APPLICATION OF FMEA TOOL TO ANALYZE NOTIFICATIONS OF TECHNICAL COMPLAINTS OF SOLID DOSAGE FORMS IN THE CONTEXT OF QUALITY BY DESIGN

The quality control in pharmaceutical industries has been gradually improved with the implementation of new strategies and technologies, in order to make it possible to obtain increasingly effective and safe products. With the advent of the Quality by Design (QbD) concept, the production of medicines started to be optimized by delimiting the quality parameters of the products from the initial stages of development and formulation planning based on the characteristics of the active pharmaceutical ingredient, aiming defect prevention and continuous improvement of the production chain. Therefore, the present study constitutes a quantitative analysis of notifications of irregularities in solid medicines published on the National Health Surveillance Agency (ANVISA) official website during the period from 2017 to 2019, using the Failure Mode Analysis and Effects (FMEA) methodology in QbD context. Of the 421 notifications of irregular pharmaceutical products analyzed, 28.5% corresponded to technical complaints and, of this total, 60.0% were related to solid medicines. After evaluating the data, it was found that approximately 80.0% of the non-conformities found were related to aspect, dissolution, packaging, dosing and purity. Thus, it can be inferred that the QbD is an efficient strategy for the management of risks related to production, aiming at cost reduction and implementation of strategies that allow the gradual reduction in the number of technical complaints of these products. ACorresponding author: AProfessor Orientador Leandro Giorgetti – E-mail: – lggiorgetti@anhembi.br – ORCID: https://orcid.org/0000-00032776-2286 _____________________________ DOI: https://doi.org/10.31415/bjns.v3i2.105 Article received on: July 17, 2020; accepted October 21, 2020; published in November 2020 in Brazilian Journal of Natural Sciences, Vol. 3, N.3, Online, ISSN: 2595-0584 – www.bjns. com.br. All authors contributed equally to the article. The authors declare no conflict of interest This is an open access article under the CC BY license: http://creativecommons.org/licenses/by/4.0


Introduction
According to a report by the World Surveillance Quality control is a key element of any industrial process to give credibility to products and stability for companies in the respective sector. With the emergence of the era of total quality management since 1980 (Figure 1), the focus of industries has shifted to controlling variables that can affect the desired quality of products from the planning stage, through guided strategies mainly in the concept of QbD (4,5). According to Nadpara et al. (6), QbD is a modern approach to pharmaceutical products that provides guidance for industries to improve their manufacturing processes, by optimizing operating systems and managing productionrelated risks.
However, the main challenge is the identification of all potential points of failure capable of compromising the quality of the products, since most processes do not have a carefully defined standard. In this context, the use of quality tools becomes an important alternative to assist in decision making involving the directing of resources to continuous improvement practices in stages considered most critical (7,8).
In view of the breadth of the bibliography regarding risk management in industrial processes, the FMEA methodology was the most appropriate tool for this study, since it allows the identification of irregularities that represent greater risks, enabling the planning of actions corrective and preventive measures capable of reducing the occurrence of nonconformities (9,10).
In this sense, the objective of the work was to quantitatively assess notifications of irregular solid medicines published by ANVISA during the period from January 2017 to December 2019, using the FMEA tool within the context of QbD.

Materials and methods
The present study was carried out through a data survey of notifications of technical complaints of solid dosage forms published in the form of Specific Resolutions (SR) in the "Irregular Products" area of the official website of ANVISA (11), during the period from January 2017 to December 2019.
After a systematic search, notifications were collected according to the dosage form and the type of irregularity presented by the products. Were considered data related to pharmacotechnical problems, contamination, non-compliance with general manufacturing standards and nonconformities in packaging, for further subdivision into 12 categories (Table 1). Contamination by active substance -Presence of substances not described in the formulation.

Description
-Differences between the description and the appearance of the product.

Dosing
-Active ingredient content out of specification.
Packaging -Product characteristics different from those in the original packaging; -Absence of information on labels or failures in recording product data on packaging; -Product packaging with different material than registered; -Lack of content in the product bottle or problems with filling.

Stability
-Stability test failure.

Formulation
-Presence of lumps or irregularities on the surface of the drugs. Average weight -Weight out of specification or variation range.
Purity -Presence of impurities or less active polymorphic forms; -Out of specification results for related substances test; -Use of irregular or prohibited raw materials.

Source: The author
Right after, the numbers of notifications were counted separately according to the respective categories and proceeded to the subsequent steps of application of the tool (Figure 2).

PÁGINA 478
In the occurrence classification ( Table 2), the main criterion adopted was the frequency at which a given failure was repeated during the period studied. On the other hand, the severity index was defined according to the possible consequences that the failure can bring, so, the main criterion adopted was the dangerousness of the effects, considering aspects such as risks to the health of patients, effectiveness commitment and loss of credibility of the product. Finally, the detection scale was established based on the probability of avoiding failure, thus, the smaller the amount of pre-existing controls, the higher the value assigned, considering that there will be an increased risk of a non-compliance reaching the customer (9,10).  (4,9).

Results and discussion
During the years 2017 to 2019, ANVISA has published a total of 421 notifications of irregular pharmaceutical products, of which 136 were for the year 2017, 108 for 2018 and 177 for 2019. Of this total, 120 (28,5%) were related pharmacotechnical problems, contamination, non-compliance with general manufacturing standards and non-conformities in packaging. Of these notifications, 72 (60,0%) were about solid medicines, such as tablets, capsules, lyophilized powders, suspension powders and sugar-coated tablets ( Table 3). -Packaging materials out of specifications; -Absence of a labeling control mechanism; -Failure in the packaging closing mechanisms.
Absence or error of information that can compromise the treatment Recall or suspension of drug sales 10 8 2 160 Aspect 7 -Incompatibility between drug and excipients; -Problems related to product stability; -Product contamination.
Effectiveness commitment or risk of non-adherence to drug treatment Dosing 5 -Equipment failures (e.g.: calibration or maintenance); -Absence of effective control mechanisms; -Failure to define specifications for the product's active ingredient content.
Risk of clinical consequences from underdose or overdose Purity 4 -Poor quality of raw materials; -Use of irregular or prohibited raw materials; -Absence of effective control mechanisms.
Clinical consequences resulting from product ineffectiveness Average weight 2 -Low robustness in process. -Absence of effective control mechanisms; -Equipment failures (e.g.: calibration or maintenance).
Recall or suspension of drug sales Description 4 -Non-compliance with regulatory standards; -Use of the incorrect standard formula or exchange of raw materials during the manufacture of the product; -Absence of effective detection mechanisms. According to the survey, the solid dosage forms that presented the highest number of notifications were tablets (58,3%) and lyophilized powders (19,4%), as shown in Figure 3. On the other hand, the dosage form that presented the lowest number of notifications was the sugarcoated tablet, with 2,8% of the total. However, due to the dredging process takes time and technique, increases the size of the tablet by 50% weight/ volume and has a higher cost, the sugar-coated tablets are being increasingly replaced on the market by film-coated tablets, which may justify the low number of notifications (12).
Of the 72 notifications, approximately 80% were related to aspect, dissolution, packaging, dosing and purity (Figure 4). In addition, based on the analysis of the RPN obtained, irregularities related to the first three parameters were classified as critical, due to the high number of notifications and significant impact on the quality of the products.

Conclusion
With the FMEA methodology, it was possible to assess notifications of technical complaints for solid drugs, according to the frequency, probability of detection and the impact generated by the failures, prioritizing them according to the level of criticality. In addition, it can be concluded that QbD strategies, use of tools based on mathematical models and real-time control mechanisms, can significantly contribute to reducing the occurrence of quality deviations, rejection of product batches, non-conformities regulatory and costs of investigating consumer complaints, by incorporating quality attributes into products since the development process.