Category: Manufacturing and Bioprocessing
Purpose: Generic drugs comprise a significant market share of all prescribed medicines, even higher percentage in developing countries. In Saudi Arabia, there are more than two thirds of registered pharmaceutical products considered generics. One of the main reasons for encouraging the development of generics is to decrease the burden of costs of health care systems. However, there is an increase in number of reports related to the quality of generic products received by National Pharmacovigilance Center at Saudi Food and Drug Authority (Saudi FDA). In addition, the Saudi FDA plays a key role in overseeing the market and promoting the trust of health care providers and the public in generic products. The main objective of this study was to evaluate and ensure the safety, efficacy and quality of the marketed generic pharmaceutical products in Saudi Arabia, encourage the pharmaceutical industry to raise the quality standards and improve public awareness and trust in marketed generic products.
Methods: First, a list of approved drugs up to October 2017 that are registered in Saudi FDA was categorized by their active ingredients into four different groups based on the biopharmaceutics classification system (BCS). The project was started with BCS class 4 (low solubility and low permeability) due to the risk associated with the nature of the active ingredient. This was followed by class 2, class 3 then class 1. The generic product was tested by conducting multi-time point in-vitro dissolution comparatively to the reference listed drug (RLD; also known as innovator) registered in the local market. The comparative in-vitro dissolution was selected because it is well established and approved approach to ensure therapeutic equivalence. In addition, it is cost and time effective measure in comparison to bioequivalence studies. One batch of a generic product was tested and compared to the RLD product. Two additional batches were tested in case the first batch failed. When two out of three batches were failed in the measures of comparative dissolution, the manufacturer were asked to provide justification with corrective action preventive action (CAPA) (see Figure 1).
Results: 100 generic oral solid dosage form product were included in the study. 121 batches of generic products were tested by comparative in-vitro dissolution. 57 percent were locally manufactured and the rest were imported from aboard, regionally and worldwide. Around two thirds of the products passed the comparative dissolution test with a similarity factor (f2) value of 50 or more. This success rate was comparable between the locally and internationally produced products. Less than one third are still under further investigation where additional batches are in line for testing. Only 5 percent failed the test in at least 2 out of 3 batches. There were several reasons behind the failure but the main reason was post-marketing modifications without submitting variation approval request that subsequently had an impact on drug-product release behavior. Examples of these modifications were use of active pharmaceutical ingredient (API) supplier other than the approved one and changes in the manufacturing procedure after approval. The legal representatives of the failed products were asked to provide a sufficient evidence, such as bioequivalence study, to continue marketing their products. Sun D. et. al. (2017) suggested to use risk-based assessment tools including but not limited to dissolution testing and physiologically based pharmacokinetic (PBPK) modeling and simulation approaches. the use of similar techniques are currently under investigation in the Saudi FDA.
Conclusion: In conclusion, our study emphasizes that in-vitro studies are helpful in distinguishing quality-related issues. Furthermore, post-marketing measures, such as comparative in-vitro dissolution testing, are as important to maintain the safety, efficacy and quality of pharmaceutical products as pre-marketing assessment. Moreover, more stringent regulations on the pharmaceutical products after marketing are encouraged. Thus, regulations regarding post-marketing variations should be enforced.