. There are two screws that will need to be removed in order to get access to the connector. Once the connector is removed from the rec ... Euro-Pro Shark Steam Mop - Gray/ Purple Vacuum
Elna 7200. The bobbin spring seems to have come loose, but cannot figure out how to get it in place again, so we cannot work, Pls help.
The best course of action in your case is to take sewing machine center and let them show you how to get it in place. They may even help for free because you might become a potential costumer. I hope that there is a repair center near you. ... Vacuums
I have a whirlpool personal valet steamer system that is mounted to the wall. The system was in the house when I purchased it so I would suspect it's about 8 - 10 years old and I cannot find the manual for it. When I push the start button it automaitcally cancels the set up and will not run. I have unplugged it for a while and then put it back in and it's worked before but not anly longer. How do i get a manual or can I find a repair person to look at it.
... Vacuums
I have taken delivery of a new Lloytron Halogen Oven E4701 WH.from a supplier in the UK (I live in Spain). On unpacking it I found that Part of the temperature control knob assembly had fallen down inside of the heater body. I dismantled the heater body to retrieve the part but I cannot now work out the order of re-assembling the fan parts so that the fan does not catch on other parts of the assembly. I cannot find a parts drawing on-line. Can you help ?
... Vacuums
Bissell 8920 proheat x2 brushes not turning i only noticed this after i finished cleaning.. or kinda cleaning because of the brushes ntot turning.. water comes out fine suction is fine but its not scrubbing so its not as clean as it could be. manual part works well water coming out hot. I did take it apart and cleaned off all the hairs in hopes maybe that was it.. put it together still nothing.. No idea how the belts should look onit and i cant find a picture or a video showing how belts look o
Hello,\015\012\015\012Here's a link to a very helpful video that shows you step by step on how to access and replace the belt on your machine. When the brushes stop spinning, but the rest of the machine works fine, this is a tell-tale ... Bissell 9500 ProHeat 2X CleanShot Upright Deep Cleaner, Red Berends Vacuum
My Hoover Deluxe Hand/mop steam cleaner (H1005) is not working. The light comes on and you can hear the steam generating but nothing comes out of the nozzle. Do you have a solution for me?
... Oreck Sanapathic DMS2000 Handheld Steam Vacuum
My wife and I own 6 IRobots: 1 Scuba 1 Dirt Dog 4 House cleaning vacume models All of them are not working, so I decided to try and solve the problems with two of them: One is a dirt dog and the other a house cleaning vacume Rumba. Given: Battery is fully charged Reaction: I start both of them. They run for about 2 to 3 seconds They come to an abrupt stop as if there is a rock in the gears. Help
Both of them have identical issues? Can you please provide the actual part number of them? It should be on the bottom or inside the battery area somewhere.ThanksTim ... iRobot 1100 Dirt Dog Bagless Robotic Vacuum
My Bissell Quicksteamer Model 1960-R won't spray cleaning solution. I have cleaned it and taken apart the whole thing. I can't find any problems. The holes are not cloged where the water comes out as I disconnected it and blew through it to be sure. The lines show water trying to go through. It is as if it doesn't have enough power to pump the water out when I squeeze the trigger. I am thinking it is the pump thing but can't find a replacement part for it.
... Bissell 1960-3 QuickSteamer Plus Upright Vacuum


text:
Use code FBJAN50 to take 50% off original priced Roamans and Jessica London items, 50% off Comfortview Shoes, 50% off select Bras, Panties, Sleep, and swim, and 20% off Ellos. Valid online only. Does apply to international orders. Discount applies to subtotal only and does not include shipping and handling or taxes. Shipping discount applies to shipping total only and does not include taxes. Returns will be credited at the discounted price. Not applicable to gift cards or prior purchases. May not be redeemed for cash or combined with other offers. Excludes Clearance, National Brands, Third Party Brands, Alex Evenings, Ashley Graham Intimates, Donna Salyer's Fabulous-Furs, Pisarro Nights, Select Lingerie and Sleep, Women Accessories, Men Accessories and Shoes. Expires 1/17/2019 at 11:59PM PT.
Plus Size Lingerie
Our plus size lingerie seamlessly blends comfort and beauty, bringing you the very best undergarments designed for full figures.
We carry the brands you know and love in a range of options that are perfect for everyday wear, as well as special occasions. From ultra sexy lingerie and hosiery to practical panties, bras, and sleepwear, our selection of plus size lingerie and specialty undergarments is second to none.
Where Can I Find Plus Size Lingerie in My Size?
Whether you're looking for practical plus size bras and panties or want to spice things up in the bedroom with a seriously sultry chemise, Fullbeauty understands the need for flattering undergarments in specialty sizes.
Our plus size lingerie collection is extensive and offers sizes ranging from 6 to 52 (XS to 8X) while being designed to help you feel your best both in and out of your clothes. From your favorite T-shirt bra and super-soft cotton briefs to an elegant satin robe and a glamorous chiffon babydoll, we have intimates for every occasion.
Do You Also Have Sleepwear and Loungewear?
You're sure to find something you'll love in our selection of plus size sleepwear and loungewear. With features like breathability, roomy cuts, and fresh styles, our selections will make you wonder how you ever lived without them.
Sleep soundly in one of our pretty pajama sets, sleepshirts, or gowns, and cuddle up in a plush robe and slippers—the perfect accompaniments for sipping your morning coffee. If you want to put a little pep in your step, check out our vibrant embroidered cotton loungers in cheerful colors and patterns. Or, bask in serene solitude while wearing our hooded terry sleep lounger—an ideal outfit for cuddling up with a good book.
Just be careful, because with loungewear this comfy and attractive, you may never resort to wearing regular clothes again!
Where Can I Find Contouring Shapewear?
A plus size lingerie collection simply isn't complete without contouring shapewear. Like the best-kept secrets, our specially designed undergarments are intended to slim, shape, and accentuate your curves without leaving a trace.
Perfect for hiding a tummy bulge in a special occasion dress, or for looking fabulous in your new skinny jeans, our contouring lingerie will make you feel good and appear instantly slimmer. If your midsection is a concern, use our high-waist tummy control briefs, a hook and eye waist shaper, or one of our seamless shaping camis to create that coveted hourglass shape.
Contour your entire body with our wear-your-own-bra full-body briefer, or the all-in-one extra-firm body briefer. Slenderize and lift your lower half by using our long-leg shapers, tummy controlling briefs, or our everyday shaping thong.
Aimed at helping you look incredible under your clothes, shapewear has become a must-have item in every woman's closet.


text:
There was an interesting 4 minutes at Sunday school today. I very briefly introduced Vav and pointed out some of the circled vav's in the pictures here. Then I took a writing implement (a thin point magic marker) and placed the strip on the floor and lightly held the marker against the strip so that I could drag it under the marker making a line as it moved. As I dragged the marker, the children watched the vav's go buy - many of them saying - 'there's a vav', 'there another vav'. Then when the line came back to the starting place - their jaws dropped and their eyes popped out and they said - 'how did you do that?' - and one picked up the strip and looked on both sides of the paper clearly seeing that both had been marked without turning the paper over.
They won't forget the Moebius strip - and I hope they won't forget the vav that connects or hooks words and the curtains of the tabernacle. Not one end to the other with a half-twist, but there are curious connections still to be discovered. There is much more to learn about hooks and they will have fun doing it.
(Incidentally, they can see the differing vowel points, but I haven't introduced them yet. The time will come.)
Sunday, October 26, 2008
Presenting Vav
Posted by Bob MacDonald at 12:42 PM
No comments:
Subscribe to: Post Comments (Atom)


text:
Stay tuned for all new exclusive deals
only on Fox & Friends
For all inquiries please call 800-373-7101 or email us at
All product names, logos, and brands are property of their respective owners. All company, product and service names used in this website are for identification purposes only. Use of these names, logos, and brands does not imply endorsement.
Copyright ©2015-2016 Mega Morning Deals. All rights reserved.