Guidance for Organizations performing in vivo Bioequivalence Note: ANVISA is constantly redesigning its website starting in Aug ANVISA. BRAZILIAN HEALTH REGULATORY AGENCY. Brazilian REPRESENT ADVICE OR GUIDANCE . BIOEQUIVALENCE. Anvisa regulatory guidelines High Impact List of Articles PPts Journals Bioequivalence Journal · Pharmaceutical Analysis Journal · Pharmacovigilance.

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A new approach to char Training Workshop on P Guidance on aspects of Waiver of In Vivo Bioa Inform that the Resolution proposal shall be availed, in its totality, during the anvsa period at the address http: Upon the end of the period under the terms of the Article One, the National Health Surveillance Agency shall join other involved Guideoines and Institutions and those who stated interest in the matter to indicate representatives for further discussions to consolidate a final text.

This Resolution shall be in effect on the date of its publication. National Health Surveillance Agency 1. Pharmaceutical Equivalence of Nasal Sprays and Aerosols 3. Pharmacopoeia Trials to Nasal Sprays and Aerosols 4. Pharmacodynamic Tests for Nasal Sprays and Aerosols 5. SinceANVISA has been publishing several Resolutions to establish criteria and requirements to conduct a bioequivalence Trial to register drugs that have been updated along the development of science.

Journal of Bioequivalence & Bioavailability

However, it is noted that several of these drugs are formulated as a suspensions. These drugs, mainly, are used to treat allergic rhinitis.

Headed by Coordination of Inspection in Pharmaceutical Equivalence and Bioequivalence Centers CIBIOa working group composed of technicians of General Office of Drugs, representatives of universities, manufacturing companies, CROs and professionals was constituted to gather and evaluate data regarding the major aspects of efficacy, safety and quality of these products. Since then, a series of activities have been conducted, including meetings, conferences, technical visitations and studies follow up to subsidize the knowledge and the course of discussions in Brazil and around the world.

The matter is complex and originates diverging opinions and this proposal does not represent the depletion of this discussion. The scientific advances, as well as new ideas will be welcomed, always, to contribute for the discussion of this matter, whose main objective is to offer safe, and efficient and quality products to population.

Objective The objective of this document is to introduce a series of recommendations and requirements for the execution of Pharmaceutical Equivalence and Bioequivalence trials with nasal sprays and aerosols, listing the necessary essays, methodology and the data to be submitted to ANVISA to prove safety and efficacy of these drugs for registration as a generic and similar drug.

Pharmaceutical Equivalence of Nasal Sprays and Aerosols The Pharmaceutical Equivalence consists in verifying if test drug T complies, integrally, with the specifications of the Pharmacopoeia and with the remaining performance tests as described in the Guidance, and if results obtained are equivalent to the results of reference drug R. The batches must be submitted in parallel to the essays established in the monograph of the Brazilian Pharmacopoeia or remaining official publications, as per the current Resolutions and the referred Guidance.

Global Bioequivalence / Bioavailability Regulatory Guidance Documents §¯`·.¸¸.·´¯`·.¸¸.

Standard Chemical Substances SQRwhich have been standardized by the Brazilian Pharmacopoeia, and other pharmacopoeia codes authorized by the current legislation, must be employed.

Trials employing working standards, as long as the certification is evidenced, in absence of SQR, shall be admitted. The results obtained for test drug Tshall be compared to the results of the reference drug Rthus, determining existence or lack of Pharmaceutical Equivalence.

Quality Assurance Management of lab must assure that staff received the proper training to perform these tests and to operate equipments. Whenever applicable, training regarding principles and theories related to techniques employed must be conducted and its efficacy must be evaluated. amvisa

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Only the analysts who are able to evidence competency, or who are properly supervised, might conduct the Pharmaceutical Equivalence essays. The continuous training must be monitored and capable of identifying improvement needs. Samples, standard reagents and reference materials must be properly stored to warrant their integrity and traceability. The environment of lab must have enough room to allow that working areas be kept clean and organized. The space must be proportional to the volume of analysis conduced and to internal organization of lab.


In case of any other authorized Pharmacopoeia be used, the requirements of monograph must be complemented with the essays that are described in General Methods of current Brazilian Pharmacopoeia, described for the pharmaceutical form studied. In the absence of Pharmacopeial method, the study must be undertaking using a method that has been validated by test drug product manufacturer and must be co-validated by the study executer lab, with the complementation of essays described in General Methods of current Brazilian Pharmacopoeia.

The essays that are required to evidence Pharmaceutical Equivalence of these drugs are: A detailed description of test and reference drug products as to appearance colorcharacteristic odor, viscosity, presence of particles to characterize each one of them. Description must follow Brazilian Pharmacopeia; 3. Determination of nominal volume in liquid products with multiple doses is executed by content weight.

Weightings are executed by a scale with proper sensitivity, duly calibrated. Analysis follows the methods of Brazilian Pharmacopeia using the amount of flasks and the specification in accordance with stated volume. The average volume must be determined, only, for drugs whose volumes are stated on the label. Analysis of acidity or alkalinity of a solution.

Follow official methodology and specification for each active ingredient; 3.

Analysis must be capable of evidencing the identity of the active ingredient in samples of the test and the reference drug product. Follow official methodology and specification of each active ingredient. In absence of an official Pharmacopeia monograph, assay must employ abvisa method provided by the requesting Company that must be co-validated by study executor lab.

Proceed the analysis using part of the content of ten 10 different flasks, disposing the first actuations necessary for priming, whenever applicable. Whenever applicable, in accordance with official methodology of each active ingredient. Follow the general methods of current Brazilian Pharmacopeia.

Uniformity of Delivered Dose: The determination of uniformity of delivered dose must be executed in accordance with the following description, taking into account the Pharmacopeia methodology available and assay method for the active ingredient. To warrant reproducibility of collection of samples, the employment of mechanical actuation methods is recommended.

Mechanical actuation proceedings must hold controls that are adequate for critical parameters such as actuation strength, speed, and time interval between actuations.

Test guudelines be conducted in unities that have been primed in accordance with the instructions of use. Test must be executed with the vertical, or close to the vertical positioning of flasks. The essay must be huidelines with the collection of the first delivered dose immediately after priming and the last labeled dose. For suspensions, the dose must be released in a proper recipient, which might allow the due transfer of the content. The analytical method for assay shall yield the determination of the quantity of active ingredient in each delivered dose and the data must be reported as percents of labeled dose.

For solutions, dose can be gravimetrically determined from the weight of the delivered dose, the concentration, and the density of tested solution. Analysis of the Guidelimes of DeliverdDose: Shall be conducted in 10 flasks, one collection in the beginning and another at the end of the doses. The number of doses generated by each of the unities tested must be counted and related to the declared by manufacturer. Actuations must be conducted in accordance with procedure described in label.

Results must be evaluated by the mean of three tested unities and it must not be smaller than the labeled number of doses. To conduct the essay, is recommended the compliance with the equipment’s manufacturing instructions regarding to obscuration and transmittance percent. Further, actuation parameters strength, speed and interval between actuationsmust be established and controlled.

Plumes generated by actuation of this kind of drug products can be characterized in three stages: All information generated, as well as SOP to conduct analysis must be printed and submitted.

Operational parameters and conditions that were established for equipment, also, must be submitted. Analysis of distribution of size of particle: Essay must be conducted with three 3 flasks for test drug and three for reference drug. In addition, data of two different distances from the laser and the orifice of flasks must be evaluated.

It is recommended a distance of 2 to 7 cm between the laser and the orifice, and that they hold a guideilnes of 3 cm, or more, between them. Analysis of the Charge and Guidflines data: Essay must be conducted using 10 flasks of test drug and 10 of reference drug. For suspensions, test must employ the methodology established in available Pharmacopoeia, or a validated methodology in the absence of a Bloequivalence methodology to determine the delivered dose.


For solutions, must be determined the relative mass of each actuation per flask by differences in weight before and after actuation. Characterizes the form and bioequivlence density of the plume generated by both test and reference spray, using non-impact mechanisms, with visualization by laser light or impact mechanism system, using a proper target that must allow the visualization of the generated spray. Spray Pattern can be characterized and quantified by manual or automatic image, as long as validated.

Data and documents generated must be submitted, as well as essay execution SOP. This analysis must be executed in 3 three unities of test and reference drug, using the same impact mechanisms, guidflines actuation on a proper target.

Simple actuation must be executed at beginning dose following the preparation in hioequivalence distances defined between orifice of flask and the impact surface, of at least 3 cm, within 3 to annvisa cm variation. Drugs that are administrated by nasal route display a characteristic pharmacokinetic behavior, which biooequivalence absorption by two distinct routes: Therefore, plasmatic concentrations of drugs that are administered by nasal route result from local and oral absorption.

Though the objective of these drugs is local action, consequences of systemic absorption, such bioequifalence suppression of the hypothalamus-pituitary-adrenal HPA axismust be taken into consideration. For drugs that are administered by nasal route, bioavailability is related to a series of factors: Study must be conducted, preferably, with one single dosage, and multiple dose studies must be justified in protocol.

Considering that drugs administered by nasal route reach low plasmatic concentrations, doses administered can be equal, or higher, than therapeutic doses, as long as safety of volunteers is warranted. The choice of the dose must be justified in the protocol and the study shall not be started before protocol bioequjvalence authorized by Independent Ethics Committee.

Schedule of collection of samples must warrant proper characterization of plasmatic profile of drugs, however it must be considerate, besides half-life of elimination, the capability of analytical method to quantify drug by proposed period. Study must be conducted with healthy volunteers, of both genders, whose weights are within the normal range. Volunteers, in order to be included in these studies, must be submitted in a guideilnes evaluation, and guidelnes respiratory disease must be found, which includes allergic rhinitis, nasal septal debytion, and adenoid, as they might alter deposition of guideilnes into nasal mucous.

Before beginning clinical phase, volunteers must receive training regarding administration of drugs. There must be an application of placebo with the same apparatus to evaluate tolerance of volunteer to receipt of drug without reactions, which, generally, result in sneezing.

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Another exclusion criteria used for nasal sprays and aerosols is the occurrence of a sneeze two hours after administration of the drug. Each volunteer must receive drug by an individual flask; All volunteers and staff must wear clean area clothing, including caps, masks, and gloves; Before each application, the device must be tested by trained staff and execution of about 5 actuations is recommended, outside the building, on the day prior to the testing day; Flasks must be weighted after 5 actuations and, again, after administration in the volunteers.

The weight of flasks after administration is an exclusion criteria, and the mean of the values. The weight of each flask must be calculated and must fall within two standard deviations. Volunteers must be previously trained to use the apparatus that will receive the formulation to inhale properly; Before nasal administration 1 minutevolunteers must blow their noses; During nasal application, one of the nostrils must be obstructed while administration is executed in the other nostril.

It is recommended that time elapsed between first and last actuation does not exceed 1 minute; After last application, volunteers must receive a ml glass of water to conduct particles of drug that might have remained in oral cavity to gastrointestinal tract; Drug must be administered in a room, and volunteers must be led to another room where blood samples will be drawn, minimizing the cross-contamination.