Literature and experimental data relevant to waiver of in vivo bioequivalence (BE) testing for the approval of immediate-release solid oral dosage forms containing amoxicillin trihydrate are reviewed. Solubility and permeability characteristics according to the Biopharmaceutics Classification System (BCS), therapeutic uses, therapeutic index, excipient interactions, as well as dissolution and BE and bioavailability studies were taken into consideration. Solubility and permeability studies indicate that amoxicillin doses up to 875 mg belong to BCS class I, whereas 1000 mg belongs to BCS class II and doses of more than 1000 mg belong to BCS class IV. Considering all aspects, the biowaiver procedure can be recommended for solid oral products of amoxicillin trihydrate immediate-release preparations containing amoxicillin as the single active pharmaceutical ingredient at dose strengths of 875 mg or less, provided (a) only the excipients listed in this monograph are used, and only in their usual amounts, (b) the biowaiver study is performed according to the World Health Organization-, U.S. Food and Drug Administration-, or European Medicines Agency-recommended method using the innovator as the comparator, and (c) results comply with criteria for "very rapidly dissolving" or "similarly rapidly dissolving." Products containing other excipients and those containing more than 875 mg amoxicillin per unit should be subjected to an in vivo BE study.

BackgroundThe regulatory requirements for approval of generic medicines and the format of compiling drug dossiers vary among regulatory authorities. The variation is particularly wide between High-income countries (HIC) and lower and middle-income countries (LMIC) with different regulatory frameworks. In this study, document requirements for approval of generic products, approval timelines, and consideration of bioequivalence and/or biowaiver data by Regulatory Authorities (RAs) of 10 selected jurisdictions was studied.MethodsThe guidelines and procedures from 5 purposively chosen RA of HIC and4 regional RAs relevant for Sri Lanka were compared with the Sri Lankan National Medicines Regulatory Authority (NMRA). Information available in the official websites of the selected RAs, published journal articles and via personal communication was collected in2016. Drug approval timelines achieved in Sri Lanka was obtained from data available from another study.ResultsCommon technical dossier (CTD) format of the International Council on Harmonization (ICH) for registration of pharmaceuticals (ICH:CTD) or the Association of South East Asian Nations (ASEAN) CTD format (ACTD) was used by all RAs studied except Sri Lanka which use its own dossier format. Nine out of ten RAs studied request BE data or justification for not submitting BE data for generic medicines. Sri Lanka requested BE studies only for antimicrobials, antiepileptic drugs and narrow therapeutic index drugs. Biowaivers are allowed for Biopharmaceutics Classification System (BCS)-based Class 1drugs in Singapore and India. USA, EMA, Canada and South Korea allowed biowaiver for BCS Class1and Class 3drugs but Sri Lanka does not accept BW at present. Nine NMRAs out of the ten studied reported legislated timelines for approval of generic pharmaceuticals except Sri Lanka.ConclusionsStreamlining the drug regulatory systems in LMIC such as Sri Lanka with that of HIC would facilitate an effective drug regulatory system based on reliance on decisions made by stringent regulatory authorities. Findings of this study encourage Sri Lanka to adopt a CTD format for regulatory submission of drug dossiers. Expanding the BE requirement drug list and accepting BCS-based biowaivers for BSC class 1 and 3 drugs during registration of generic drugs when it is scientifically justified is also recommended for Sri Lanka.

BackgroundLithium is a first line drug used to treat bipolar affective disorder requiring frequent monitoring due to its narrow therapeutic index. Flame photometry is a reliable quick and cost-effective method of serum lithium estimation. ObjectiveWe aimed to validate a flame photometry method for serum lithium estimation to compare the results with a different model flame photometer and an ionselective electrode. MethodSherwood 410 flame photometer was used for the analysis. Serum samples were diluted 1:2 using a lithium blank solution containing sodium and potassium. Aqueous lithium standards were prepared using the same blank. The method was validated for the concentration range 0.2-1.5mmol/l. Linearity, recovery, accuracy, precision and stability were determined by standard lithium serum samples representing the lower limit of quantification (LLOQ) 0.2mmol/l, median level of quantification (MLOQ) 0.8mmol/l and the upper limit of quantification (ULOQ) 1.5mmol/l. Five replicates of serum and aqueous lithium samples were used to determine linearity in the range between LLOQ and ULOQ using the coefficient of determination (R2). Five standard serum replicates were used for recovery, accuracy and precision studies. Precision was determined by the coefficient of variation (CV%) on three different days. Results of the flame photometric method were compared with those of a different flame photometric method and an ion-selective electrode method. Results:The R2 for the aqueous samples and the serum samples was >0.995 demonstrating linearity. The matrix effect ranged between 92.5% and 105% for the LLOQ, MLOQ and ULOQ. The accuracy and precision for LLOQ, MLOQ of and ULOQ were below 15%. Similar results were obtained for the QC samples with the different model flame photometer and ion-selective electrode method.

An important component of evaluation of generic medicines is assessing their therapeutic equivalence, which is done by a comparative study with an appropriate comparator, such as an in vivo bioequivalence study or an in vitro dissolution study. In vivo bioequivalence studies are cumbersome and expensive. Their need might be waived using in vitro dissolution for selected drugs. In this post marketing study, we conducted in vitro dissolution testing according to the WHO guideline for biowaiver studies comparing a generic metronidazole product available in Sri Lanka with an appropriate comparator. The results showed that both products complied with the pharmacopoeial specifications, and that the generic (test) product is similar to the comparator product, with very rapid dissolution properties. In vitro dissolution of the test product was similar to the comparator in media with pH 1.2, 4.5, and 6.8, representing gastric, duodenal, and jejunal conditions. Based on the study findings, the tested metronidazole product demonstrates in vitro equivalence to the comparator product. Similarity of the dissolution profile indicates high probability of in vivo bioequivalence of the generic product compared to the brand name product, in the absence of bioequivalence data. According to the International Pharmaceutical Federation (FIP) biowaiver monograph for metronidazole, the quality and quantity of the excipient also needs evaluation for the two products to be considered therapeutically equivalent. Therefore, if the excipient composition is available, the decision of interchangeability of the two products could be made.

Guidance documents on biowaivers and published literature, including the biowaiver monograph on amoxicillin, recommend conducting biopharmaceutics classification system (BCS)-based in vitro dissolution studies as a surrogate for in vivo bioequivalence (BE) studies for solid oral amoxicillin products. Until now, comparative in vitro dissolution studies have not been used in regulatory submissions in Sri Lanka. This post-marketing study was conducted to compare dissolution profiles of three registered amoxicillin products. In vitro dissolution testing was conducted according to the WHO guideline for biowaiver studies. We compared three generic solid oral amoxicillin products of 500 mg (generic A, B, and C) available in Sri Lanka with the innovator product. Dissolution samples were quantified using a validated highperformance liquid chromatography (HPLC) method with ultraviolet (UV) absorption at 229 nm. The results showed that all products complied with pharmacopoeial specifications, but variation of dissolution data greater than 20% was noted at the 10-min time point, and 10% variation was noted at later time points with product A at pH 4.5 and product C at pH 4.5 and 6.8. Therefore, both conventional similarity factor (f 2) and model-independent multivariate confidence region procedures (bootstrap approach) were used to compare the dissolution profiles. Only generic A met dissolution study criteria at all three pH conditions. Generic B failed to meet dissolution study criteria at pH 4.5, and generic C, with highly variable dissolution data, met the dissolution criteria at pH 4 using bootstrap f 2 and failed to meet dissolution criteria at pH 6.8. This study highlights the need for careful consideration of an appropriate mathematical model or models for comparing dissolution profiles, especially when the coefficient of variation (CV) warrants application of two models for different pH conditions. The international guidelines on BCS-based dissolution studies do not provide adequate guidance on these issues.

Primary hypomagnesemia with secondary hypocalcemia (PHSH) is a genetically defined disease in which there is a malabsorption of magnesium from the intestine. The aim of this research was to encapsulate magnesium into autologous erythrocytes to be used in PHSH patients. A scheme to use a single syringe closed sterile system for the process is proposed. Controlled lysis of erythrocytes and the ability to reseal the loaded erythrocytes were investigated. Method: Suitable concentrations of salt solutions required for making reversible pores and resealing of erythrocytes were identified. For making reversible pores, 0.7% NaCl and 2.3% MgSO 4 were used separately. A solution of 3.5% MgSO 4 was used as the drug loading solution. After the loading step, the isotonicity for the erythrocytes was restored with 0.9% NaCl and 3.0% MgSO 4 solutions separately. The ability to load and reseal erythrocytes were assessed by determining the resulting Mg 2+ concentration through Microwave Plasma Atomic Emission Spectrophotometric (MP-AES) analysis. Results: Analysis of results revealed that Mg 2+ ions can be successfully loaded into erythrocytes through the formation of reversible pores. Resealing failed with 3.0% MgSO 4 , but the erythrocytes were successfully resealed with 0.9% NaCl solution. Conclusion: The need for strictly controlled salt solution concentrations for lysis and resealing were identified. In theoretical concentration determinations, the osmotic coefficient had to be taken into account. The study showed the possibility of loading Mg 2+ into erythrocytes as a successful drug delivery system.

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This post-marketing study on prednisolone products in Sri Lanka was conducted using BCS-based biowaiver procedures for performing in vitro bioequivalence studies. The market leader product with the highest availability was selected as the comparator in the absence of the innovator product. A validated UV/Visible spectrophotometric method was used to quantify the drug dissolution. Cumulative drug release profiles were determined in dissolution media at pH 1.2, 4.5, and 6.8 using the paddle apparatus. Although the two test products and the comparator met pharmacopoeial requirements for quality, they failed to meet in vitro biowaiver criteria. Acceptability of biowaiver study results depends on the performance of the comparator product. Information on the comparator product's bioequivalence to the innovator product was not available. This study revealed the difficulties in low and middle-income countries (LMICs) when conducting biowaiver studies for regulatory submission and highlights the necessity to have bioequivalence data and excipient information for the comparator product for better decision making. The study supports having an international standard comparator product used by LMICs when manufacturing and registering generic drug products.