Common Deficiencies Found in the Active Pharmaceutical Ingredient (API) Section of Non-sterile Generic Products Submitted for Registration by SAHPRA

Abstract

Purpose This research study aims to determine the qualitative and quantitative common deficiencies included in the API section of dossiers submitted to SAHPRA. The study was conducted retrospectively over a 7-year period (2011-2017) for non-sterile generic products that were finalised by the Pharmaceutical and Analytical pre-registration Unit. In this period, the restricted part of the CTD was evaluated when needed therefore this was not conducted on all applications. The requirement to evaluate the restricted part for all applications was initiated in January 2020, thus, a separate study has been conducted to identify the common deficiencies in the restricted part. Methods There were 2089 applications finalised between 2011 and 2017 and in order to attain a representative sample for the study, the multi-stage statistical sampling called the 'stratified systematic sampling' was selected as the method of choice. Sample size was obtained using the statistical tables found in the literature and confirmed by a sample size calculation with a 95% confidence level, resulting in the selection of 325 applications. Subsequently, all the deficiencies were collected and categorised according to CTD subsections. For the restricted part study, all new applications evaluated between January to May 2020 were used. Results A total of 1130 deficiencies were collected from 325 applications sampled. The majority of the identified deficiencies were from Module 3.2.S.3.1 (19.38%) on characterisation, Module 3.2.S.1.3 (19.11%) on general properties, Module 3.2.S.4.1 (10.44%) on specifications and Module 3.2.S.4.3 (8.32%) on validation of analytical methods. The study on the restricted parts included the five most common deficiencies that SAHPRA has identified, which are similar to those observed from the 2011-2017 applications. This confirms that the quality of the evaluations has been maintained over the years. Comparison of the deficiencies with those reported by other agencies such as the USFDA, EMA, WHOPQTm and TFDA are discussed with similarities clearly outlined. Conclusions The most common deficiencies observed by SAHPRA were extensively discussed. These findings could serve as a guidance for API manufacturers to submit better quality APIMFs which will improve turnaround times for registration and accelerate access to medicines for patients.

Regulatory registration timelines of generic medicines in South Africa: Assessment of the performance of SAHPRA between 2011 and 2022

“…The sample selected becomes a true representation of the population and results of the study can be generalised to the population. The method of selection and calculation of the representative sample is comprehensively described by Moeti et al where a sample size of 325 non-sterile products is obtained and used in the study [13,18,19]. By comparing the quality requirements for sterile and non-sterile products it is witnessed that the sterile products require additional assessments in the pharmaceutical development Sect.…”

“…The other aspect which led to multiple response cycles is common deficiencies observed in the quality and bioequivalence study evaluations which resulted in backand-forth communication with the applicant [13,18,19]. The deficiencies in the specification sections of the API and FPP were the most prevalent and included requests to tighten the proposed specifications of the product.…”

“…The stability sections also had recurring deficiencies such as the request for further stability data to support the proposed retest or shelf life. These fell under the common deficiencies reported by SAHPRA and are discussed extensively in the recent publications [13,18,19]. The response cycles would be shortened as all requirements could be met with the approach of informing manufacturers of the common deficiencies identified.…”