Biowaiver monographs for immediate release solid oral dosage forms: ethambutol dihydrochloride.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing ethambutol dihydrochloride as the only active pharmaceutical ingredient (API) are reviewed. Ethambutol dihydrochloride is a Biopharmaceutics Classification System (BCS) Class III drug with permeability properties approaching the border between BCS Class I and III. BE problems of ethambutol formulations containing different excipients and different dosages forms have not been reported and hence the risk of bioinequivalence caused by excipients is low. Ethambutol has a narrow therapeutic index related to ocular toxicity. However, as long as the prescribers' information of the test product stipulates the need for regular monitoring of ocular toxicity, the additional patient risk is deemed acceptable. It is concluded that a biowaiver can be recommended for IR solid oral dosage forms provided that the test product (a) contains only excipients present in ethambutol IR solid oral drug products approved in ICH or associated countries, for instance as presented in this paper, (b) complies with the criteria for "very rapidly dissolving" and (c) has a prescribers' information indicating the need for testing the patient's vision prior to initiating ethambutol therapy and regularly during therapy.

Biowaiver monographs for immediate release solid oral dosage forms: prednisolone.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing prednisolone are reviewed. Data on its solubility, oral absorption, and permeability are not totally conclusive, but strongly suggest a BCS Class 1 classification. Prednisolone's therapeutic indications and therapeutic index, pharmacokinetics, and the possibility of excipient interactions were also taken into consideration. Available evidence indicates that a biowaiver for IR solid oral dosage forms formulated with the excipients tabulated in this article would be unlikely to expose patients to undue risks.

Biowaiver monographs for immediate release solid oral dosage forms: isoniazid.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing isoniazid as the only active pharmaceutical ingredient (API) are reviewed. Isoniazid's solubility and permeability characteristics according to the Biopharmaceutics Classification System (BCS), as well as its therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA) problems were taken into consideration. Isoniazid is "highly soluble" but data on its oral absorption and permeability are inconclusive, suggesting this API to be on the borderline of BCS Class I and III. For a number of excipients, an interaction with the permeability is extreme unlikely, but lactose and other deoxidizing saccharides can form condensation products with isoniazid, which may be less permeable than the free API. A biowaiver is recommended for IR solid oral drug products containing isoniazid as the sole API, provided that the test product meets the WHO requirements for "very rapidly dissolving" and contains only the excipients commonly used in isoniazid products, as listed in this article. Lactose and/or other deoxidizing saccharides containing formulations should be subjected to an in vivo BE study.

Biowaiver monographs for immediate release solid oral dosage forms: prednisone.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing prednisone are reviewed. Due to insufficient data prednisone cannot be definitively classified according to the current Biopharmaceutics Classification System (BCS) criteria as both the solubility and the permeability of prednisone are on the borderline of the present criteria of BCS Class I. Prednisone's therapeutic indications and therapeutic index, pharmacokinetics and the possibility of excipient interactions were also taken into consideration. Available evidence indicates that a biowaiver for IR solid oral dosage forms formulated with the excipients tabulated in this article would be unlikely to expose patients to undue risks.

Biowaiver monographs for immediate release solid oral dosage forms: cimetidine.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing cimetidine are reviewed. According to the current Biopharmaceutics Classification System (BCS), cimetidine would be assigned to Class III. Cimetidine's therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions, and reported BE/bioavailability (BA) problems were also taken into consideration. On the basis of the overall evidence, a biowaiver can be recommended for cimetidine IR products, provided that the test product contains only those excipients reported in this paper in their usual amounts, and that the test and the comparator drug products both are "rapidly dissolving" as per BCS.

Biowaiver monographs for immediate release solid oral dosage forms: amitriptyline hydrochloride.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing amitriptyline hydrochloride are reviewed. Its therapeutic uses, its pharmacokinetic properties, the possibility of excipient interactions and reported BE/bioavailability (BA) problems are also taken into consideration. Literature data indicates that amitriptyline hydrochloride is a highly permeable active pharmaceutical ingredient (API). Data on the solubility according to the current Biopharmaceutics Classification System (BCS) were not fully available and consequently amitriptyline hydrochloride could not be definitively assigned to either BCS Class I or BCS Class II. But all evidence taken together, a biowaiver can currently be recommended provided that IR tablets are formulated with excipients used in existing approved products and that the dissolution meets the criteria defined in the Guidances.

Review of global regulations concerning biowaivers for immediate release solid oral dosage forms.

The regulations with respect to biowaivers for immediate release (IR) solid oral dosage forms in the USA, the EU, Japan and from the World Health Organization (WHO) are summarized and compared. Two case studies are presented, one from our own files and one from the open literature, showing the similarities and the differences among the qualification requirements of the four systems. The regulatory experience gained up to now is reviewed and expected future trends are discussed.

Screening suspected counterfeit Viagra and imitations of Viagra with near-infrared spectroscopy.

We describe a near-infrared spectroscopy (NIRS) method for fast-screening Viagra tablets, counterfeit Viagra tablets, and imitations of Viagra. The method can (1) check the homogeneity of a batch; (2) distinguish counterfeits and imitations from authentic Viagra; (3) screen for the presence of sildenafil citrate, the pharmacologically active substance in Viagra, irrespectively of the excipients present; (4) and detect whether similar samples have been previously analysed. We applied the method to 103 samples with a diversity of appearance, chemical composition, and origin. Other analytical methods confirmed the positive screening results for sildenafil citrate and the presence of other pharmacological active substances. The NIRS screening indicated the absence of sildenafil citrate in the presence of another pharmacological substance for only 2 samples, where the reference methods showed the presence of sildenafil citrate in addition to that of clomifene citrate. Otherwise, the method gave no false positive or negative results. The NIRS screening method is very fast and reliable for detecting counterfeits and imitations, and it correctly predicts the presence or absence of sildenafil citrate in 98% of the samples.

Biowaiver monographs for immediate release solid oral dosage forms based on biopharmaceutics classification system (BCS) literature data: chloroquine phosphate, chloroquine sulfate, and chloroquine hydrochloride.

Literature data on the properties of chloroquine phosphate, chloroquine sulfate, and chloroquine hydrochloride related to the Biopharmaceutics Classification System (BCS) are reviewed. The available information indicates that these chloroquine salts can be classified as highly soluble and highly permeable, i.e., BCS class I. The qualitative composition of immediate release (IR) tablets containing these Active Pharmaceutical Ingredients (APIs) with a Marketing Authorization (MA) in Belgium (BE), Germany (DE), Finland (FI), and The Netherlands (NL) is provided. In view of these MA's and the critical therapeutic indication of chloroquine, it is assumed that the registration authorities had evidence that these formulations are bioequivalent to the innovator. It is concluded that IR tablets formulated with these excipients are candidates for a biowaiver.

Biowaiver monographs for immediate release solid oral dosage forms: ranitidine hydrochloride.

Literature and experimental data relevant to the decision to allow a waiver of in vivo bioequivalence testing for the approval of immediate release (IR) solid oral dosage forms containing ranitidine hydrochloride are reviewed. According to the current Biopharmaceutics Classification System (BCS), ranitidine hydrochloride should be assigned to Class III. However, based on its therapeutic and therapeutic index, pharmacokinetic properties and data related to the possibility of excipient interactions, a biowaiver can be recommended for IR solid oral dosage forms that are rapidly dissolving and contain only those excipients as reported in this study.

Biowaiver monographs for immediate release solid oral dosage forms: ibuprofen.

Literature data are reviewed on the properties of ibuprofen related to the biopharmaceutics classification system (BCS). Ibuprofen was assessed to be a BCS class II drug. Differences in composition and/or manufacturing procedures were reported to have an effect on the rate, but not the extent of absorption; such differences are likely to be detectable by comparative in vitro dissolution tests. Also in view of its therapeutic use, its wide therapeutic index and uncomplicated pharmacokinetic properties, a biowaiver for immediate release (IR) ibuprofen solid oral drug products is scientifically justified, provided that the test product contains only those excipients reported in this paper in their usual amounts, the dosage form is rapidly dissolving (85% in 30 min or less) in buffer pH 6.8 and the test product also exhibits similar dissolution profiles to the reference product in buffer pH 1.2, 4.5, and 6.8.

In vitro/in vivo correlations of dissolution data of carbamazepine immediate release tablets with pharmacokinetic data obtained in healthy volunteers.

The aim of the study was to select a dissolution test method for carbamazepine (CBZ) immediate release tablets, giving the best in vitro/in vivo correlations (IVIVC) and to determine the potential of this method as an estimate for bioequivalence testing. Four 200 mg CBZ products which are sold on the Dutch market, covering the innovator and three generic products, were selected. They had been tested in a randomised, fourway cross-over bioavailability study in healthy volunteers. Their dissolution rate behaviour in vitro was investigated in two dissolution media: (1) 1% sodium lauryl sulphate in water (SLS), in accordance with the United States Pharmacopeia (USP); (2) 0.1 mol/l Hydrochloric acid in water (HC). In the bioavailability study these products had shown no large differences in the extent of absorption (AUC(0-infinity);) but large differences in absorption rate. The products now also showed large differences in dissolution rate in vitro in both dissolution media, the rank order being the same as for the absorption rate. It was concluded that the absorption rate in vivo depends on the dissolution rate in vivo. 'Level C' IVIVC according to the USP were optimised by plotting percentages dissolved on selected time points (D values) or their reciprocals (1/D values), against several pharmacokinetic parameters primarily related to the absorption phase and against AUC(0-infinity). In this way for each IVIVC the optimum D or 1/D value, was calculated. For both media no meaningful IVIVC were obtained with AUC(0-infinity), but favourable IVIVC were obtained with the parameters primarily related to the absorption phase. In the bioavailability study indicated above it was found that, among the pharmacokinetic characteristics primarily related to the absorption phase, C(max) is the most promising in expressing rate of absorption in bioequivalence testing in single dose studies with CBZ immediate release tablets. Consequently, C(max) was selected for expressing rate of absorption. The most favourable IVIVC were obtained with D(20) in SLS versus C(max). From this IVIVC and the requirements for bioequivalence (AUC(0-infinity): 0.8-1.25 and C(max) : 0.75-1.35; 90% confidence interval), a specification for dissolution testing in SLS was calculated as follows: 'after 20 minutes, 34-99% dissolved'. Owing to the fact that the rate of absorption in vivo depends on i.a. the dissolution rate in vivo, it can be concluded that with this specification bioequivalence with respect to both rate of absorption and extent of absorption is ensured. As this specification is comparable with the USP specification: 'not less than 75% dissolved after 1 h', it is concluded that the USP specification is suitable to ensure bioequivalence of CBZ immediate release tablets.

Breaking of scored tablets: a review.

The literature was reviewed regarding advantages, problems and performance indicators of score lines. Scored tablets provide dose flexibility, ease of swallowing and may reduce the costs of medication. However, many patients are confronted with scored tablets that are broken unequally and with difficulty, reducing compliance and reliance on the drug. Possibilities to reduce breaking difficulties are breaking instructions, tablet-splitters and breaking in advance. Factors influencing the performance of score lines are shape, size, curvature and thickness of the tablet and the form and deepness of the score line. Performance of score lines can be defined by breaking ease, uniformity of mass of subdivided tablets and loss of mass by the subdivision. For breaking ease, an in-vivo reference test and a routinely applicable in-vitro test need to be established. For the uniformity of mass of subdivided tablets a requirement has recently been set by the European Pharmacopoeia. Loss of mass upon breaking can be limited to not more than 1%.

Choice and validation of a near infrared spectroscopic application for the identity control of starting materials. practical experience with the EU draft Note for Guidance on the use of near infrared spectroscopy by the pharmaceutical industry and the data to be forwarded in part II of the dossier for a marketing authorization.

Recently the CPMP/CVMP sent out for consultation the draft Note for Guidance (dNfG) on the use of near infrared spectroscopy (NIRS) by the pharmaceutical industry and the data to be forwarded in part II of the dossier for a marketing authorization. We explored the practicability of this dNfG with respect to the verification of the correct identity of starting materials in a generic tablet-manufacturing site. Within the boundaries of the dNfG, a release procedure was developed for 12 substances containing structurally related compounds and substances differing only in particle size. For the method development literature data were also taken into consideration. Good results were obtained with wavelength correlation (WC), applied on raw spectra or second derivative spectra both without smoothing. The defined threshold of 0.98 for raw spectra differentiated between all molecular structures. Both methods were found to be robust over a period of 1 year. For the differentiation between the different particle sizes a subsequent second chemometric technique had to be used. Soft independent modelling of class analogy (SIMCA) with a probability level of 0.01 proved suitable. Internal and external validation I according to the dNfG showed no incorrect rejections or false acceptances. External validation II according to the dNfG was carried out with 95 potentially interfering substances from which 46 were tested experimentally. Macrogol 400 was not distinguished from macrogol 300. For the complete verification of the identity of macrogol 300 test A of the European Pharmacopoeia is needed in addition to the NIRS application. A release procedure developed with WC applied on raw spectra and SIMCA as a second method, which is different from the preferred method of the dNfG, was tested in practice with good results. We conclude that the dNfG has good practicability and that deviations from the preferred methods of the dNfG can also give good differentiation.

An improved in vitro method for the evaluation of antacids with in vivo relevance.

An improved in vitro method for the evaluation of antacids for use with standard equipment is described. The method is a modification of an older method (RIGO method) and has in vivo relevance. The improved method uses USP dissolution test apparatus 2 with a stirring rate of 125 rpm in combination with a computerized automatic burette. The test solution is 250 ml 0.02 M HCl. A total of 20 min after addition of an antacid to the test solution titration starts at a constant speed of 2.0 ml/min 0.1 M HCl. The proposed acceptance criteria for a waiver for clinical studies are: pH after 4 min not less than 2.5 to ensure a rapid onset of effect, pH after 20 min not exceeding 7.0 to ensure that the pH in the stomach remains within physiological values, buffering capacity between pH 2.5 and 4.5 not less than 8 meq/dose and neutralizing capacity not less than 10 meq/dose to ensure sufficient efficacy within the physiological range. The improved method has been validated with respect to robustness to variations in sample preparation, repeatability and intermediate precision and has been cross-validated versus the RIGO method. The improved method has been found to be rather insensitive to variations in sample pretreatment and at least equivalent to the RIGO method.

Equivalence testing and equivalence limits of metered-dose inhalers and dry powder inhalers measured by in vitro impaction.

In this study, criteria for the acceptability of comparative in vitro equivalence testing are proposed. Furthermore, the following equivalence limits for in vitro impaction methods are postulated: the 90% confidence interval (CI) of the in vitro deposition ratio of the test product and the reference product should lie within 0.80-1.20. The aim of this study was to challenge these limits by applying them to in vitro impaction results of several groups of pressurized metered-dose inhalers and dry powder inhalers containing salbutamol and beclomethasone dipropionate. The deposition results were obtained with the Twin Impinger. All products had a marketing authorization in The Netherlands and were considered therapeutically equivalent within each group. The postulated equivalence limits/group were challenged by fictitiously assigning a preparation as a test product or reference product and calculating the 90% CI of the deposition ratio of the test and reference products. All possible combinations of products within a group were tested. The products were considered equivalent if the 90% CI of the quotient lay within 0.80-1.20. In most cases, the quotient of the test product and reference product remains within 0.80-1.20, but due to a high variability in the deposition results of several products, the 90% CI of the quotient sometimes falls outside the proposed equivalence limits. It is concluded that the equivalence limits postulated are rather conservative, with respect to accepting equivalence. The limits can therefore serve as a prudent predictor of equivalence within the acceptability criteria proposed, but have to be further validated.

Biowaiver monographs for immediate release solid oral dosage forms based on biopharmaceutics classification system (BCS) literature data: verapamil hydrochloride, propranolol hydrochloride, and atenolol.

Literature data related to the Biopharmaceutics Classification System (BCS) are presented on verapamil hydrochloride, propranolol hydrochloride, and atenolol in the form of BCS-monographs. Data on the qualitative composition of immediate release (IR) tablets containing these active substances with a Marketing Authorization (MA) in the Netherlands (NL) are also provided; in view of these MA's the assumption was made that these tablets were bioequivalent to the innovator product. The development of a database with BCS-related data is announced by the International Pharmaceutical Federation (FIP).

An investigation into the predictive value of cascade impactor results for side effects of inhaled salbutamol.

The aim of this study was to compare the Multistage Liquid Impinger (MSLI) and the Andersen Cascade Impactor (ACI) with respect to their power to predict differences in side effects of salbutamol delivered by a dry powder inhaler. Three preparations with the same nominal dose and the same inhaler device but generating aerosols with different aerodynamic particle size distributions were administered to six healthy volunteers in a randomized, placebo-controlled, four-way crossover study. Cumulative doses from 400 up to 1600 microg were given. The serum potassium level (K+-serum) and the heart rate (HR) were measured at baseline and 15 min after each dose. Both the MSLI and ACI showed large differences between the aerodynamic particle size distributions of the three preparations. The decrease in K+-serum revealed significant differences between the three active preparations and was significant for doses of 800 microg and higher. The HR results showed differences between the active preparations only at a nominal dose of 1600 microg and only for the preparation with the highest fine particle dose (FPD) compared to the other two preparations. The K+-serum appears to be a more sensitive measure for side effects than the HR. In vivo-in vitro correlations (IVIVCs) were established between the amounts of salbutamol deposited on the various cumulative impactor stages and the K+-serum. The best IVIVCs were obtained in the FPD range, resulting in correlation coefficients of at least 0.78. It is concluded that cascade impactor results in the FPD range of the MSLI as well as the ACI correlate well with the K+-serum. Cascade impactor analysis thus provides a clinically meaningful tool in the development and the quality control of salbutamol inhalation powders.

Equivalence testing of salbutamol dry powder inhalers: in vitro impaction results versus in vivo efficacy.

The aim of the study was to evaluate several impactors for in vitro equivalence testing of salbutamol with respect to efficacy and to define in vitro equivalence limits validated with in vivo efficacy data. The four impactors described in Supplement 2000 of the European Pharmacopoeia were used: Glass Impinger (GI), Metal Impinger (MI), Multistage Liquid Impinger (MSLI) and Andersen Cascade Impactor (ACI). Three salbutamol dry powder formulations with different fine particle doses (FPDs) were prepared and the aerodynamic particle size distribution was measured. For each impactor also the recovery was determined. The same three preparations were administered to 12 asthmatic patients in a randomized, placebo-controlled, four-way crossover study. Cumulative doses from 50 microg up to 400 microg were given. The FEV(1) was measured at baseline and 15 min after each dose. The in vitro results showed large differences between the FPDs of the three preparations with all impactors, whereas only small differences were observed between the four impactors. Since the recoveries of the MI and GI were low, in vitro equivalence testing should only be performed with the MSLI or ACI. The in vivo measurements did not show significant differences in efficacy between the three active preparations, even at the most discriminatory dose of 50 microg. It is concluded that in case there are no relevant differences between delivered dose, inhalation device and excipients, for salbutamol dry powder inhalers equivalence can be assumed when the 90% confidence interval for the FPD ratio of the test product and reference product is within 0.50-1.20 and each of the two products has a FPD (particles <6 microm) of at least 10 microg.

Drug output of unvented jet nebulizers as a function of time.

Nebulizer drug output rate increases during the nebulization. For unvented jet nebulizers, a physical and mathematical model based on the efficiency of the nebulization process is presented for this phenomenon. Formulas are derived for the cumulative drug output and the drug output rate of the nebulization process. The model is compared with the model proposed by Coates et al. [J. Aerosol. Med. 11 (1998) 101]. Both models are supported by experimental literature data. Both models predict the experimental values well but the proposed model allows more easy prediction of the influence of small changes in the nebulization conditions and the calculation of the cumulative drug output for a related process. From literature data it is shown that the efficiency of an unvented jet nebulization process of diluted aqueous solutions is relatively insensitive to small changes in the concentration as well as to small changes in aspiration flow but is sensitive to the humidity of the compressor gas only.