Where is Industry Getting it Wrong? A Review of Quality Concerns Raised at Day 120 by the Committee for Medicinal Products for Human Use during European Centralised Marketing Authorisation Submissions for Chemical Entity Medicinal Products

Abstract

-Purpose. The aim of this study was to identify common trends in the deficiencies identified in the quality part of the dossier during the evaluation of marketing authorisation applications for medicinal products for human use submitted through the EU's centralised procedure. Methods. We analysed all the adopted Day 120 list of questions on the quality module of 52 marketing authorisation applications for chemical entity medicinal products submitted to the European Medicines Agency and evaluated by the Committee for Medicinal Products for Human Use (CHMP), during 12 consecutive plenary meetings held in 2007 and 2008. Subsequently we calculated the frequency of common deficiencies identified across these applications. Results. Frequencies and trends on quality deficiencies have been recorded and presented for 52 marketing authorisation applications. 32 "Major Objections" originated from 13 marketing authorisation applications. 13 concerned were raised regarding drug substances and 19 for drug products. Furthermore, 905 concerns on drug substance and 1,054 on drug product were also adopted. Conclusions. The impact of the frequencies and trends in quality deficiencies that were identified are discussed from a regulatory point of view. It is expected that the results of this study will not only be of interest to pharmaceutical companies but will also aid regulators' in obtaining consistent information on drug products based on transparent rules safeguarding the necessary pharmaceutical quality of medicinal products.

Review of Quality Deficiencies Found in Active Pharmaceutical Ingredient Master Files Submitted to the WHO Prequalification of Medicines Programme

“…To our knowledge this is the first time a review of API quality deficiencies covers all dossiers over such a long time period; the European Directorate for the Quality of Medicines (EDQM) top ten deficiencies documents are based on the contents of a sample of the deficiency letters in each year and the European Medicines Agency (EMA) quality deficiencies publication included questions raised over a period of only two years (16)(17)(18)(19)(20)(21). In addition our study includes the quantification and description of all deficiencies to the level of the CTD subsection; the EDQM reported the ten most frequent groups of deficiencies and in the review of deficiencies raised by EMA these were quantified to the level of the CTD section only (16)(17)(18)(19)(20)(21). Furthermore, to our knowledge this is the first time a study on API quality deficiencies has been performed on APIs intended for generic medicines from emerging markets.…”

“…Limited information is available in the public domain with respect to the actual API deficiencies found by assessors in SRAs, but specific studies have been published by the EDQM (16)(17)(18)(19)(20). There are also two publications on the review of API deficiencies raised by the United States Food and Drug Administration (USFDA) and the EMA (21)(22).…”

“…In the EMA study the API assessment was part of the assessment of the finished product dossier, because the API information was provided as part of a full dossier submitted by the marketing authorization applicant (21). Still the API deficiencies were broken down into CTD sections, which allowed a quantitative and qualitative comparison.…”

Statistics, Quality Review Issues, and Beyond for Generic Drug Applications in Taiwan

“…Since it was a newly implemented measure, deficiencies related to the lack of information regarding the source of the drug substance are unique in the review process for submissions in Taiwan, which were rarely found in the applications submitted to other agencies such as the EMA, 15 the FDA, 10,11 and the WHO. 14 …”

“…The presentation of the above-mentioned issues provided an overview on the regulatory considerations for generic drug applications in Taiwan. The similarities in the deficiencies listed in the final quality assessment reports to the common deficiencies observed by the EMA, 15 the FDA, [10][11][12][13] and the WHO 14 might suggest the harmonization of regulatory requirements, while the dissimilarities could reflect the difference in the regulatory framework. Through the analysis of the deficiencies in the present article, applicants will be able to have a clearer outline on the review issues in Taiwan, which may aid the applicants to prepare further informational details for clarification or for the development of a new generic drug product.…”