Solid Oral Drug Products Research Articles

Guidance for Industry Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting

Biotechnology Law ReportVol. 28, No. 5 DOCUMENTSGuidance for Industry Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for AnticounterfeitingPublished Online:10 Dec 2009https://doi.org/10.1089/blr.2009.9935AboutSectionsPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetails Volume 28Issue 5Oct 2009 Information© 2009 Mary Ann Liebert, Inc.To cite this article:Guidance for Industry Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting.Biotechnology Law Report.Oct 2009.628-633.http://doi.org/10.1089/blr.2009.9935Published in Volume: 28 Issue 5: December 10, 2009PDF download

ChemInform Abstract: Regulatory Considerations in the Development of Low‐Dose Solid Oral Drug Products

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Aciclovir

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing (biowaiver) for the approval of immediate release (IR) solid oral dosage forms containing aciclovir are reviewed. Aciclovir therapeutic use and therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA) studies were also taken into consideration in order to ascertain whether a biowaiver can be recommended. According to the Biopharmaceutics Classification System (BCS) and considering tablet strengths up to 400 mg, aciclovir would be BCS Class III. However, in some countries also 800 mg tablets are available which fall just within BCS Class IV. Aciclovir seems not to be critical with respect to a risk for bioinequivalence, as no examples of bioinequivalence have been identified. It has a wide therapeutic index and is not used for critical indications. Hence, if: (a) the test product contains only excipients present in aciclovir solid oral IR drug products approved in ICH or associated countries, for instance as presented in this article; and (b) the comparator and the test product both are very rapidly dissolving, a biowaiver for IR aciclovir solid oral drug products is considered justified for all tablet strengths. © 2008 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:5061–5073, 2008

Computer simulations using GastroPlus™ to justify a biowaiver for etoricoxib solid oral drug products

Purpose The purpose of this study was to compare the dissolution behaviour of etoricoxib in different dissolution media and to establish in vitro/in vivo correlation (IVIVC) using computer simulations. Methods Drug solubility was measured in different media. The dissolution behaviour of etoricoxib was studied in the USP Apparatus 2 using different dissolution media. A dissolution transfer model was used to investigate if the drug stays in solution when the pH of the medium changes. Drug permeability assessment was performed using the caco-2 cell culture technique. The in vitro data were used as input functions in GastroPlus™ to simulate the in vivo profiles of the drug. Results Solubility of etoricoxib was highest at low pH, and there was no significant difference in the solubility observed between blank buffers and biorelevant media of similar pH. The drug remained solubilised when transferred into simulated intestinal fluids. Using the in vitro data as input function in Gastro Plus, an IVIVC was established. Further simulations confirmed that the drug absorption occurs similar to the absorption of an oral solution. Conclusions Due to the solubility behaviour within the physiological pH gradient of the gastrointestinal tract, etoricoxib can be classified as an intermediate class 1/2 drug rather than BCS class 2. In vitro results combined with in silico simulations using GastroPlus support scientifically that a biowaiver for immediate release etoricoxib solid oral dosage forms is justified.

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Pyrazinamide

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 pyrazinamide as the only active pharmaceutical ingredient (API) are reviewed. Pyrazinamide is BCS Class III, with linear absorption over a wide dosing range. The risk of bioinequivalence is estimated to be low. Depending on the definition used, pyrazinamide can be classified as a narrow therapeutic index (NTI) drug, which is usually a caveat to biowaiving but may be deemed acceptable if the Summary of Product Characteristics (SmPCs) of the test product stipulates the need for regular monitoring of liver function. It is concluded that a biowaiver can be recommended for IR solid oral dosage only when the test product (a) contains only excipients present in pyrazinamide IR solid oral drug products approved in ICH or associated countries, (b) these excipients are present in amounts normally used in IR solid oral dosage forms, (c) the test product is very rapidly dissolving, (d) the SmPC of the test product indicates the need for monitoring of the patient's liver function.

Biowaiver Monographs for Immediate Release Solid Oral Dosage forms: Metoclopramide Hydrochloride

Literature data are reviewed relevant to the decision for a biowaiver of immediate release (IR) solid oral dosage forms containing metoclopramide hydrochloride. In addition, new solubility data, obtained under Biopharmaceutics Classification System (BCS) conditions are presented. Metoclopramide HCl is conservatively assigned to BCS Class III. Taken also into consideration excipient interactions reported in metoclopramide drug products, its pharmacokinetic properties and therapeutic use and therapeutic index, a biowaiver can be recommended when: (a) the test product contains only excipients present also in metoclopramide HCl containing IR solid oral drug products approved in ICH or associated countries, for instance as presented in this paper, (b) in amounts in normal use in IR solid oral dosage forms, and (c) the test product and the comparator both comply with the criteria for very rapidly dissolving.

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: 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: Acetaminophen (paracetamol)

Literature data are reviewed on the properties of acetaminophen (paracetamol) related to the biopharmaceutics classification system (BCS). According to the current BCS criteria, acetaminophen is BCS Class III compound. Differences in composition seldom, if ever, have an effect on the extent of absorption. However, some studies show differences in rate of absorption between brands and formulations. In particular, sodium bicarbonate, present in some drug products, was reported to give an increase in the rate of absorption, probably caused by an effect on gastric emptying. In view of Marketing Authorizations (MAs) given in a number of countries to acetaminophen drug products with rapid onset of action, it is concluded that differences in rate of absorption were considered therapeutically not relevant by the Health Authorities. Moreover, in view of its therapeutic use, its wide therapeutic index and its uncomplicated pharmacokinetic properties, in vitro dissolution data collected according to the relevant Guidances can be safely used for declaring bioequivalence (BE) of two acetaminophen formulations. Therefore, accepting a biowaiver for immediate release (IR) acetaminophen solid oral drug products is considered scientifically justified, if the test product contains only those excipients reported in this paper in their usual amounts and the test product is rapidly dissolving, as well as the test product fulfils the criterion of similarity of dissolution profiles to the reference product.

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.

Is the use of a 200 ml vessel suitable for dissolution of low dose drug products?

This work evaluated the use of a commercially available 200 ml vessel for dissolution of five drug products with various solubilities. Each of the five drug products (four with USP monographs and one proprietary tablet formulation) was run at four different conditions (USP 25 monograph, six dosage units in single 1 l vessel, 200 ml at the USP Monograph speed, and 200 ml at calculated paddle speed which matches the hydrodynamics of the USP vessel). Six dosage units in a single vessel were used as a comparison to increase the drug concentration for dissolution testing. Due to the different dissolution hydrodynamics, drug dissolution from the dosage forms was slower using the 200 ml conversion kit than when the USP method with a 1 l vessel was used. However, use of the 200 ml vessel at higher paddle speeds calculated by the power/volume equation, yielded similar results as the monograph method. Thus, it appears that using the power/volume ratio calculation to obtain comparable hydrodynamics lends utility to the 200 ml vessel as a means for characterizing the dissolution profile of low dose solid oral drug products. The results of the multiple dosage units per vessel also gave similar results to that of the USP monograph method.

Evaluation of key sources of variability in the measurement of pharmaceutical drug products by near infrared reflectance spectroscopy

Potential sources of variability in the measurement of solid oral drug products by near infrared reflectance spectroscopy were evaluated with statistical experimental design. Spectra were collected for two different tablet types according to the data collection and treatment parameters defined by the experimental design. Each tablet had three different dose-levels. Libraries were constructed using second-derivative spectra. Key figures-of-merit generated during internal and external library validation were used to calculate which parameters most strongly influence the library performance for dose-level discrimination. These responses and their corresponding experimental conditions were evaluated with the screening model in the JMP® program. Segment value used for the second-derivative calculation was an influential factor and had a complex effect. Orientation on the sampling platform also had an influential effect for embossed tablets. Collection of spectra over fewer days decreased variability within the library. More frequent reference spectrum collection improved the performance of libraries to a small degree. A larger sample population increased the range of spectral variability within a dose-level but apparently not the overall performance of the library. The number of scans averaged per spectrum was not an influential factor in this study. These results are summarized and used to recommend an approach to dose-level discrimination.

New Regulation Requires Imprinting on Solid Oral Dosage Form Drug Products

New Regulation Requires Imprinting on Solid Oral Dosage Form Drug Products