3.1. General provisions
A biowaiver based on the biopharmaceutical classification system (BCS) aims to reduce the number of in vivo
bioequivalence studies, i.e. it can serve as a substitute for in vivo
bioequivalence. In vivo
bioequivalence studies can be avoided if in vivo
equivalence is confirmed by valid in vitro
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 2.9 of the standard). 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. 3.2. 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 4.1), the in vitro
dissolution characteristics of the investigational and reference medicinal products are defined as very fast (> 85% within 15 minutes) or fast (85% within 30 minutes);
c) the qualitative and quantitative composition of excipients that can affect the bioequivalence is the same. 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 4.1), the in vitro
dissolution characteristics of the investigational and reference medicinal products are defined as very fast (> 85% within 15 minutes);
c) the qualitative and quantitative composition of excipients that can affect the bioequivalence is the same. At the same time, it is advisable to use the same excipients in comparable quantities (see subsection 4.2);
It should be more critical to assess the fulfillment of conditions (for example, the site of absorption, the possibility of interaction with carrier proteins at the site of absorption, the composition of excipients, and therapeutic risks) for BCS class III medicinal products than BCS class I medicinal products. 3.3. 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 3.1 and 3.2). 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 2.9.1 of the standard). 3.3.1. Solubility
It is required to establish and analyze the pH-solubility profile of the active substance. The active substance is recognized as highly soluble if at 37 ± 1 °C its maximum single dose (for an immediate-release medicinal product) is completely dissolved in 250 ml of buffer solution with pH ranged from 1 to 6.8. This requires a study with at least 3 buffer solutions of different pH in the above range (preferably at pH 1.2; 4.5 and 6.8) and, if possible, at pKa, if pKa is within the specified pH range. 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). pH of the solution should be determined before and after adding the active substance to the buffer. 3.3.2. 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. For this purpose, total absorption means absorption ≥ 85%. total absorption is usually caused by high penetrability of the active substance through the intestinal barrier.
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). Thus, based on data from inventory balance studies, absorption is recognized as total, if the total parent compound content in the urine and its metabolites (past phase I and (or) phase II metabolism) in urine and feces is ≥ 85% of the dose taken.
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 4.2 "Excipients"). 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. 3.4. Medicinal product 3.4.1. 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.e. to confirm the in vitro
equivalence dissolution kinetics between the investigational and reference medicinal products at physiological pH values under experimental conditions. However, it is not possible to establish an in vitro/in vivo
correlation. The in vitro
dissolution kinetics should be studied in pH range of 1.0-6.8 (at least at 3 pH values: 1.2, 4.5, and 6.8). 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 2.2 of the standard. 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. The standard study conditions are as follows:
- apparatus: paddle stirrer or basket;
- volume of the dissolution medium: – 900 mL or less;
- dissolution media temperature: 37±1°С
- rotation speed: paddle stirrer – normally 50 rpm, basket – normally 100 rpm;
- sampling schedule: e.g., at 10, 15, 20, 30 and 45 minutes;
- buffer solutions: pH 1.0-1.2 (usually 0.1 M HCl or imitation of gastric juice without enzymes), 4.5 and 6.8 (or imitation of intestinal juice without enzymes), pH value should be monitored regularly. Pharmacopeial buffer solutions should be used;
- other conditions: no surfactants. The use of enzymes is allowed for gelatin capsules or gelatin-coated tablets.
It is required to submit a full analytical report of equivalence dissolution test (EDT) i vitro, including a study protocol, data on studied batches and comparison batches, a detailed description of experimental conditions, results of validation of the used methods, individual and average values, as well as relative statistical parameters. 3.4.2. Evaluation of in vitro equivalence dissolution test results
Medicinal products are recognized as very soluble if 85% of the claimed content of the active substance dissolves within 15 minutes. In this case, the dissolution profiles of the investigational and reference medicinal products are considered comparable without further mathematical calculations.
If the dissolution process with the release degree of 85% of the claimed content of the active substance lasts more than 15 minutes, but does not exceed 30 minutes, then it is necessary to prove the absence of significant differences (comparability). To confirm compatibility of dissolution profiles of the studied and reference medicinal products, the f2
criterion (see Appendix 1) and other suitable tests are used. However, an explanation of differences in dissolution profiles from clinical or therapeutic point of view is impractical because the dissolution test does not reflect the in vitro/in vivo
correlation. 3.4.3. Excipients
Although, the effect of excipients contained in the immediate-release dosage forms on the bioavailability of highly soluble and completely absorbed active substances (i.e. belonging to BCS class I) is considered unlikely, it cannot be completely excluded. In this regard, in all cases (including with the active substance of BCS class I) of the investigational medicinal product it is recommended to use similar amounts of the same excipients as in the reference medicinal product.
In order to exclude various effects on membrane carriers, one of the biowaiver conditions with regard to active substance of BCS class III is the absence of differences in quality and high comparability in the quantitative composition of excipients.
Usually, it is necessary to use standard quantities of well-studied excipients along with the active substances of BCS class I or III, as well as to analyze and explain their possible effect on bioavailability and/or solubility. It is necessary to describe the purpose of each of the excipients with the justification that the amount of each of them is in an acceptable range. It is necessary to describe all excipients that can affect the bioavailability (e.g., sorbitol, mannitol, sodium lauryl sulfate and other surfactants), indicating their effect on:
a) gastrointestinal motility;
b) susceptibility to interaction with the active substance (for example, complexation);
c) penetrability of the active substance;
d) interaction with membrane carriers.
The qualitative and quantitative composition of excipients proven to affect the bioequivalence of the investigational and reference medicinal products should be the same. 3.4.4. Fixed-dose combination finished pharmaceutical products
The BCS-based biowaiver for immediate-release FDC-FPPs is possible if all active substances belong to BCS class I or III, and excipients meet the requirements set by subsection 4.2. In other cases, the in vivo
bioequivalence studies are required.