Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Fexofenadine.

In this monograph, the potential use of methods based on the Biopharmaceutics Classification System (BCS) framework to evaluate the bioequivalence of solid immediate-release (IR) oral dosage forms containing fexofenadine hydrochloride as a substitute for a pharmacokinetic study in human volunteers is investigated. We assessed the solubility, permeability, dissolution, pharmacokinetics, pharmacodynamics, therapeutic index, bioavailability, drug-excipient interaction, and other properties using BCS recommendations from the ICH, FDA and EMA. The findings unequivocally support fexofenadine's classification to BCS Class IV as it is neither highly soluble nor highly permeable. Further impeding the approval of generic equivalents through the BCS-biowaiver pathway is the reference product's inability to release ≥ 85 % of the drug substance within 30 min in pH 1.2 and pH 4.5 media. According to ICH rules, BCS class IV drugs do not qualify for waiving clinical bioequivalence studies based on the BCS, even though fexofenadine has behaved more like a BCS class I/III than a class IV molecule in pharmacokinetic studies to date and has a wide therapeutic index.

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Isavuconazonium Sulfate.

A Biopharmaceutics Classification System (BCS)-based biowaiver monograph is presented for isavuconazonium sulfate. A BCS-based biowaiver is a regulatory option to substitute appropriate in vitro data for in vivo bioequivalence studies. Isavuconazonium sulfate is the prodrug of isavuconazole, a broad-spectrum azole antifungal indicated for invasive fungal infections. While the prodrug can be classified as a BCS Class III drug with high solubility but low permeability, the parent drug can be classified as a BCS Class II drug with low solubility but high permeability. Interestingly, the in vivo behavior of both is additive and leads isavuconazonium sulfate to act like a BCS class I drug substance after oral administration. In this work, experimental solubility and dissolution data were evaluated and compared with available literature data to investigate whether it is feasible to approve immediate release solid oral dosage forms containing isavuconazonium sulfate according to official guidance from the FDA, EMA and/or ICH. The risks associated with waiving a prodrug according to the BCS-based biowaiver guidelines are reviewed and discussed, noting that current regulations are quite restrictive on this point. Further, results show high solubility but instability of isavuconazonium sulfate in aqueous media. Although experiments on the dissolution of the capsule contents confirmed 'very rapid' dissolution of the active pharmaceutical ingredient (API) isavuconazonium sulfate, its release from the commercial marketed capsule formulation Cresemba is limited by the choice of capsule shell material, providing an additional impediment to approval of generic versions via the BCS-Biowaiver approach.

Biowaiver Monograph for Immediate-Release Dosage Forms: Levamisole Hydrochloride.

This work describes the potential applicability of the BCS-based Biowaiver to oral solid dosage forms containing Levamisole hydrochloride, an anthelmintic drug on the WHO List of Essential Medicines. Solubility and permeability data of levamisole hydrochloride were searched in the literature and/or measured experimentally. Levamisole hydrochloride is a highly soluble drug, but there is no clear evidence of high permeability in humans, indicating that it should provisionally be assigned to BCS class III. The biowaiver procedure would thus be applicable for solid oral dosage forms containing levamisole hydrochloride as the only active ingredient. Due to the lack of data in the literature regarding excipient effects on the bioequivalence of products containing levamisole, it is currently recommended that the products comply with the ICH and WHO guidelines: the test formulation should have the same qualitative composition as the comparator, contain very similar quantities of those excipients, and be very rapidly dissolving at pH 1.2, 4.5, and 6.8. However, for certain well-studied excipients, there appears to be opportunity for additional regulatory relief in future versions of the ICH BCS Guidance M9, such as not requiring that the quantities of these common excipients in the test and comparator be the same.

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Levocetirizine Dihydrochloride.

Levocetirizine, a histamine H1-receptor antagonist, is prescribed to treat uncomplicated skin rashes associated with chronic idiopathic urticaria as well as the symptoms of both seasonal and continual allergic rhinitis. In this monograph, the practicality of using Biopharmaceutics Classification System (BCS) based methodologies as a substitute for pharmacokinetic studies in human volunteers to appraise the bioequivalence of immediate-release (IR) oral, solid dosage forms containing levocetirizine dihydrochloride was investigated, using data from the literature and in-house testing. Levocetirizine's solubility and permeability properties, as well as its dissolution from commercial products, its therapeutic uses, therapeutic index, pharmacokinetics and pharmacodynamic traits, were reviewed in accordance with the BCS, along with any reports in the literature about failure to meet bioequivalence (BE) requirements, bioavailability issues, drug-excipient interactions as well as other relevant information. The data presented in this monograph unequivocally point to classification of levocetirizine in BCS Class 1. For products that are somewhat supra-equivalent or somewhat sub-equivalent, clinical risks are expected to be insignificant in light of levocetirizine's wide therapeutic index and unlikelihood of severe adverse effects. After careful consideration of all the information available, it was concluded that the BCS-based biowaiver can be implemented for products which contain levocetirizine dihydrochloride, provided (a) the test product comprises excipients that are typically found in IR oral, solid drug products that have been approved by a country belonging to or associated with ICH and are used in quantities that are typical for such products, (b) data supporting the BCS-based biowaiver are gathered using ICH-recommended methods, and (c) all in vitro dissolution requirements specified in the ICH guidance are met by both the test and comparator products (in this case, the comparator is the innovator product).

In vitro release test (IVRT): Principles and applications.

In vitro drug release test has become one of the most important tools for drug development and approval process of semisolid dosage forms. In vitro release test (IVRT) has the ability to reflect the combined effects of several physicochemical characteristics, particle or droplet size, viscosity, microstructure arrangement of the matter and state of aggregation of dosage form. Genesis of IVRT, its principles and rank order relationship with pharmacodynamic response such as vasoconstriction or dermatopharmacokinetic (skin stripping) results and the evolution of test requirements for regulatory approval is discussed. IVRT reflects various parameters and is an essential part of the stepwise approach to compare topical formulation and its ability to release active in similar quantity at similar rate. Therefore, it is an essential tool, in addition to similar qualitative and quantitative composition (Q1 Q2), to assess the similarity of microstructural arrangement (Q3) as proposed in the Topical drug Classification System (TCS) approach of classes 1 and 3. The TCS system along with evolving concept for topical dermatological drug products from Q1, Q2, Q3 sameness to Q1, Q2, Q3 similar allowing greater permissiveness in formulation changes is discussed.

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Sitagliptin Phosphate Monohydrate.

Sitagliptin is an antihyperglycemic drug used in adults for the treatment of diabetes Type 2. Literature data and in-house experiments were applied in this monograph to assess whether methods based on the Biopharmaceutics Classification System (BCS) could be used to assess the bioequivalence of solid immediate-release (IR) oral dosage forms containing sitagliptin phosphate monohydrate, as an alternative to a pharmacokinetic study in human volunteers. The solubility and permeability characteristics of sitagliptin were reviewed according to the BCS, along with dissolution, therapeutic index, therapeutic applications, pharmacokinetics, pharmacodynamic characteristics, reports of bioequivalence (BE) / bioavailability problems, data on interactions between the drug and excipients and other data germane to the subject. All data reviewed in this monograph unambiguously support classification of sitagliptin as a BCS Class 1 drug. In light of its broad therapeutic index and lack of severe adverse effects, the clinical risks associated with moderately supraoptimal doses were deemed inconsequential, as were the risks associated with moderately suboptimal doses. Taking all evidence into consideration, it was concluded that the BCS-based biowaiver can be implemented for solid IR oral drug products containing sitagliptin phosphate monohydrate, provided (a) the test product is formulated solely with excipients commonly present in solid IR oral drug products approved in ICH or associated countries and used in amounts commonly applied in this type of product, (b) data in support of the BCS-based biowaiver are obtained using the methods recommended by the WHO, FDA, EMA or ICH and (c) the test product and the comparator product (which is the innovator product in this case) meet all in vitro dissolution specifications provided in the WHO, FDA, EMA or ICH guidance.

Are European marketed acyclovir 5% cream products similar? Comparison with EU and US reference product.

OBJECTIVE: The aim was to perform a comparative evaluation of composition and in vitro release performance of multisource acyclovir 5% creams. SIGNIFICANCE: The outcome was analyzed in relation with the principles of the Topical drug Classification System (TCS). METHODS: The in vitro drug release testing (IVRT) was based on selection of an inert artificial membrane and a medium providing sink conditions, and utilizing the vertical diffusion cells. US and European innovator products, with marked difference in excipients, were used as references for the assessment of the in vitro release similarity. The qualitative composition of the topical semisolid products was inventoried, with no quantitative details being available. A Principal Component Analysis was applied by either dichotomy ranking or grouping the individual excipients into categories according to their functional role. RESULTS: The results confirmed the sensitivity and discriminative characteristics of IVRT with respect to the qualitative composition, as well as its relevance in the comparative assessment of multisource drug products beyond the current strict requirements of Q1 and Q2 similarity. CONCLUSIONS: This is in line with the principles of the TCS and with the central role assigned to IVRT.

A pragmatic regulatory approach for complex generics through the U.S. FDA 505(j) or 505(b)(2) approval pathways.

The diverse nature of complex drug products poses challenges for the development of regulatory guidelines for generic versions. While complexity is not new in medicines, the technical capacity to measure and analyze data has increased. This requires a determination of which measurements and studies are relevant to demonstrate therapeutic equivalence. This paper describes the views of the NBCD Working Group and provides pragmatic solutions for approving complex generics by making best use of existing U.S. Food and Drug Administration's abbreviated approval pathways 505(j) and 505(b)(2). We argue that decisions on the appropriateness of submitting a 505(j) or 505(b)(2) application can build on the FDA's complex drug product classification as well as the FDA's much applauded guidance document for determining whether to submit an ANDA or a 505(b)(2) application. We hope that this paper contributes to the discussions to increase the clarity of regulatory approaches for complex generics, as well as the predictability for complex generic drug developers, to facilitate access to much-needed complex generics and to promote the sustainability of the healthcare system.

Rheological and in vitro release measurements of manufactured acyclovir 5% creams: confirming sensitivity of the in vitro release.

Previous evaluation of marketed acyclovir 5% creams using in vitro release testing (IVRT) and its correlation with the qualitative composition confirmed the discriminative characteristics of this methodology. This was in line with the principles of Topical drug Classification System (TCS). For the current research, experimental formulations were designed and prepared by applying controlled changes in manufacturing process, sources of raw materials, and amount of the excipients. The topical semisolids were representative for the four classes of TCS. The outcome of the IVRT and rheological assessments was evaluated in relation with the nature of the change and the functional role of the excipients. The variations in propylene glycol content from 5% to 40% impacted both the in vitro release rates (gradual decrease from 16.23 to 8.97 µg/cm2/min0.5) and the microstructural characteristics (proportional increase of yield stress from 17.98 to 46.40 Pa). The inert excipients e.g. cetostearyl alcohol or white soft paraffin altered majorly the rheological behavior, as their functionality is mainly related to vehicle properties. IVRT was discriminative for the microstructural differences induced by both categories of excipients according to TCS dichotomy. This simple, reliable, and reproducible test reflected the impact of difference in quantitative composition and characteristics of excipients.

Tackling the challenges of nanomedicines: are we ready?

PURPOSE: This review provides an overview of the proceedings of the symposium "Tackling the Challenges of Nanomedicines: Are We Ready?" organized by the International Pharmaceutical Federation (FIP) Hospital Pharmacy Section and Non-Biological Complex Drugs (NBCDs) Working Group at the 2019 FIP World Congress of Pharmacy and Pharmaceutical Sciences. Debate centered on reasons underlying the current complex regulatory landscape for nanomedicines and their follow-on products (referred to as nanosimilars) and the pivotal role of hospital pharmacists in selecting, handling, and guiding usage of nanomedicines and nanosimilars. SUMMARY: The evaluation and use of nanomedicines are recognized among scientific, pharmaceutical, and regulatory bodies as complex. Interchangeability and substitutability of nanomedicines and nanosimilars are confounded by a lack of pharmaceutical and pharmacological equivalence, reflecting the inherent complex nature of these drug products and manufacturing processes. Consequences include implications for clinical safety and efficacy and, ultimately, comparability. Local regulatory approvals of some nanomedicines have occurred, but there is no standard to ensure streamlined evaluation and use of consistent measures of therapeutic equivalence of reference products and their nanosimilars. Hospital pharmacists are expected to be experts in the selection, handling, and substitution of nanomedicines and familiarize themselves with the limitations of current methods of assessing pharmaceutical and clinical equivalence of nanosimilars in order to ensure informed formulary decision-making and eventual patient benefit. CONCLUSION: Supportive guidance for pharmacists focusing on the substitutability and/or interchangeability of nanomedicines and their nanosimilars is needed. Current FIP guidance for pharmacists on therapeutic interchange and substitution should be extended to include nanomedicines and nanosimilars.

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Carbamazepine.

Literature relevant to assessing whether BCS-based biowaivers can be applied to immediate release (IR) solid oral dosage forms containing carbamazepine as the single active pharmaceutical ingredient are reviewed. Carbamazepine, which is used for the prophylactic therapy of epilepsy, is a non-ionizable drug that cannot be considered "highly soluble" across the range of pH values usually encountered in the upper gastrointestinal tract. Furthermore, evidence in the open literature suggests that carbamazepine is a BCS Class 2 drug. Nevertheless, the oral absolute bioavailability of carbamazepine lies between 70 and 78% and both in vivo and in vitro data support the classification of carbamazepine as a highly permeable drug. Since the therapeutic and toxic plasma level ranges overlap, carbamazepine is considered to have a narrow therapeutic index. For these reasons, a BCS based biowaiver for IR tablets of carbamazepine cannot be recommended. Interestingly, in nine out of ten studies, USP dissolution conditions (900 mL water with 1% SLS, paddle, 75 rpm) appropriately discriminated among bioinequivalent products and this may be a way forward to predicting whether a given formulation will be bioequivalent to the comparator product.

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Metformin Hydrochloride.

Data are examined regarding possible waiver of in vivo bioequivalence testing (i.e. biowaiver) for approval of metformin hydrochloride (metformin) immediate-release solid oral dosage forms. Data include metformin's Biopharmaceutics Classification System (BCS) properties, including potential excipient interactions. Metformin is a prototypical transporter-mediated drug and is highly soluble, but only 50% of an orally administered dose is absorbed from the gut. Therefore, metformin is a BCS Class III substance. A BCS-based approval approach for major changes to marketed products and new generics is admissible if test and reference dosage forms have the identical active pharmaceutical ingredient and if in vitro dissolution from both are very rapid (i.e. at least 85% within 15 min at pH 1.2, 4.5, and 6.8). Recent International Council for Harmonisation BCS guidance indicates all excipients for Class III biowaivers are recommended to be qualitatively the same and quantitatively similar (except for preservatives, flavor agents, colorant, or capsule shell or film coating excipients). However, despite metformin being a prototypical transporter-mediated drug, there is no evidence that commonly used excipients impact metformin absorption, such that this restriction on excipients for BCS III drugs merits regulatory relief. Commonly used excipients in usual amounts are not likely to impact metformin absorption.

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Moxifloxacin Hydrochloride.

In this monograph, literature data is reviewed to evaluate the feasibility of waiving in vivo bioequivalence testing and instead applying the Biopharmaceutics Classification System (BCS) based methods to the approval of immediate-release solid oral dosage forms containing moxifloxacin hydrochloride as the sole active pharmaceutical ingredient. To facilitate the feasibility decision, solubility and permeability and dissolution characteristics in the context of the BCS, therapeutic index, therapeutic use, pharmacokinetic parameters, bioequivalence/bioavailability issues, drug-excipient interactions and other relevant data were taken into consideration. Moxifloxacin is a BCS class I drug with a wide therapeutic index. Bioequivalence risks arising from the presence of different excipients in the formulation and due to manufacturing variables were deemed to be low. The risks can be further reduced if the choice of excipients is limited to those present in products already approved in International Conference on Harmonisation or associated countries and if the results of in vitro dissolution studies comply with the specifications stipulated in the appropriate biowaiver guidelines. Under these conditions, we conclude that a BCS-based biowaiver can be recommended for moxifloxacin immediate-release solid oral dosage forms.

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Cephalexin Monohydrate.

Literature data and results of experimental studies relevant to the decision to allow waiver of bioequivalence studies in humans for the approval of immediate release solid oral dosage forms containing cephalexin monohydrate are presented. Solubility studies were performed in accordance with the current biowaiver guidelines of the Food and Drug Administration, World Health Organization and European Medicines Agency, taking the degradation at some pH values into consideration. Together with solubility and permeability data for cephalexin monohydrate from the literature, it was demonstrated to be a Biopharmaceutics Classification System Class 1 drug. The pharmacokinetic behavior, results of bioequivalence studies published in the literature, as well as the therapeutic uses, potential toxicity and potential excipient effects on bioavailability were also assessed. Cephalexin has a wide therapeutic index and no bioequivalence problems have been reported. Dissolution studies were run under Biopharmaceutics Classification System-biowaiver conditions for the pure drug and 2 generic formulations available on the German market. Considering all relevant aspects, it was concluded that a biowaiver-based approval for products containing cephalexin monohydrate as the single active pharmaceutical ingredient is scientifically justified, provided that well-established excipients are used in usual amounts and that both test and reference dosage forms meet the guideline criteria of either "rapidly dissolving" or "very rapidly dissolving."

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Ondansetron.

Literature data pertaining to the physicochemical, pharmaceutical, and pharmacokinetic properties of ondansetron hydrochloride dihydrate are reviewed to arrive at a decision on whether a marketing authorization of an immediate release (IR) solid oral dosage form can be approved based on a Biopharmaceutics Classification System (BCS)-based biowaiver. Ondansetron, a 5HT3 receptor antagonist, is used at doses ranging from 4 mg to 24 mg in the management of nausea and vomiting associated with chemotherapy, radiotherapy, and postoperative treatment. It is a weak base and thus exhibits pH-dependent solubility. However, it is able to meet the criteria of "high solubility" as well as "high permeability" and can therefore be classified as a BCS class I drug. Furthermore, ondansetron hydrochloride 8 mg IR tablets (Zofran® 8 mg) and multiples thereof (16 mg = Zofran® 8 mg × 2 tablets and 24 mg = Zofran® 8 mg × 3 tablets) meet the criteria of "rapidly dissolving" in dissolution testing. Ondansetron hydrochloride has a wide therapeutic window and is well-tolerated after oral administration. Based on its favorable physicochemical properties, pharmacokinetic data and the minimal risks associated with an incorrect bioequivalence decision, the BCS-based biowaiver procedure can be recommended for ondansetron hydrochloride dihydrate IR tablets.

Report on the AAPS Immunogenicity Guidance Forum.

In September 2018, the American Association of Pharmaceutical Scientists (AAPS) conducted an Annual Guidance Forum on the considerations related to immunogenicity testing for therapeutic protein products. In addition to a broad representation by the pharmaceutical industry, the event included strong representation by leading scientists from the US Food and Drug Administration (FDA). The agency and industry perspectives and updates to the guidance were presented. Specific topics that were discussed included the strategies of anti-drug antibody (ADA) assay cut-point assessments, the selection of ADA-positive controls (PCs), and the evaluation of PC performance. Assessment strategies and relevance of ADA assay attributes were also discussed, including assay drug tolerance and ADA assay sensitivity. The following is a summary of the discussion.

Report of the AAPS Guidance Forum on the FDA Draft Guidance for Industry: "Drug Products, Including Biological Products, that Contain Nanomaterials".

To guide developers of innovative and generic drug products that contain nanomaterials, the U.S. Food and Drug Administration issued the draft guidance for industry titled: "Drug Products, Including Biological Products, that Contain Nanomaterials" in December 2017. During the AAPS Guidance Forum on September 11, 2018, participants from industry, academia, and regulatory bodies discussed this draft guidance in an open setting. Two questions raised by the AAPS membership were discussed in more detail: what is the appropriate regulatory pathway for approval of drug products containing nanomaterials, and how to determine critical quality attributes (CQAs) for nanomaterials? During the meeting, clarification was provided on how the new FDA center-led guidance relates to older, specific nanomaterial class, or specific product-related guidances. The lively discussions concluded with some clear observations and recommendations: (I) Important lessons can be learned from how CQAs were determined for, e.g., biologics. (II) Publication of ongoing scientific discussions on strategies and studies determining CQAs of drug products containing nanomaterials will significantly strengthen the science base on this topic. Furthermore, (III) alignment on a global level on how to address new questions regarding nanomedicine development protocols will add to efficient development and approval of these much needed candidate nanomedicines (innovative and generic). Public meetings such as the AAPS Guidance Forum may serve as the place to have these discussions.

FIP Guidelines for Dissolution Testing of Solid Oral Products.

Dissolution testing is an important physiochemical test for the development of solid oral dosage forms, tablets, and capsules. As a quality control test, the dissolution test is used for assessment of drug product quality and is specified for batch release and regulatory stability studies. In vitro dissolution test results can often be correlated with the biopharmaceutical behavior of a product.This article provides a summary of views from major global agencies (Europe, Japan, United States), pharmacopoeias, academia, and industry. Based on available guidance and literature, this article summarizes highlights for development and validation of a suitable dissolution method, setting appropriate specifications, in vitro-in vivo comparison, and how to obtain a biowaiver.

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: Folic Acid.

This work presents a review of literature and experimental data relevant to the possibility of waiving pharmacokinetic bioequivalence studies in human volunteers for approval of immediate-release solid oral pharmaceutical forms containing folic acid as the single active pharmaceutical ingredient. For dosage forms containing 5 mg folic acid, the highest dose strength on the World Health Organization Essential Medicines List, the dose/solubility ratio calculated from solubility studies was higher than 250 mL, corresponding to a classification as "not highly soluble." Small, physiological doses of folic acid (≤320 µg) seem to be absorbed completely via active transport, but permeability data for higher doses of 1-5 mg are inconclusive. Following a conservative approach, folic acid is classified as a Biopharmaceutics Classification System class IV compound until more reliable data become available. Commensurate with its solubility characteristics, the results of dissolution studies indicated that none of the folic acid products evaluated showed rapid dissolution in media at pH 1.2 or 4.5. Therefore, according to the current criteria of the Biopharmaceutics Classification System, the biowaiver approval procedure cannot be recommended for immediate-release solid oral dosage forms containing folic acid.