Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Ciprofloxacin Hydrochloride

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of new multisource and reformulated immediate release (IR) solid oral dosage forms containing ciprofloxacin hydrochloride as the only active pharmaceutical ingredient (API) are reviewed. Ciprofloxacin hydrochloride's solubility and permeability, its therapeutic use and index, pharmacokinetics, excipient interactions and reported BE/bioavailability (BA) problems were taken into consideration. Solubility and BA data indicate that ciprofloxacin hydrochloride is a BCS Class IV drug. Therefore, a biowaiver based approval of ciprofloxacin hydrochloride containing IR solid oral dosage forms cannot be recommended for either new multisource drug products or for major scale-up and postapproval changes (variations) to existing drug products.     

Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Zidovudine (Azidothymidine)

Literature data on the properties of zidovudine relevant to waiver of in vivo bioequivalence (BE) testing requirements for the approval of immediate-release (IR) solid oral dosage forms containing zidovudine alone or in combination with other active pharmaceutical ingredients (APIs) are reviewed. Solubility, dissolution, and permeability data for zidovudine, along with its dosing schedule, therapeutic index and pharmacokinetic properties, and reports related to BE/bioavailability were all taken into consideration. Data for solubility and permeability suggest that zidovudine belongs to Class I according to the Biopharmaceutics Classification System. Also, zidovudine is not a narrow therapeutic index drug. Although five out of 13 formulations tested in vivo (mostly of unreported composition) failed to show BE, it appears that in vitro studies performed according to biowaiver methods could predict in vivo behavior. Nevertheless, it is highly recommended that if a biowaiver is to be applied, excipient choices be limited to those found in IR drug products approved in International Conference on Harmonisation (ICH) or associated countries in the same dosage form (Table 2 of this monograph), in their usual amounts. These conclusions apply to products containing zidovudine as the only API and also to fixed combination products containing zidovudine with respect to the zidovudine component of the formulation. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2409–2423, 2013     

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Furosemide

Literature and new experimental 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 furosemide are reviewed. The available data on solubility, oral absorption, and permeability are sufficiently conclusive to classify furosemide into Class IV of the Biopharmaceutics Classification System (BCS). Furosemide’s therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA) problems are also taken into consideration. In view of the data available, it is concluded that the bio waiver procedure cannot be justified for either the registration of new multisource drug products or major postapproval changes (variations) to existing drug products. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:2544-2556, 2010     

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: Ketoprofen

Literature and experimental 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 ketoprofen are reviewed. Ketoprofen's solubility and permeability, its therapeutic use and therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions, and reported BE/bioavailability (BA)/dissolution data were taken into consideration. The available data suggest that according to the current Biopharmaceutics Classification System (BCS) and all current guidances, ketoprofen is a weak acid that would be assigned to BCS Class II. The extent of ketoprofen absorption seems not to depend on formulation or excipients, so the risk of bioinequivalence in terms of area under the curve is very low, but the rate of absorption (i.e., BE in terms of peak plasma concentration, C_max) can be altered by formulation. Current in vitro dissolution methods may not always reflect differences in terms of C_max for BCS Class II weak acids; however, such differences in absorption rate are acceptable for ketoprofen with respect to patient risks. As ketoprofen products may be taken before or after meals, the rate of absorption cannot be considered crucial to drug action. Therefore, a biowaiver for IR ketoprofen solid oral dosage form is considered feasible, provided that (a) the test product contains only excipients present also in IR solid oral drug products containing ketoprofen, which are approved in International Conference on Harmonisation or associated countries, for instance, as presented in this paper; (b) both the test drug product and the comparator dissolve 85% in 30 min or less in pH 6.8 buffer; and (c) test product and comparator show dissolution profile similarity in pH 1.2, 4.5, and 6.8. When one or more of these conditions are not fulfilled, BE should be established in vivo.     

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Piroxicam

Literature and experimental 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 piroxicam in the free acid form are reviewed. Piroxicam solubility and permeability, its therapeutic use and therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA), and corresponding dissolution data are taken into consideration. The available data suggest that according to the current biopharmaceutics classification system (BCS) and all current guidances, piroxicam would be assigned to BCS Class II. The extent of piroxicam absorption seems not to depend on manufacturing conditions or excipients, so the risk of bioinequivalence in terms of area under the curve (AUC) is very low, but the rate of absorption (i.e., BE in terms of C_max) can be affected by the formulation. Current in vitro dissolution methods may not always reflect differences in terms of C_max for BCS Class II weak acids; however, minor differences in absorption rate of piroxicam would not subject the patient to unacceptable risks: as piroxicam products may be taken before or after meals, the rate of absorption cannot be considered crucial to drug action. Therefore, a biowaiver for IR piroxicam solid oral dosage form is considered feasible, provided that (a) the test product contains only excipients, which are also present in IR solid oral drug products containing piroxicam, which have been approved in ICH or associated countries, for instance, those presented in Table 3 of this paper; (b) both the test and comparator drug products dissolve 85% in 30 min or less at pH 1.2, 4.5, and 6.8; and (c) the test product and comparator show dissolution profile similarity in pH 1.2, 4.5, and 6.8. When not all of these conditions can be fulfilled, BE of the products should be established in vivo.     

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Proguanil Hydrochloride

Literature data relevant to the decision to waive in vivo bioequivalence testing for the approval of generic immediate release solid oral dosage forms of proguanil hydrochloride are reviewed. To elucidate the Biopharmaceutics Classification System (BCS) classification, experimental solubility and dissolution studies were also carried out. The antimalarial proguanil hydrochloride, effective via the parent compound proguanil and the metabolite cycloguanil, is not considered to be a narrow therapeutic index drug. Proguanil hydrochloride salt was shown to be highly soluble according to the U.S. Food and Drug Administration, World Health Organization, and European Medicines Agency guidelines, but data for permeability are inconclusive. Therefore, proguanil hydrochloride is conservatively classified as a BCS class 3 substance. In view of this information and the assessment of risks associated with a false positive decision, a BCS-based biowaiver approval procedure can be recommended for orally administered solid immediate release products containing proguanil hydrochloride, provided well-known excipients are used in usual amounts and provided the in vitro dissolution of the test and reference products is very rapid (85% or more are dissolved in 15 min at pH 1.2, 4.5, and 6.8) and is performed according to the current requirements for BCS-based biowaivers.     

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Amodiaquine Hydrochloride

The present monograph reviews data relevant to applying the biowaiver procedure for the approval of immediate release (IR) multisource solid dosage forms containing amodiaquine hydrochloride (ADQ) as the single active pharmaceutical ingredient (API). Both biopharmaceutical and clinical data of ADQ were assessed. Solubility studies revealed that ADQ meets the “highly soluble” criteria according to World Health Organization (WHO) and European Medicines Agency (EMA) but fails to comply with the United States Food and Drug Administration (US FDA) specifications. Although metabolism hints at high permeability, available permeability data are too scanty to classify ADQ inequivocably as a Class I drug substance. According to WHO and EMA guidances, ADQ would be conservatively categorized as a Class III drug, whereas according to the US FDA specifications, it would fall into Class IV. ADQ has a wide therapeutic index. Furthermore, no cases of bioinequivalent products have been reported in the open literature. As risks associated with biowaiving appear minimal and requirements for “highly soluble” API are met in the WHO and EMA jurisdictions, the biowaiver procedure can be recommended for bioequivalence (BE) testing of multisource IR products containing ADQ as the only API, provided the test product contains excipients used in ADQ products approved in International Conference of Harmonisation and associated countries, and in similar amounts. Furthermore, both comparator and test should conform to “very rapidly dissolving” product criteria (≥85% dissolution of the API in 15 min at pH 1.2, 4.5, and 6.8) and the labeling should specify that the product not be coadministered with high‐fat meals. If the comparator and/or test product fails to meet these criteria, BE needs to be established by pharmacokinetic studies in humans. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:4390–4401, 2012     

Biowaiver monographs for immediate release solid oral dosage forms: Doxycycline hyclate

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 doxycycline hyclate are reviewed. According to the Biopharmaceutics Classification System (BCS), doxycycline hyclate can be assigned to BCS Class I. No problems with BE of IR doxycycline formulations containing different excipients and produced by different manufacturing methods have been reported and hence the risk of bioinequivalence caused by these factors appears to be low. Doxycycline has a wide therapeutic index. Further, BCS-based dissolution methods have been shown to be capable of identifying formulations which may dissolve too slowly to generate therapeutic levels. It is concluded that a biowaiver is appropriate for IR solid oral dosage forms containing doxycycline hyclate as the single Active Pharmaceutical Ingredient (API) provided that (a) the test product contains only excipients present in doxycycline hyclate IR solid oral drug products approved in the International Conference on Harmonization (ICH) or associated countries; and (b) the comparator and the test products comply with the BCS criteria for “very rapidly dissolving” or, alternatively, when similarity of the dissolution profiles can be demonstrated and the two products are “rapidly dissolving.”. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1639–1653, 2010     

Biowaiver monographs for immediate-release solid oral dosage forms: primaquine phosphate

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 the antimalarial drug primaquine phosphate as the only active pharmaceutical ingredient (API) are reviewed. On the basis of permeability data and solubility studies, primaquine phosphate was found to be "highly soluble" and "highly permeable" API, thus conforming to Class I of the Biopharmaceutical Classification System (BCS). It has a wide therapeutic index. BCS-conform dissolution studies showed the products to be rapidly dissolving. No data pertaining to BE or bioinequivalence of IR primaquine phosphate products could be located in open literature. On the basis of the available data, a biowaiver-procedure-based approval can be recommended for IR solid oral dosage forms of primaquine phosphate, provided the generic product contains excipients present in products already approved by the International Conference on Harmonisation or associated countries in similar amounts and the test and reference products meet the dissolution criteria for "rapidly dissolving" (>85% drug release in 30 min in standard media at pH 1.2, 4.5, and 6.8; similarity factor (f(2)) > 50) or "very rapidly dissolving" products (>85% drug release in 15 min in standard media at pH 1.2, 4.5, and 6.8).     

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Efavirenz

Literature data pertaining to the decision to allow a waiver of in vivo bioequivalence testing for the approval of immediate-release (IR) solid oral dosage forms containing efavirenz as the only active pharmaceutical ingredient (API) are reviewed. Because of lack of conclusive data about efavirenz's permeability and its failure to comply with the “high solubility” criteria according to the Biopharmaceutics Classification System (BCS), the API can be classified as BCS Class II/IV. In line with the solubility characteristics, the innovator product does not meet the dissolution criteria for a “rapidly dissolving product.” Furthermore, product variations containing commonly used excipients or in the manufacturing process have been reported to impact the rate and extent of efavirenz absorption. Despite its wide therapeutic index, subtherapeutic levels of efavirenz can lead to treatment failure and also facilitate the emergence of efavirenz-resistant mutants. For all these reasons, a biowaiver for IR solid oral dosage forms containing efavirenz as the sole API is not scientifically justified for reformulated or multisource drug products. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:318–329, 2013     

Applications of In Vitro–In Vivo Correlations in Generic Drug Development: Case Studies

In vitro–in vivo correlation (IVIVC) is a predictive mathematical model describing the relationship between an in vitro property and a relevant in vivo response. The main objective of an IVIVC is to serve as a surrogate for human bioequivalence (BE) studies, which may reduce the number of BE studies performed during the initial approval process as well as with certain scale-up and postapproval changes. The US Food and Drug Administration (FDA) published a regulatory guidance related to development, evaluation, and applications of IVIVC for extended-release (ER) oral dosage forms in September 1997. Despite the publication of this guidance, the deficiencies related to IVIVC are still identified by the Division of Bioequivalence in the process of Abbreviated New Drug Application (ANDA) review. Thus, the main objective of this article is to present the most commonly occurring deficiencies associated with IVIVCs via selected case studies from the ANDAs for oral ER drug products only. We searched internal FDA databases from January 1996 to December 2014 to identify the ANDAs for proposed generic oral ER drug products containing IVIVC. Only 14 ANDA submissions had IVIVC data, and most were not acceptable. Only one ANDA submission included adequate information related to IVIVC data enabling the completion of BE review within first review cycle. It is hoped that awareness of the deficiencies presented in our article would help the generic drug applicants to submit complete and appropriate information related to IVIVC data, ultimately, resulting in a more timely approval of ANDAs.KEY WORDS: bioequivalence, extended-release drug products, generics, IVIVC, SUPAC     

Biowaiver monographs for immediate release solid oral dosage forms: quinidine sulfate

Literature data are reviewed relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of new multisource and reformulated immediate release (IR) solid oral dosage forms containing quinidine sulfate. Quinidine sulfate's solubility and permeability, its therapeutic use and index, pharmacokinetics, excipient interactions and reported BE/bioavailability (BA) problems were taken into consideration. The available data are not fully conclusive, but do suggest that quinidine sulfate is highly soluble and moderately to highly permeable and would likely be assigned to BCS Class I (or at worst BCS III). In view of the inconclusiveness of the data and, more important, quinidine's narrow therapeutic window and critical indication, a biowaiver based approval of quinidine containing dosage forms cannot be recommended for either new multisource drug products or for major postapproval changes (variations) to existing drug products.     

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Bisoprolol Fumarate

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 bisoprolol as the sole active pharmaceutical ingredient (API) are reviewed. Bisoprolol is classified as a Class I API according to the current Biopharmaceutics Classification System (BCS). In addition to the BCS class, its therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions, and reported BE/bioavailability problems are taken into consideration. Qualitative compositions of IR tablet dosage forms of bisoprolol with a marketing authorization (MA) in ICH (International Conference on Harmonisation) countries are tabulated. It was inferred that these tablets had been demonstrated to be bioequivalent to the innovator product. No reports of failure to meet BE standards have been made in the open literature. On the basis of all these pieces of evidence, a biowaiver can currently be recommended for bisoprolol fumarate IR dosage forms if (1) the test product contains only excipients that are well known, and used in normal amounts, for example, those tabulated for products with MA in ICH countries and (2) both the test and comparator dosage form are very rapidly dissolving, or, rapidly dissolving with similarity of the dissolution profiles demonstrated at pH 1.2, 4.5, and 6.8. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:378–391, 2014     

Biowaiver monograph for immediate-release solid oral dosage forms: acetylsalicylic acid

A biowaiver monograph for acetylsalicylic acid (ASA) is presented. Literature and experimental data indicate that ASA is a highly soluble and highly permeable drug, leading to assignment of this active pharmaceutical ingredient (API) to Class I of the Biopharmaceutics Classification System (BCS). Limited bioequivalence (BE) studies reported in the literature indicate that products that have been tested are bioequivalent. Most of the excipients used in products with a marketing authorization in Europe are not considered to have an impact on gastrointestinal motility or permeability. Furthermore, ASA has a wide therapeutic index. Thus, the risks to the patient that might occur if a nonbioequivalent product were to be incorrectly deemed bioequivalent according to the biowaiver procedure appear to be minimal. As a result, the BCS-based biowaiver procedure can be recommended for approval of new formulations of solid oral dosage forms containing ASA as the only API, including both multisource and reformulated products, under the following conditions: (1) excipients are chosen from those used in ASA products already registered in International Conference on Harmonization and associated countries and (2) the dissolution profiles of the test and the comparator products comply with the BE guidance.     

Biowaiver monographs for immediate release solid oral dosage forms: acetazolamide

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 acetazolamide are reviewed. Acetazolamide'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 are taken into consideration. The available data on solubility, on oral absorption and permeability are not sufficiently conclusive to classify acetazolamide with certainty. Taking a conservative approach, no biowaiver is considered justified for the registration of new multisource drug products. However, SUPAC level 1 and level 2 postapproval changes and most EU Type I variations can be approved waiving in vivo BE studies.     

Influence of Drug Properties and Formulation on <Emphasis Type="Italic">In Vitro</Emphasis> Drug Release and Biowaiver Regulation of Oral Extended Release Dosage Forms

Bioequivalence (BE) studies are often required to ensure therapeutic equivalence for major product and manufacturing changes. Waiver of a BE study (biowaiver) is highly desired for such changes. Current regulatory guidelines allow for biowaiver of proportionally similar lower strengths of an extended release (ER) product provided it exhibits similar dissolution to the higher strength in multimedia. The objective of this study is to demonstrate that (1) proportionally similar strengths of ER tablets exhibiting similar in vitro dissolution profiles do not always assure BE and (2) different strengths that do not meet the criteria for dissolution profile similarity may still be bioequivalent. Four marketed ER tablets were used as model drug products. Higher and lower (half) strength tablets were prepared or obtained from commercial source. In vitro drug release was compared using multi-pH media (pH 1.2, 4.5, 6.8) per regulatory guidance. In vivo performance was assessed based on the available in vivo BE data or established in vitro-in vivo relationships. This study demonstrated that the relationship between in vitro dissolution and in vivo performance is complex and dependent on the characteristics of specific drug molecules, product design, and in vitro test conditions. As a result, proportionally similar strengths of ER dosage forms that meet biowaiver requirements per current regulatory guidelines cannot ensure bioequivalence in all cases. Thus, without an established relationship between in vitro and in vivo performance, granting biowaiver based on passing in vitro tests may result in the approval of certain bioinequivalent products, presenting risks to patients. To justify any biowaiver using in vitro test, it is essential to understand the effects of drug properties, formulation design, product characteristics, test method, and its in vivo relevance. Therefore, biowaiver requirements of different strengths of ER dosage forms specified in the current regulatory guidance should be reevaluated to assure consistent safety and efficacy among different strengths.     

Biowaiver monographs for immediate release solid oral dosage forms: lamivudine

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 lamivudine as the only active pharmaceutical ingredient were reviewed. The solubility and permeability data of lamivudine as well as its therapeutic index, its pharmacokinetic properties, data indicating excipient interactions, and reported BE/bioavailability (BA) studies were taken into consideration. Lamivudine is highly soluble, but its permeability characteristics are not well-defined. Reported BA values in adults ranged from 82% to 88%. Therefore, lamivudine is assigned to the biopharmaceutics classification system (BCS) class III, noting that its permeability characteristics are near the border of BCS class I. Lamivudine is not a narrow therapeutic index drug. Provided that (a) the test product contains only excipients present in lamivudine IR solid oral drug products approved in the International Conference on Harmonization or associated countries in usual amounts and (b) the test product as well as the comparator product fulfills the BCS dissolution criteria for very rapidly dissolving; a biowaiver can be recommended for new lamivudine multisource IR products and major post-approval changes of marketed drug products.     

Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Codeine Phosphate

The present monograph reviews data relevant to applying the biowaiver procedure for the approval of immediate-release multisource solid dosage forms containing codeine phosphate. Both biopharmaceutical and clinical data of codeine were assessed. Solubility studies revealed that codeine meets the “highly soluble” criteria according to World Health Organization (WHO), the European Medicines Agency (EMA), and the United States Food and Drug Administration (US FDA). Codeine's fraction of dose absorbed in humans was reported to be high (>90%) based on cumulative urinary excretion of drug and drug-related material following oral administration. The permeability of codeine was also assessed to be high in both Caco-2 monolayers and rat intestinal perfusion studies. The main risks associated with codeine, that is, toxicity (attributed to CYP2D6 polymorphism) and its abuse potential, are present irrespective of the dosage form, and do not need to be taken into account for bioequivalence (BE) considerations. Taken together, codeine is a class 1 drug with manageable risk and is a good candidate for waiver of in vivo BE studies. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1592–1600, 2014     

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.