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Guangdong Lingmu Elevator Co. Joylive Elevator Suzhou Co. United Elevator Suzhou Co. 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.
Parenteral solutions If the investigational medicinal product is an aqueous solution for intravenous administration and contains the same active substance as the authorized product, the bioequivalence study is usually not required.
However, if one of the excipients is able to interact with the active substance for example, with the formation of complexes or otherwise affect its distribution, metabolism and excretion, the bioequivalence study is required.
It can be avoided if the compared medicinal products contain approximately the same amount of excipients and it has been properly proven that the differences in their content do not affect the active substance pharmacokinetics.
For other parenteral routes of administration, for example, intramuscular and subcutaneous, if the investigational medicinal product has the same type of solvent for example, an aqueous or oily medium , contains the same active substance in the same concentration and the same excipients in similar amounts as the authorized one, no bioequivalence studies are required.
Moreover, the bioequivalence study of aqueous solutions with approximately the same content of excipients is not required, if the latter do not affect the viscosity.
Liposomal, micellar and emulsion dosage forms for intravenous administration Liposomal dosage forms: pharmacokinetic features of liposomal products for intravenous administration require special approaches to confirm the bioequivalence that are not provided for in this standard.
Emulsions: the emulsions are generally not subject to a biowaiver procedure. In such cases, the qualitative and quantitative composition of the medicinal product should not differ from the authorized one; It is necessary to provide reasonable data confirming the high similarity of physicochemical properties, including the fractional composition of the dispersed lipid phase and other significant characteristics of the emulsion, including surface properties e.
Lipid-based medicinal products for intravenous parenteral nutrition: if reasonable data on the comparability of physicochemical properties are presented for these medicinal products, a biowaiver procedure is possible.
Differences in the composition can be justified by the properties and indications for use of such dosage forms. Micelle-forming drugs: micellar solutions for intravenous administration can be considered as "complex" solutions, so they do not fall under the biowaiver.
However, if the following conditions are met, the biowaiver procedure is possible: a when diluting a medicinal product in accordance with the recommendations for its route of administration, the micelles undergo the rapid disintegration, and the dosage form is not intended for controlled release or distribution; b the administration route and rate coincide with those for the authorized medicinal product; c excipients do not affect the distribution, metabolism and elimination of the active substance.
In such cases, qualitative and quantitative composition of the micellar solution immediately before administration should not differ from the authorized medicinal product; It is required to provide reasonable data confirming the similarity of physicochemical properties.
For example, the critical concentration of micelle formation, the ability of the dosage form to solubilize e. These rules also apply to minor changes in the qualitative or quantitative composition of the medicinal product, provided that such changes do not affect the qualitative or quantitative composition of surfactants.
Modified-release dosage forms for oral or transdermal use Modified-release dosage forms for oral or transdermal use require the bioequivalence studies in accordance with the set requirements.
Modified-release dosage forms for intramuscular and subcutaneous administration When confirming bioequivalence in relation to suspensions or other dosage forms intended to modify the release of the active substance upon its intramuscular or subcutaneous administration, the requirements for confirming the bioequivalence of extravascular modified-release dosage forms e.
Topical medicinal products used topically or externally Recommendations for the test of topical medicinal products with oral, nasal, pulmonary, ocular, dermal, rectal, vaginal, etc.
If an investigational medicinal product which is a solution for example eye drops, nasal spray except for hormonal nasal sprays or a solution for external use has the same dissolution medium water or oil and has the same concentration of the same active ingredient as a registered medicinal product, there is no need to confirm their equivalency.
Minor differences in the content of excipients are allowed provided that significant pharmaceutical properties of the investigational and reference medicinal products are identical or similar.
Any qualitative or quantitative differences in the content of excipients must be justified within the context of their effect on therapeutic equivalence.
If there are no grounds for it, method and routes of administration must comply with those of the registered medicinal product. If there is a risk of systemic adverse reactions due to systemic absorption after topical administration of topical medicinal products, it is necessary to measure systemic exposure.
None of topical medicinal products used topically or externally can be regarded as a generic medicinal product as they are all classified as hybrid medicinal products.
Gases If the medicinal product is a gas for inhalation, the bioequivalence studies are not required. Annex 3 reference. Biowaiver based on the biopharmaceutical classification system.
General provisions A biowaiver based on the biopharmaceutical classification system BCS aims to reduce the number of in vivo bioequivalence studies, i.
In vivo bioequivalence studies can be avoided if in vivo equivalence is confirmed by valid in vitro data.
BCS-based biowaiver is limited to oral immediate-release medicinal products in solid dosage forms of systemic action, containing highly soluble active substances with predictable absorption in humans, provided that these active substances have a wide therapeutic range see subsection 2.
However, it is not applicable to sublingual, cheek dosage forms and modified-release dosage forms. For orally disintegrating dosage forms, this approach is applicable if absorption from the oral cavity is excluded.
BCS-based biowaiver is designed to set bioequivalence between the specific investigational and reference medicinal products. The biowaiver concept principles can be applied to confirm the bioequivalence of generic drugs, extensions of original medicinal products, when changes are made to the bioequivalence dossier, to set bioequivalence between the medicinal products used in the initial clinical trials, as well as medicinal products introduced to the market.
General requirements BCS-based biowaiver is applicable to an immediate-release medicinal product, provided that all of the following requirements are met: a the active substance is highly soluble and undergoes full absorption BCS class I see section 3 ; b taking into account the special requirements see subsection 4.
At the same time, it is advisable to use the same excipients in comparable quantities see section 3 ; d there are no risks associated with the probability to accept the erroneous conclusion about the possibility of using the biowaiver procedure, taking into account the therapeutic index value and clinical indications for the active substance as part of the medicinal product.
BCS-based biowaiver is also applicable to an immediate-release medicinal product, provided that all of the following requirements are met: a the active substance is highly soluble and undergoes the limited absorption see section 3 ; b taking into account the special requirements see subsection 4.
At the same time, it is advisable to use the same excipients in comparable quantities see subsection 4. Active substance To describe the properties of the active substance covered by the biowaiver concept, clear abstract literature data can be enough.
If the active substances of the investigational and reference medicinal products are the same, the biowaiver is possible.
The biowaiver is also possible if the investigational and reference medicinal products contain different salts, provided that they belong to BCS class I high solubility and full absorption; see subsections 3.
If the investigational medicinal product contains esters, stereo-isomers and their mixtures, complexes or derivatives of the active substance of the reference drug, the biowaiver is impossible, because the differences can lead to different bioavailability not detected by experiments used in the BCS-based biowaiver concept.
The active ingredient shall not be characterized by a narrow therapeutic range see clause 2. Solubility It is required to establish and analyze the pH-solubility profile of the active substance.
This requires a study with at least 3 buffer solutions of different pH in the above range preferably at pH 1. To unambiguously determine the solubility classification property, it may be necessary to repeat the tests at each pH for example, a shaking method or another suitable one.
Absorption penetrability When applying for the medicinal product authorization as a BCS-based biowaiver, it is recommended to confirm the total absorption of the active substance in humans.
The presence of complete absorption should be based on human studies. As a justification, it is allowed to use the results of the following studies: - absolute bioavailability; - inventory balance.
When using the inventory balance method to calculate the absorbed fraction, it is required to ensure that the metabolites taken into account when calculating the absorbed fraction were formed after absorption.
In this regard, when calculating the total radioactivity excreted in the urine, it is required to ensure that no partial degradation or biotransformation of the unchanged active substance has occurred in the gastric or intestinal juice.
Phase I for example, oxidation or phase II for example, conjugation responses of metabolism can occur only after absorption not in the gastric or intestinal juice.
In addition, the highly soluble active substances with incomplete absorption BCS class III may also fall under the biowaiver if certain requirements for the medicinal product composition and in vitro dissolution profile are fulfilled see subsection 4.
When classifying compounds as BCS Class I and the absence of substantiated evidence in favor of their complete absorption, more stringent requirements are also placed on them.
The established bioequivalence between immediate-release aqueous and solid dosage forms of some oral compound is taken as confirmation, because it indicates that the limitation of absorption due to the dosage form properties of the immediate release medicinal product is insignificant.
In vitro qualitative permeability studies, including with reference standards, also argue in favor of the results obtained in vivo. Medicinal product 3.
In vitro equivalence dissolution test management When studying the medicinal product properties, it is required to prove the immediate release and comparability of the investigational medicinal products, i.
The in vitro dissolution kinetics should be studied in pH range of 1. Additional studies may be required at pH with the lowest solubility of the active substance a justification should be provided to ensure that such studies are not required.
The use of any surfactants is not allowed. The investigational and reference medicinal products shall meet the requirements stipulated by subsection 2.
In accordance with these requirements, it is recommended to conduct a study with respect to more than 1 batch of investigational medicinal products.
In vitro equivalence dissolution tests should comply with the pharmacopeial requirements. Tt is necessary to provide a detailed description of the study conditions and analytical procedures, including data on their validation.
For statistical validity, each experiment is recommended to be carried out with 12 samples of the medicinal product. Pharmacopeial buffer solutions should be used; - other conditions: no surfactants.