Guidance documents and FAQs. FAQ - APIs (English) · FAQ - APIs (English) - pdf · Guidance document - Degradation profiles of drug products (Portuguese). This guide is based on documents VOLUME 9A of The Rules Governing Medicinal. Products in the European Union – Guidelines on Pharmacovigilance for. 1 Brazilian Health Regulatory Agency (ANVISA), Brasilia, DF, Brazil, . Furthermore, poor compliance with GMP guidelines lead to transparency /publicdisclosure/glossaryofacronymsandabbreviations/ucmpdf.

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Manufacturing Sites subject to GMP. Certification party auditing organization recognized by Anvisa;. • V – by making a risk analysis to assess. Harmonization of GMP guidelines and inspection procedures are the key steps to avoid . Deficiencies often found during ANVISA inspections (article of Brazilian .. /publicdisclosure/glossaryofacronymsandabbreviations/ucmpdf. Anvisa regulatory guidelines High Impact List of Articles PPts Journals You Mie Lee Cell signalling and Biochips PPT Version | PDF Version GMP deficiencies found by ANVISA in foreign inspections. Andrea Geyer, Varley D Sousa.

For generic and similar drugs, drug scientific evaluation includes their equivalence to the brand name drug from the viewpoint of quality, efficacy, and safety, proved by bioequivalence studies, as in other agencies [ 7 — 9 ]. After evaluation, the registration application can be approved and questioned through major objections, when deficiencies that can be solved are identified, as other noncritical issues that require clarification, or refused, when regulatory requirements are not accomplished [ 1 ].

The rejection is a disadvantage to the applicant, who may have to review the entire process or even redevelop the product, in case the decision has reached final instances and no further appellations are allowed, to ANVISA, who spent public resources reviewing the applications, and mostly to society, which will not have access to an alternative treatment with guaranteed quality, safety, and efficacy.

Moreover, scientific assessment carried on rejected applications is not published, and it prevents the study of the most important factors associated with refusal reasons. In this note, a retrospective analysis of the main reasons for marketing authorization refusal of generic and similar pharmaceutical drug products in Brazil is presented.

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The aim is to publish useful information for future applications, so that processes can be better prepared and time required for analysis reduced. Material and Methods A retrospective search of approved and refused drug products registration processes was performed on the Government Official Gazette GOG from January 1, , and December 31, GOG publishes brief information about process, as company name, drug product name and its API, and presentations including dosage form, strengths, container closure types, and configurations.

ANVISA databank is an internal software which contains information about drug products, that is, their applicants, application date, and motivation reports for approval or refusal. After data review, refusal reasons were classified as administrative nontechnical or scientific technical , categorized in general areas and further subdivided and detailed in specific categories, according to subjects described on particular regulatory regulations.

Results Between January 1, , and December 31, , new, generics, and similar pharmaceutical drug products applications were published on Government Official Gazette. Any new drug product was refused. Six of them referred to clone petitions, simplified application linked to a matrix petition, which contains all technical and clinical information requested for drug product registration. Clone is based on a matrix petition and they differ exclusively in drug product name, packaging layout, and legal information [ 10 ].

Retrieved processes were submitted between and Major nontechnical refusals occurred on documents applied on and Figure 1. Figure 1: Number of refused marketing authorization applications in accordance with process submission year.

The retrospective analysis revealed reasons for refusal. Each reason was classified in general areas according to major themes described in registration regulations and detailed in specific categories [ 7 , 8 ] Table 1. Table 1: Distribution of main reasons for refusal to approve generic and similar pharmaceutical drug products. Drug product quality control was the main reason for registration refusal.

Analytical method validation problems, related to quality control, involved lack of specificity, linearity, accuracy in assay, dissolution, and impurity methods. Main reasons related to API quality control were also analytical validation problems including absence of validated analytical method for impurities assay and lack of specificity in impurities analytical method. The topic related to impurities represented an important registration reason for refusal, which was related not only to drug product quality control but also to drug analytical method validation or verification, drug stability and photostability, and API quality control performed by drug product manufacturer and API manufacturer, as represented in Figure 2.

Figure 2: Distribution of problems related to impurity which led to refusal of marketing authorization application for generic and similar pharmaceutical products. Between and , 80 new drug products were not approved in the USA: 76 Pignatti et al.

Quality major objections were related to API quality control In Europe, major objections are sent to the applicant during the review. Applicants have to accomplish them in a predetermined period of time [ 16 ]. The process is essentially the same in Brazil [ 17 ].

Failure to solve all major objections may lead to a refusal. The same does not happen in Brazil. There is also an instrument to being withdrawn [ 18 ] but it is not as representative.

Application submission procedure was established in [ 17 ], detailed in [ 19 ] and [ 20 ] through orientations. Therefore, a possible explanation for the persistency of nontechnical refusals would be that although regulatory requirement was available, it was not applied as they should be, neither by companies nor by ANVISA. The procedure began to be better applied only after both orientations [ 19 , 20 ]. In , a preliminary analysis procedure was determined, by which a screening approach should briefly review all applications received, checking if it was sufficiently complete to permit a substantial review.

Hence, transparency actions as this one are strongly encouraged, so new processes are submitted in accordance with guidelines.

FDA also has established some requirements to refuse submissions that are not sufficiently complete to permit substantive review [ 21 ]. Repairing an incomplete file during the analysis is a waste of resources, because it needs many cycles of FDA response and applicant repair [ 13 ].

Apart from this, deadline accomplishment, a nontechnical reason, was the third major reason of refusal, mainly due to absence of clone drug product petition.

Clone drug product is identical to another one, named matrix petition, differing exclusively in name and labeling [ 10 ]. It was a particular situation in the year , due to deadline established by regulation to clone adequacy. It will not happen in the next years [ 10 ].

This data reinforces the importance of transparency initiatives to ameliorate technical quality of national drug products and expand internal and international generic and similar drugs market. Table 2: Obligations of an application. Drug product quality control problems had the highest occurrence For pharmaceutical drug products registration, quality, safety, and efficacy for the proposed use have to be recognized through scientific evidence and analysis [ 1 ] using established methods accepted by ANVISA [ 28 ].

When a specific analytical method is not described in any official pharmacopeia accepted by ANVISA, it has to be validated [ 7 , 8 , 29 ].

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In USA, the concept is similar [ 30 ]. Since then, there are regulatory requirements for this theme which are not yet fully accomplished. Brazilian regulation is also quite similar with ICH guideline. The main difference is robustness requirement and precision parameter relative standard deviation [ 32 ]. However, such differences do not justify the large number of rejections on this subject.

Regulatory requirements establish which parameters must be validated, but they do not bring detailed descriptions of how to perform the assays. We believe such absence may be the main reasons to stand validation as one of the most common reasons for refusal. The validation procedure is an important step of method development [ 33 ] and it has to be suitable for each product [ 32 ].

Main challenge for a method validation may not be the method development itself rather the experiments planning and results interpretation based on proper statistical analysis. An iconic representation of this may be found in one of the process submitted in in which specificity was not proved for both assay and impurity test.

The regulatory requirement states that specificity should be conducted during the validation of identification tests for the determination of impurities and the analyte [ 29 ]. For the analyte assay and impurity test, specificity can be determined comparing the results obtained on samples spiked with appropriate levels of impurities or excipients, with unspiked samples, to demonstrate that the results are unaffected by the presence of these materials.

When a possible impurity is not available, it is necessary to perform forced degradation tests [ 29 ].

In the example depicted here, impurities standards were not available, and the absence of forced degradation test was not justified, demonstrating lack of proper experiment planning and noncompliance with regulatory requirement, consequently. Hence, the necessity of training programs is evident [ 33 ].

Drug product stability study was the second main reason for marketing authorization refusal. It is an obligatory study for drug product registration [ 7 , 8 ]. Stability first regulation from had already discussed the importance of tests to effectively assess the dosage form, including assay, impurity, and dissolution.

In addition, it established that evaluation methods should be validated and stability-indicating [ 34 ]. It brings some obligatory tests or the possibility for justifying its absence.

Nonetheless, results demonstrated that despite the increased rigidity of the current legislation, it has been published for more than 10 years, so it is still lagging when compared to the Stability ICH guidelines [ 36 ]. Even so, some refusals motivations were already covered in the Brazilian legislation for 30 years. Moreover, many stability reasons are also related to analytical method, validation and development problems, as already discussed. Stability specifications have to be determined based on each drug product.

Dissolution methods and specification recommended by other regulatory agencies to methods not described in official compendia, as FDA-Recommended Dissolution Methods [ 37 ], cannot be applied without prior critical analysis, because they are not always suitable for Brazilian products. They are just aids of industry personnel development. API quality control, made by drug product manufacturer, is fourth main refusal reasons, after deadline accomplishment, already discussed.

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Considering that the API quality is critical to drug product quality, it is essential that drug manufacturers assure and confirm that API accomplishes quality requirements. It means drug products manufacturers have to establish internal API quality control specifications and methodology.

Although this information is present in registration regulatory requirements, absence of API methodology development is still a failure point on drug registration.

Internal API quality control specifications and methodology should be adopted based on impurity profile and residual solvents arising from API manufacturer synthetic route, official compendia, and also international guidelines as ICH quality guidelines [ 36 ]. When a drug product is approved, an API manufacturer is also approved for that drug [ 7 , 8 ]. Therefore, API manufacturer has to comply with Brazilian regulatory requirements.

Within API manufacturer category, great part of denials corresponded to lack of stability studies performed on Brazilian climatic zone.

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Brazil is classified as IVb climatic zone [ 38 ]. It is mandatory to present complete accelerated stability studies and at least long term stability studies protocol in IVb climatic zone [ 39 , 40 ]. The problem is that many international API manufacturers refuse to comply with Brazilian regulation, as countries representing major consumer markets belong to climatic zones of milder conditions.

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