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Sitz der K+S Aktiengesellschaftu. a. cutlehntem -z'(vgl. ё aum. 1); nom. f.)waarin Vg. i, II, KS; acc. ш. hwa'rz'n SK, G. a, hwariën mschw. Anm. 2. Die ё anni. 3 erwähnten sg. nom. f. und. Willkommen bei Reifenservice der Keller & Keller Gbr. Wir freuen uns unsere App vorzustellen. Seit sind wir der richtige Ansprechpartner für Rund um Ihr. НLz,2; МG II, 30 cm ,01 DM/m3 ,29 е/m3 м Trag. AuBenw. Aufenw., Zulage für KS statt KS 33,86 DM/m3 17,31 e/mз
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Jinan Nostec Equipment Co. Liyang Yuda Machinery Co. Suzhou Dazen Electromechanical Technology Co. Huzhou ORIA Elevator Co. Fuji Elevator Passenger Lift.
Weibo Elevator Co. Shanghai Fuji Elevator Co. Huzhou OTSTEC Elevator Co. Nova Elevator Parts Co. Shandong Lift Machinery Co. Guangdong Lingmu Elevator Co.
Joylive Elevator Suzhou Co. United Elevator Suzhou Co. Nantong Fuji Elevator Co. Shanghai Czanf Technology Co.
Hydraulic system 2T Cargo Lift Platform Vertical Platform Lift. Shandong Tavol Machinery Co. Taian Shelley Engineering Co.
Zhejiang Aoma Elevator Co. SIGLEN Elevator China Co. Qingdao Lianhai Hydraulic Machinery Co. Wemet Lift Machinery Co.
XIWEI Elevator Jiangsu Co. Huixian Qidong Construction Machinery Co. Desenk Elevator China Co. Shandong Aizhou Tech Co. If only one of the enantiomers has a pharmacological activity pharmacological activity of the second enantiomer is low or completely absent , it is sufficient to confirm the bioequivalence only for the pharmacologically active enantiomer.
Use of urine as a biological material If it is impossible to reliably determine the plasma concentration-time profile of the parent compound, it is acceptable to use data on urinary excretion to determine the exposure value as a substitute for plasma concentration.
In this case, it's required to clearly justify use of urine as a biological material by the maximum exposure value determination.
If it is possible to obtain reliable information about plasma C max , to assess bioequivalence these data shall be presented along with the exposure value obtained using urine.
When using urine as a biological material, the applicant shall provide all available information confirming that urinary excretion reflects plasma exposure.
Endogenous substances In case of study of endogenic active ingredients, pharmacokinetic parameters shall be calculated with an adjustment according to their background content so as the calculated pharmacokinetic parameters should be related to an increase in concentration obtained as a result of the drug administration.
For the purpose of reliable measurement of increase in concentration of the investigational substance if compared with the background concentration thereof, which is determined by the drug administration, one can apply supra-therapeutic doses under the condition of acceptable tolerance thereof.
In case no exposure difference after administration of different doses of the endogenic substance has been demonstrated, it shall be determined either in the pilot study or within the framework of one of the stages of the main bioequivalence study with the use of different doses of the reference drug in order to confirm suitability of the dose selected for bioequivalence study and to ensure identification of possible differences between the compared medicinal products.
In the study protocol, it is necessary to determine in advance and describe the method used to adjust for the background content of the endogenous substance.
As a correction, it is preferable to use the standard subtraction: either the average concentration of the endogenous substance, determined before taking the medicinal product, or the average AUC is subtracted.
Occasionally, when the endogenous substance concentration after taking the product exceeds significantly the background, a correction for background content of the endogenous substance is not required.
In the bioequivalence studies of endogenous substances, it is not possible to directly assess the carry-over effect; therefore, special care shall be taken in choosing the duration of the wash-out period.
Test dosages. If several dosages are subject to authorization, then depending on the composition proportionality between the different dosages and other properties of the medicinal product, it is sufficient to conduct a bioequivalence study for one or two dosages.
The choice of dosage strengths for study depends on the linearity of the active substance pharmacokinetics. If the pharmacokinetics are non-linear an increase in AUC disproportionately to the dose taken , the suitability of different dosages for determining potential differences between the comparable medicinal products may vary.
Linearity of pharmacokinetics is recognized not exceed 25 percent, if the difference between dose-adjusted average AUCs for the test dose dose used in the bioequivalence study and the dosage s for which the bioequivalence study is not planned.
To assess the linearity, the applicant shall study and critically evaluate all available scientific literature in terms of dose proportionality.
If the bioequivalence for the highest sensitivity dosages with respect to establishing differences between the comparable medicinal products is confirmed, the in vivo bioequivalence studies with other dosages are not required.
General criteria of the biowaiver for different In case of the statement that there is no need to conduct a bioequivalence study for additional dosages, the following conditions shall be met: a manufacturing process of the medicinal products with different dosages is the same; b the qualitative composition of the medicinal product with different dosages is the same this requirement does not apply to dyes and flavors ; c the composition of medicinal products with different dosages should be quantitatively proportional: the relationship between the content of the active substance s and each of the excipients is the same for all dosages this requirement does not apply to membranes of immediate-release medicinal products, capsules, dyes and flavors.
If the quantitative proportionality of the composition is absent, the specified condition is considered to be fulfilled when the conditions "i" and "ii" or "i" and "iii" are observed in respect of the test dosage s subject to bioequivalence studies: i the quantitative content of active substance s does not exceed 5 percent of the tablet core weight, the capsule content weight; ii the quantitative content of the tablet core excipients or the capsule content is the same for all the dosages recorded, only the active substance content changes; iii the quantitative content of fillers varies depending on the active substance content; the quantitative content of the remaining core excipients or the capsule content for the dosages in question remains unchanged; d data on comparative dissolution kinetics test confirm the absence of the need for additional in vivo bioequivalence studies.
Linear pharmacokinetics If the conditions described in paragraphs a —d hereof are met, it is sufficient to conduct a bioequivalence study for a single dosage.
Typically, the bioequivalence study is conducted to the highest dosage. For medicinal products with linear pharmacokinetics, provided that the pharmaceutical substance is highly soluble see Appendix 3 , the bioequivalence studies can be carried out with lower dosages.
Choosing a lower dosage can also be justified from the standpoint of safety or tolerability, when the use of the highest dosage in healthy volunteers is unacceptable.
In addition, if the analytical procedure sensitivity does not allow to accurately measure the concentration of the active ingredient when taking the highest dosage, a higher dose of the medicinal product is allowed it is preferable to use several tablets with the highest dosage.
Exceeding the maximum therapeutic dose is allowed only if it is well tolerated by healthy volunteers and there are no restrictions on the absorption or solubility extent of the active ingredient taken in such a dose.
Non-linear pharmacokinetics If, in a therapeutic range, the extent of AUC increase for the medicinal products with non-linear pharmacokinetics is proportionately greater than the extent of increase in dose, the bioequivalence study is usually carried out with the highest dosage of the medicinal product.
As in the case of medicinal products with linear pharmacokinetics, the choice of a lower dosage can be justified from the standpoint of safety of subjects and tolerability of products, when the use of the highest dosage in healthy volunteers is unacceptable.
Due to the low sensitivity of the analytical procedure, similar to medicinal products with linear pharmacokinetics, higher doses of medicinal products with non-linear pharmacokinetics are also allowed.
The bioequivalence study of medicinal products in which therapeutic ranged AUC increases less than the corresponding dose increase, in most cases, is required for the highest and lowest dosages or for the dosage, the pharmacokinetics of which are in the linear range , If non-linearity is not due to low solubility, but explained, for example, by vector saturation and the conditions of biowaivers specified in paragraph a —d hereof are met, and the comparable medicinal products do not contain any excipients affecting the motility of gastrointestinal tract or carrier proteins, the bioequivalence study with the smallest dosage or a dosage, the pharmacokinetics of which is in the linear range is sufficient.
The selection of other dosages may be justified by the low sensitivity of the analytical procedure, when conducting the study with the lowest dosage is impossible or using the highest dosage in healthy volunteers is unacceptable from the standpoint of safety or tolerability.
Bracketing If the bioequivalence study is required for more than 2 dosages, for example, due to differences in the composition proportionality, an approach is used that allows one to limit the study of extreme variants.
In this case, it is allowed to conduct two bioequivalence studies if the doses selected for study are presented by extreme values, e.
In case the bioequivalence study implies a study by administration of drugs in two doses before and after a meal as a result of non-linear absorption or deviations from the content proportionality , it is acceptable just to conduct a study before and after a meal for one dose.
When selecting the study conditions on an empty stomach or after meal , for studying the remaining dosages, preference is given to conditions that are most sensitive in identifying possible differences between the comparable medicinal products.
When calculating the quantitative content of each active substance in the fixed combination, other active substances should be considered as excipients.
Each layer of bilayer tablets can be considered independently. Methodology of the bioanalytical part of the study. The biological part of bioequivalence studies shall be conducted in accordance with the Good Clinical Practices GLP applied in the sphere of circulation of medicinal products.
To obtain reliable study results and adequate interpretation thereof, it is required to conduct a comprehensive assessment of the used bioanalytical methods, perform full validation thereof and document them.
In each analytical run within the study, it is necessary to confirm the method feasibility using the quality control samples.
The main characteristics of the bioanalytical procedure for ensuring the acceptability and reliability of obtained analytical data are: selectivity, lower limit of quantification, response function calibration curve form , accuracy, precision, and stability.
In the study protocol, it is necessary to provide for the possibility of incurred sample reanalysis. Under normal conditions, the incurred sample reanalysis due to pharmacokinetic reasons is unacceptable, which is especially important for bioequivalence studies, as this may distort the study results.
Persons performing the sample analysis should not be aware of the investigational medicinal products taken by the subjects. Results evaluation.
A correction for assay differences between the batches of investigational and reference medicinal products in bioequivalence studies for pharmacokinetic parameters usually is not allowed.
The correction, along with the assay results of the active ingredient in the studied product shall be reflected in the study documents. Selection of subjects for the study result analysis Whenever possible, all subjects who have taken the drug product should be included in the statistical analysis.
However, the subjects participated in a cross-sectional study with lacked data on both the investigational medicinal product and the reference medicinal product, or the subjects participated in the parallel study with lacked data from a single stage should not be included in the analysis.
Data processing of all subjects, who took the medicinal product, is necessary to carry out by the same methods. The study protocol is not allowed to include in the analysis of data on the " spares" of volunteers only to replace the data of excluded subjects.
Even during the study there was no drops out, it is necessary to include all subjects who took the drug in the analysis.
Thus, it is not allowed to include spares undergoing the bioequivalence study procedures separately from the main sampling. In a study with more than 2 comparison groups for example, a three-period study with 2 reference products or a four-period study on fasting and after meals , the analysis for each pair being compared should be performed only after the pre-exclusion of data not related to the comparison groups.
Subject exclusion criteria For an objective assessment of the randomized study results, the follow up and management of all subjects shall be carried out in accordance with the same rules.
These rules should not depend on the medicinal product taken or the outcome, so the decision on the subject exclusion from the statistical analysis shall be made before the laboratory analysis of samples.
Any reason may be a criterion for excluding subjects, if it is described in advance in the study protocol, and the decision on exclusion was made before the sample analysis.
However, due to a decrease in the statistical power of the study, as well as with the necessary minimum of 12 subjects, the exclusion of the latter should be avoided.
Acceptable exclusion criteria for subjects are vomiting or diarrhea, which can distort the results of the analyte concentration measurement.
In exceptional situations, the simultaneous use of other medicinal products can also serve as an exclusion criterion. The study protocol shall describe in advance the acceptable exclusion criteria for subjects.
If a situation arises that is interpreted as an exclusion criterion, information about it shall be entered into an individual registration card during the study course.
The exclusion of subjects based on predetermined criteria shall be clearly reflected and listed in the study report. Due to the inability to separate the effect of medicinal products from other factors affecting the pharmacokinetics, the exclusion of data based on statistical analysis or for pharmacokinetic reasons is not allowed.
Exceptions to this rule are: a subjects in whose plasma the reference product concentration is not determined or is determined only in small amounts.
The plasma analyte concentration in a subject is recognized as very low if its AUC does not exceed 5 percent of the geometric mean AUC of the reference product calculated without taking into account the subject's data with the emissions.
The exclusion of data for this reason is allowed only in isolated cases, and as a whole it concerns the reliability validity of the conducted study; b subjects with a non-zero initial concentration of the analyte greater than 5 percent of C max.
Such data shall remove from the bioequivalence study see "Carry-over Effects". For immediate-release medicinal products, the abovementioned situations may arise if the subjects do not observe the study regime or in an insufficient wash-out period.
To prevent such situations, in the first case, it is necessary to examine the subject's oral cavity to make sure that the medicinal product has been swallowed, in the second — to provide for a sufficient wash-out period.
The biological samples of subjects excluded from the statistical analysis should be analyzed, and their results should be provided in the study report see subsection "Data submission" hereof.
As specified in subsection 2. Nevertheless, if this rule is not fulfilled, the subjects should not be excluded from the statistical analysis.
This requirement does not apply to studies with a sampling duration of 72 hours or more, when AUC 72 h is used instead of AUC 0-t. The ratio of these parameters of the investigational medicinal product to the reference medicinal product should be in the range of The range limits shall be rounded to two decimal places.
The statistical evaluation of t max is not required. However, if it is indicated that fast clearance is of clinical important and affects the start of action or leads to any unfavorable reactions, there shall be no considerable differences in t max and its variability between the investigational and reference medicinal products.
The acceptance bioequivalence limits of medicinal products with a narrow therapeutic range should be narrowed see subsection 2.
For medicinal products with a high variability of C max , if there is an appropriate justification, these limits can be extended see subsection 2.
Statistical analysis As a main criterion for bioequivalence, 90 percent confidence intervals are used for the ratio of geometric mean test pharmacokinetic parameters of the investigational and reference medicinal products.
Such an approach is equivalent to two unilateral checks of a zero hypothesis regarding lack of bioequivalence non-bioequivalence at a 5-percent level of significance for each test.
Comparison of the test pharmacokinetic parameters is carried out using the analysis of variance ANOVA. Logarithmic transformation of data shall be performed before that.
Then carry out an analysis of variance and on the basis of its results build the confidence intervals in a logarithmic scale to find the differences between the comparable medicinal products.
The obtained confidence intervals are inversely transformed to construct the desired confidence intervals for the ratio of means in the original not converted units.
The use of non-parametric statistical analysis methods is not allowed. In the study protocol, it is necessary to foresee the choice of a specific statistical analysis model.
Statistical analysis should take into account the sources of variability that can affect the test variable.
In this model of analysis of variance, it is customary to use such factors as sequence, subject of sequence, period, and a medicinal product.
For all of these factors, fixed and not random effects should be used. Carry-over effects It is not allowed to use the carry-over test results to make any decisions that affect the analysis e.
The probability of carry-over can be directly taken into account when taking a biological fluid sample before the medicinal product administration in the second study period and, if applicable, in subsequent ones.
This means that in a two-period study, such a subject drops out of the analysis. Continuation of the study is unacceptable, if the number of subjects to be analyzed is less than This approach is not applicable to the endogenous compound study.
Two-stage bioequivalence study design The bioequivalence studies can be conducted in two stages. At the first stage, a study is conducted on the initial primary group of subjects with an analysis of results obtained.
If the bioequivalence is not confirmed, an additional group can be collected and the results obtained in both groups can be combined for final analysis.
If such an approach is chosen, certain measures need to be taken to keep the probability of type I error unchanged for the entire study, and the statistical criteria for stopping the study should be clearly defined before it begins.
The analysis of data obtained during the first stage can be considered as an intermediate one, and both analyzes should be carried out at corrected significance levels.
For example, the use of The protocol shall provide in advance the two-stage study design along with the corrected significance level. When analyzing the combined data obtained during the two stages, the "stage" factor should be included in the analysis of variance model.
Data submission For each comparable medicinal product mentioned in the reporting documents, it is required to provide all values of individual concentrations and pharmacokinetic parameters along with descriptive statistical data, including a geometric mean, a median, an arithmetic mean, a standard deviation, a variation ratio, maximum and minimal values.
Individual concentration-time curves should be presented on linear and logarithmic scales. The standard result tables of analysis of variance, including the results of statistical tests for all effects in the model used should also be applied.
The report shall be detailed so that the pharmacokinetic and statistical analyzes could be reproduced, i.
It is necessary to describe in detail all cases of drop-out and exclusion. If possible, for each such subject it is necessary to present data on the concentration and pharmacokinetic parameters in a separate document, but not to include them in the overall statistical analysis.
The bioanalytical method shall be assessed and documented before the start of the bioequivalence study a validation report before the study start.
It is necessary to submit a bioanalytical report as part of the final bioequivalence study report. It should include a brief description of the used bioanalytical procedure, results for all calibration solutions standards and quality control samples.
If several studies have been carried out with respect to a specific dosage of a certain medicinal product, some of which confirm its bioequivalence, and some do not, the entire set of data should be considered as integral.
Only the studies stipulated by section 2. The presence of studies confirming the bioequivalence is not a reason to consider studies in which it is not confirmed.
It is required to carefully analyze all the results and justify the presence of bioequivalence.
Alternatively, in addition to individual studies, where possible, a generalized analysis of all studies is allowed. It is unacceptable to summarize studies that do not confirm the presence of bioequivalence, if there are no studies confirming the bioequivalence.
Medicinal products with narrow therapeutic index. The allowable limit for AUC of the medicinal products with a narrow therapeutic range should be narrowed to Since C max occupies a special place in terms of efficacy, safety and concentration monitoring of the analyte, the allowable interval for this parameter should also be narrowed to It is impossible to provide a comprehensive definition of medicinal products with a narrow therapeutic range so a decision to referral of the active ingredient to this group shall be made individually based on clinical peculiarities of effect and application of such medicinal product.
Medicinal products with high variability. If it is supposed that the medicinal product may have a high variability in absorption rate and or extent, it is recommended to conduct studies with replicative cross-design.
In this case, the acceptance criterion for C max can be extended to It should be proved that the calculated intra-individual variability is reliable, and not due to emissions.
The possibility of permissible interval extension shall be specified in advance in the study protocol.
The table below shows the examples of bioequivalence recognition calculated on the basis of the procedure depending on the varying degree of variability of the medicinal product pharmacokinetic parameters.
The ratio of geometric mean pharmacokinetic parameters should be in the range of The expansion of acceptable bioavailability limits based on intra-individual variability does not apply to AUC, the boundaries of which, regardless of variability, should be in the range of When re-designing, use a 3 or 4-stage cross study design.
In vitro equivalence dissolution test. The equivalence dissolution test hereinafter, the EBT is briefly described in Appendix 1, including the main requirements to the repeatability similarity factor application, f 2 -criterion.
In vitro equivalence dissolution test as an addition to study It is required to provide the EDT results of the investigational and the reference medicinal product batches used in the bioequivalence study in three different buffer media usually at pH 1.
The study of some dosage forms, for example, orally disintegrating tablets, shall be carried out in various conditions. The report on study results should be presented in the form of profiles of the dissolved amount proportion in time, indicating the mean values and summary statistics.
In the absence of other justifications, the specification normative document on the product quality control for quality control in terms of "Dissolution" parameter of the investigational medicinal product, should be compiled on the dissolution profile of the investigational medicinal product batch, which confirmed the bioequivalence of the reference medicinal product see Appendix No.
If the results of EDT carried out with different batches do not confirm the bioequivalence previously proved in vivo studies, they rely on the in vivo study results.
However, it is necessary to study and explain the reasons for this discrepancy. Equivalence dissolution test for additional dosage biowaiver The validity of not conducting any additional in vivo bioequivalence studies shall be confirmed by properly conducted EDT.
Unless otherwise indicated, it is necessary to study the dissolution at different pH values usually at pH 1. For all the provided batches, it is required to confirm the comparability of in vitro dissolution profiles between the additional dosages and the dosages from the batches used in the bioequivalence study under all conditions see Appendix No.
With pH values, at which complete dissolution cannot be achieved for any of the dosages, the EDT conditions of dosages may vary.
However, to confirm that this is due to the properties of the active substance, and not the dosage form, it is required to compare it with the appropriate reference product dosage.
Moreover, it is allowed to confirm the compatibility of profiles for the similar doses e. Study report. Study report on a bioequivalence study The bioequivalence study report should contain all the necessary information about the study protocol, study and its analysis conduction.
The report shall be drawn up in accordance with the ICH guidelines for generating a report on the clinical study and signed by the researcher.
The report shall include full name of the responsible researchers, their place of work, study site and duration, certificates or conclusions drawn on the audit results if available.
The report should contain the confirmation that the choice of the reference drug meets the set requirements. In particular, it is necessary to indicate its trade name, strength, dosage form, batch number, manufacturer, shelf life and country in which the reference drug was purchased.
The report should indicate the name, composition, size and batch number, date of manufacture and, if possible, shelf life of the investigational medicinal product.
Certificates of analysis of the investigational and reference medicinal products used in the study are attached to the report as an Appendix.
Information on concentrations, pharmacokinetic parameters and statistical analysis results shall be submitted to the extent stipulated by "Data submission" in subsection 2.
Other data provided in the registration dossier The dossier shall include a signed official document confirming that the quantitative content and technology of manufacturing of the investigational drug used during the bioequivalence study and the drug released into circulation are not different.
Besides, it is required to attach the results of the comparison dissolution test see subsection 3. The bioanalytical method validation report shall be submitted, which shall be included into Module 5 of the drug registration dossier.
Upon request, you shall provide data for example, in the form of an electronic text file with data separated by commas or spaces, or an Excel file, or in another format as agreed with the authorized body sufficient to reproduce the pharmacokinetic and statistical analysis, including data on sampling time, drug concentration, pharmacokinetic parameters of each subject in each period and randomization schedule.
Scope of the study when making changes to the registration dossier. When changing the previously approved composition or production technology that may affect the bioavailability, the in vivo bioequivalence studies shall be conducted, unless otherwise justified.
Any justification submitted should be based on general principles, in particular, those specified in Appendix No.
If the bioavailability of the modified medicinal product has been previously studied and the acceptable level A correlation is set between in vivo pharmacokinetic parameters and in vitro dissolution kinetics, while the in vitro dissolution profile is comparable between the modified and previously approved medicinal product under the same test conditions used to establish the correlation, the bioequivalence study is not required see Appendix No.
When changing the Marketing Authorization Applications for the products that are generic e. When changing the Marketing Authorization Application for a generic drug, a commercially available reference drug batch is used as a reference comparator, control for bioequivalence studies.
If the medicinal product is not available on the market, the comparison is allowed to be carried out with a previously approved formulation investigational generic drug with the presentation of the corresponding justification.
Terms and definitions. Pharmaceutical equivalence: Medicinal products are deemed pharmaceutically equivalent if they contain an equal amount of active ingredients in the same dosage form that meet the same or compatible standards.
Pharmaceutical optionality: Pharmaceutically optional medicinal products means medicinal products in the form of different salts, simple or compound ethers, isomers or mixes thereof, sets or derivatives of the active ingredient or products differing by their pharmaceutical form or dosage.
Annex 1 mandatory. Dissolution Test and Comparability of dissolution profiles. General aspects of in vitro equivalence dissolution test When developing the composition of a medicinal product, the comparative dissolution kinetics test EDT serves as a tool for determining the biopharmaceutical properties of a medicinal product, that is, properties that can affect bioavailability.
Upon completion of the formulation of the drug and the manufacturing process, EDT is used to control the quality of scaling and industrial batches to ensure both the consistency of the quality of the batches and the comparability of dissolution profiles with the batches used in the reference clinical studies.
Moreover, in some cases, the EDT may serve as a substitute for bioequivalence studies. The EDT can be used for different purposes: a Quality Review of Medicinal Product s - to characterize the batches used in bioavailability studies bioequivalence and support clinical trials to substantiate specifications regulatory document on quality control ; - as a tool for quality control of a batches of medicines in order to confirm the constancy of production; - to characterize the reference drug used in bioavailability studies bioequivalence and supporting clinical studies; b to replace bioequivalence studies: - to confirm in individual cases similarity of different compositions of the investigational medicinal product and reference medicinal product biowavers, e.
Analytical methods shall be developed for each medicinal product on the basis of general and or particular pharmacopoeial requirements.
It is always necessary to take into account current information including the interaction of drug characteristics based on the biopharmaceutical classification system and the type of dosage form.
In order to obtain complete dissolution profiles, the intervals between sampling should be quite frequent at least every 15 minutes.
During the period of maximum change in the dissolution profile, sampling is recommended to be carried out even more often. To build the correct dissolution profile of rapidly dissolving drugs, which are completely dissolved in 30 minutes, samples shall be taken every 5 or 10 minutes.
If the active substance is highly soluble, it is assumed that bioavailability problems will not arise if, in addition, the dosage form dissolves rapidly at physiological pH values, and excipients do not affect bioavailability.
On the contrary, if the active substance is sparingly soluble or slightly soluble, the solubility of the dosage form may become a factor limiting the rate of absorption.
A similar situation occurs if the excipients affect the release and subsequent dissolution of the active substance. In such cases it is necessary to conduct EDT in different conditions with the appropriate sampling scheme.
Comparability of dissolution profiles The EDT results and the conclusions based on them for example, in support of a biowaiver are considered correct if the construction of the dissolution profile was based on a sufficient number of time points.
In addition to the requirements set out in section I of this Appendix, for immediate-release dosage forms, a comparison should be made at a time point of "15 minutes" to find out if complete dissolution occurred before gastric emptying.
Comparability of dissolution profiles can be determined using f 2 by the following formula above. When using this formula, it is necessary to determine the degree of release of the active substance from the investigational medicinal product and the reference medicinal product.
The acceptance criterion for the similarity factor f 2 is from 50 to , which confirms the comparability of dissolution profiles. In the case of non-compliance with the acceptance criterion for f 2 , dissolution profiles can be compared using alternative methods for example, calculating the difference factor f 2 , Weibull distribution function or comparing release rates at different time points for example, using Student's t-test.
Alternative methods for calculating by f 2 are considered acceptable if they are statistically correct and their use is sufficiently justified.
In addition, the variability of dissolution between the data of the investigational and reference medicinal product should also be comparable, but lower variability for the test drug is acceptable.
It is necessary to provide a justification that the statistical software has been validated. It is necessary to give a detailed description and explanation of all actions taken during the study, with the presentation of the relevant summary tables.
Annex 2 reference. General requirements to study of bioequivalence of different dosage forms. Besides the standard recommendations concerning bioequivalence studies of immediate release dosage forms, the appendix contains general recommendations for study of different dosage forms and particular types of dosage forms with immediate release of the active ingredient.
If the investigational medicinal product contains a different salt, ester, stereoisomer or their mixture, another complex compound or derivative of the active substance compared to the reference medicinal product, the bioequivalence shall be confirmed with in vivo bioequivalence studies.
However, if the active ingredient of the investigational medicinal product is identical to the active ingredient of the reference medicinal product or contain salts with similar properties according to the criteria of section 3, Appendix 3 , in several cases described below and in Appendix 3, no bioequivalence study in vivo is required.
Oral systemically acting, immediate release dosage forms In the absence of conditions for biowaiver see Appendix No. For orally disintegrating tablets and oral solutions, the special recommendations are described below.
Orally disintegrating tablets Orally disintegrating tablets hereinafter — ODTs are intended for rapid dissolution in the mouth.
If the active substance is also soluble in saliva and able to be absorbed through the mucous membrane of the oral cavity, the time of drug intake and its contact with the mucous membrane are important factors.
After swallowing the active substance released from the coated ODTs, depending on the product composition, the gastrointestinal absorption also occurs.
If it can be confirmed that the active substance is not absorbed from the oral cavity, but requires swallowing for the gastrointestinal absorption, the medicinal product can meet the biowaiver criteria based on the Biopharmaceutical Classification System BCS see Appendix No.
If this cannot be confirmed, the bioequivalence study in humans shall be conducted. If ODTs are an additional new dosage form and or expansion of the dosage range for a different oral drug formulation, a three-period study shall be conducted to evaluate the use of orally disintegrating tablets, with or without concomitant use of water.
However, if the bioequivalence between ODTs taken without water and the reference medicinal product washed down with water, is shown in a two-period study, the bioequivalence of ODT washed down with water is considered proven.
If the ODT with respect to the reference medicinal product, which is an ODT, is a generic or hybrid drug, the following requirements should be followed at study planning: a if the reference medicinal product is acceptable both to wash down and not wash down with water, the bioequivalence study should be carried out without taking water, since this is more appropriate for the method of product administration in real conditions.
This is especially important if the active substance is dissolved and absorbed from the oral cavity. If bioequivalence without water is confirmed, bioequivalence with simultaneous fluid intake is considered proven; b if the reference medicinal product is either washed down or not washed down with water, the bioequivalence study shall be carried out under appropriate conditions with a standard two-period cross-design ; c if the reference medicinal product is either washed down or not washed down with water, and the investigational medicinal product is intended for both routes of administration, the comparison shall be carried out, taking the investigational medicinal product by washed down or not washed down with water, while the medicinal product is used in accordance with the recommended method three-period 3 groups study in 6 sequences.
In studies on ODTs, if the latter is not washed down with water, it is recommended immediately before taking the product to moisten the oral mucosa with 20 mL of water.
Fluid intake for 1 hour after the product administration is prohibited. The bioequivalence study with respect to films dispersed in the oral cavity, films or cheek tablets, sublingual tablets and chewable tablets shall be carried out by analogy with the ODTs.
The bioequivalence study should be carried out in accordance with the recommended route of administration of the investigational medicinal product.
Oral solutions If the investigational medicinal product is an oral aqueous solution and contains the same concentration of the active substance as the authorized solution, then bioequivalence studies are not required.
However, if excipients can affect the gastrointestinal motility e. The requirements to oral solution excipients are similar to the biowaiver conditions see Appendix 3.
If bioequivalence of the investigational medicinal product, which is an oral solution, should be confirmed in relation to another immediate-release medicinal product, a bioequivalence study shall be conducted.
Fixed-dose combination finished pharmaceutical products The requirements to study of combination finished pharmaceutical products are set by other documents.
The biowaiver conditions for FDC-FPPs are set out in Part V of Appendix No. Oral systemically acting, immediate release dosage forms This subsection covers, in particular, the rectal dosage forms.
For them, the bioequivalence studies are usually required. If the medicinal product is a solution containing the active substance in the same concentration as the authorized medicinal product with the same qualitative and similar quantitative content of excipients, a biowaiver is possible thus, similar requirements for oral solutions can be used.
The provisions of this section do not apply to inhaled medicinal products used to treat bronchial asthma and chronic obstructive pulmonary diseases, as well as hormonal sprays for nasal use.Sechenov First MSMU. Exceptions to this rule are: a subjects in whose plasma the reference product concentration is not determined or is determined only in small amounts. Е‚ks based on the biopharmaceutical classification system. It is unacceptable to summarize studies that do not confirm the presence of bioequivalence, if Freihaus Brenner Bad Wiessee Speisekarte are no studies Mahjong Master Kostenlos the bioequivalence. KS · @KSR6S · @xjuventa -_- new project @watchsiege. Berlin, Deutschland. cliftonvillecc.com Регистриран през юли г. +49 е мејл: [email protected] [sr] Web: е мејл: [sr] Web: COP BT PZ, COP BT SZ. DE-KS Nl'. mq'. „_ q'. |02 b'. wie q., aber FORD Re. 'Il SIGISMVRD'I ROMHRÜRM вех wie q'. Ks. wie a'. wie b., aber ЕВПЦПНЧ Кв. wie l.. Ъ. —е'. wie b'. Ks. wie e. Abonnenten, folgen, 65 Beiträge - Sieh dir Instagram-Fotos und -Videos von К С Е Н Я (@cliftonvillecc.comskaya) an.