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.

Nitroso Impurities in Drug Products: An Overview of Risk Assessment, Regulatory Milieu, and Control Strategy.

Many nitrosamines have been recognized to be carcinogenic for many decades. Despite the fact that several nitrosamine precursors are frequently used in the manufacturing of pharmaceutical products, their potential presence in pharmaceutical products has previously been overlooked due to a lack of understanding on how they form during the manufacturing process. From the risk assessment, it is clear that nitrosamines or their precursors may be present in any component of the finished dosage form. As a risk mitigation strategy, components with a high potential to form nitrosamine should be avoided. In the absence of suitable alternatives, sufficient measures to maintain nitrosamines below acceptable intake levels must be applied. Excipient manufacturing pathways must be extensively studied in order to identify probable excipient components that may contribute to nitrosamine formation. The manufacturers must not solely rely on pharmacopeial specifications for APIs and excipients, rather, they should also develop and implement additional strategies to control nitrosamine impurities. The formulation can be supplemented with nitrosating inhibitors, such as vitamin C, to stop the generation of nitrosamine. The purpose of this review is to identify key risk factors with regard to nitrosamine formation in pharmaceutical dosage forms and provide an effective control strategy to contain them below acceptable daily intake limits.

Data integrity issues in pharmaceutical industry: Common observations, challenges and mitigations strategies.

Data integrity (DI) reaffirms the pharmaceutical industry's commitment to manufacture drugs that are safe, effective and fulfil quality standards. At the same time, DI is a crucial tool for regulatory authorities to use in protecting public health. Recent FDA Form-483 observations and warning letters indicate that DI is the main issue the pharmaceutical industry is currently dealing with. Failure to comply with DI requirements may result in a high number of un-validated results, which may cause post-marketing issues and frequent product recalls. To address the underlying causes of DI problems, a comprehensive approach is necessary. The majority of DI issues are caused by poor quality culture, organizational or individual behaviour, leadership, processes, or technology. DI should be effectively integrated into the quality management system, and it should apply to both paper and electronic records. Employees should be trained on 21 CFR Part 11. Consistent review and audit are required to ensure that procedures are followed and audit trails are generated. Electronic systems, in addition to being an efficient solution (system integration, data verification at both input and output, security), offer advantages over traditional paper-based systems in terms of improved compliance with DI regulatory requirements. For example, many electronic system platforms provide enhanced security features and audit trail capabilities. Finally, management support for data governance is essential for successful implementation of DI. This article reviews commonly observed deviations by FDA pertaining to DI and discusses measures to be undertaken to avoid them.

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).

Hyperpigmentation: Looking beyond hydroquinone.

Hyperpigmentation is the most common complaint in the age group 40-45 years, seeking consultation for skin disorders. Hydroquinone is a commonly used depigmenting agent in clinical practice for treating hyperpigmentation. Prolonged use of hydroquinone has been associated with cancer risk and exogenous ochronosis. The CARES (The Coronavirus Aid, Relief, and Economic Security Act) Act of 2020 has instituted significant changes to hydroquinone containing OTC (over the counter) products, and consequently, many hydroquinone-based OTC products had to be withdrawn from the market. Henceforth, products containing hydroquinone would need US Food and Drug Administration approval via new drug application pathways for commercialization. Alternative treatment options to hydroquinone in clinical practice are reviewed in this paper with regard to their safety and efficacy vis a vis hydroquinone. Also, new potential treatment options such as thiamidol, Polypodium leucotomos, and glutathione are discussed. The review shows that these alternative depigmenting agents can be rationally combined to achieve desired treatment goals in the management of hyperpigmentation.

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.

Converging Generic Drug Product Development: Bioequivalence Design and Reference Product Selection.

Different regulatory agencies provide criteria for selecting a reference product for bioequivalence (BE) studies. In most cases, the criteria vary from one regulatory agency to another, and, consequently, the generic companies often have to repeat the BE studies comparing the same test product with the reference product purchased from a particular country. In addition to being a cost-intensive exercise, this practice is also unethical. The purpose of this article is to discuss the current policy of major regulatory authorities on the selection of the reference product for pharmaceutical equivalence (PE) and BE studies, the cost implications of such regulatory practices, and to also explore the opportunity to harmonize the reference product selection criteria for reducing repetitive BE studies. The regulatory guidance documents of major jurisdictions are reviewed for similarities and differences in generic product definition, BE study design and conduct, and reference product selection criteria for PE and BE studies. A case study is presented to understand how harmonisation can be achieved and how the economic benefits of this harmonisation cannot be underestimated. Harmonisation in reference product selection criteria can pave the way for a common BE study(s) that would be acceptable to the majority of regulatory agencies, and would not only significantly reduce operating costs but would also minimize the exposure of healthy human beings to drugs.

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.

Selective laser sintering 3D printing - an overview of the technology and pharmaceutical applications.

Food and Drug Administration (FDA) has approved a drug product (Spritam®) and many medical devices manufactured by three-dimensional printing (3DP) processes for human use. There is immense potential to print personalized medicines using 3DP. Many 3DP methods have been reported in the literature for pharmaceutical applications. However, selective laser sintering (SLS) printing has remained least explored for pharmaceutical applications. There are many advantages and challenges in adopting a SLS method for fabrication of personalized medicines. Solvent-free nature, availability of FDA approved thermoplastic polymer/excipients (currently used in hot melt-extrusion process), minimal/no post-processing step, etc. are some of the advantages of the SLS printing process. Major challenges of the technology are requirement of at least one thermoplastic component in the formulation and thermal stability of drug and excipients. This review provides an overview of the SLS printing method, excipient requirements, process monitoring, quality defects, regulatory aspects, and potential pharmaceutical applications.

Integrating QbD Tools for Flexible Scale-Up Batch Size Selection for Solid Dosage Forms.

The pilot scale batch size for solid oral dosage forms is currently defined by major regulatory agencies as one-tenth of the full production, or 100,000 units, whichever is larger. The current criterion is arbitrary and is not based on scientific and risk assessment principles. The approach does not consider geometric, kinematic, and dynamic changes that come into play on scale-up. Even if this criterion is met, impact of scale-up on critical quality attributes cannot be ruled out and also reproducibility cannot be assured simply by restricting the scale-up size. In keeping with the vision for the 21st Century Good Manufacturing Practice initiative to build quality into the product, it is imperative that the selection of scale-up batch size be based on science and risk assessment principles and be part of the product development program. Scale-up should never be seen as an isolated activity. This article will review various tools that can be integrated with quality by design for flexible batch size selection during scale-up.

Lesson Learnt from Recall of Valsartan and Other Angiotensin II Receptor Blocker Drugs Containing NDMA and NDEA Impurities.

The presence of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) impurities in angiotensin II receptor blocker (ARB) drugs containing tetrazole ring has triggered worldwide product recalls. The purpose of this article is to identify the potential gap area in current pharmaceutical industry practice that might have led to the NMDA and NDEA impurities escaping the drug manufacturer's and FDA's attention. The impact of process change was not adequately assessed by the manufacturer of contaminated APIs (active pharmaceutical ingredients), and potential for generation of mutagenic or other toxic impurities was not considered. The safety and risk associated with a chemical synthetic process was also not evaluated. This is primarily due to current industry practice which focuses on controlling the impurities above reporting threshold. ICH Q3A and FDA guidance on genotoxic and carcinogenic impurities in drug substances and products need to be integrated so that the ICH Q3A decision tree (attachment 3) begins by checking whether the synthetic process has been evaluated for the potential to generate toxic impurities. The compliance with ICH Q3A limits should be carried out only after the process has been determined to be safe without the risk of generating mutagenic and carcinogenic impurities.

Additive Manufacturing with 3D Printing: Progress from Bench to Bedside.

Three-dimensional (3D) printing was discovered in the 1980s, and many industries have embraced it, but the pharmaceutical industry is slow or reluctant to adopt it. Spiritam® is the first and only 3D-printed drug product approved by FDA in 2015. Since then, the FDA has not approved any 3D-printed drug product due to technical and regulatory issues. The 3D printing process cannot compete with well-established and understood conventional processes for making solid dosage forms. However, pharmaceutical companies can utilize it where mass production is not required; rather, consistency, precision, and accuracy in quality are paramount. There are many 3D printing technologies available, and not all of them are amenable to pharmaceutical manufacturing. Each 3D technology has certain prerequisites in terms of material that it can handle. Some of the pertinent technical and regulatory issues are as follows: Current Good Manufacturing Practice, in-process tests and process control, and cleaning validation. Other promising area of 3D printing use is printing medications for patients with special needs in a hospital and/or pharmacy setting with minimum regulatory oversight. This technology provides a novel opportunity for in-hospital compounding of necessary medicines to support patient-specific medications. However, aspects of the manufacturing challenges and quality control considerations associated with the varying formulation and processing methods need to be fully understood before 3D printing can emerge as a therapeutic tool. With these points in mind, this review paper focuses on 3D technologies amenable for pharmaceutical manufacturing, excipient requirement, process understanding, and technical and regulatory challenges.

Is the demonstration of bioequivalence for clavulanic acid required in amoxicillin-clavulanic acid orally administered immediate-release products?

OBJECTIVES: Bioequivalence (BE) criteria for amoxicillin-clavulanic acid (Co-amoxiclav) oral formulations are based on 90% confidence interval for both amoxicillin and clavulanic acid. The aim of this work is to explore the relevance of demonstrating BE of clavulanic acid in Co-amoxiclav oral formulations and also to assess the impact on safety and efficacy of product due to bioinequivalent clavulanic acid. METHODS AND KEY FINDINGS: The subtherapeutic levels of clavulanic acid would continue to exert their action against ß-lactamases due to postß-lactamase inhibitor effect. Additionally, only minute quantities are required to inhibit ß-lactamases. Majority of adverse effects associated with Co-amoxiclav are of less serious nature, therefore, risk due to suprabioavailable clavulanic acid was determined to be low. 'Very rapid clavulanic acid release' in in vitro dissolution test would ensure that clinically significant differences between test and reference formulations if any are detected in advance. As an additional risk mitigation strategy, WHO recommends qualitative and quantitative composition similarity between test and reference formulations to ensure excipients do not adversely impact bioavailability. CONCLUSIONS: Co-amoxiclav with non-bioequivalent clavulanic acid, but bioequivalent amoxicillin would still achieve its therapeutic objectives without exposing patients to unwanted adverse effects. Therefore, the current regulatory criterion of demonstrating BE of clavulanic acid appears conservative.

Sample Size for Tablet Compression and Capsule Filling Events During Process Validation.

During solid dosage form manufacturing, the uniformity of dosage units (UDU) is ensured by testing samples at 2 stages, that is, blend stage and tablet compression or capsule/powder filling stage. The aim of this work is to propose a sample size selection approach based on quality risk management principles for process performance qualification (PPQ) and continued process verification (CPV) stages by linking UDU to potential formulation and process risk factors. Bayes success run theorem appeared to be the most appropriate approach among various methods considered in this work for computing sample size for PPQ. The sample sizes for high-risk (reliability level of 99%), medium-risk (reliability level of 95%), and low-risk factors (reliability level of 90%) were estimated to be 299, 59, and 29, respectively. Risk-based assignment of reliability levels was supported by the fact that at low defect rate, the confidence to detect out-of-specification units would decrease which must be supplemented with an increase in sample size to enhance the confidence in estimation. Based on level of knowledge acquired during PPQ and the level of knowledge further required to comprehend process, sample size for CPV was calculated using Bayesian statistics to accomplish reduced sampling design for CPV.

Integrating biopharmaceutics risk assessment and in vivo absorption model in formulation development of BCS class I drug using the QbD approach.

OBJECTIVE: Clinically relevant critical quality attributes (CQA's) were identified for the development of generic drug products containing fluconazole and potential design spaces relevant to the clinical application of the drug candidate was explored. SIGNIFICANCE: A simplified scoring system for the biopharmaceutics risk assessment roadmap (BioRAM) is proposed to guide product development. METHODS: Factorial design of experiments was employed to study the effect of formulation and process variables on CQA's. The in vivo model was developed for predicting the fraction of drug absorbed and to identify the effect of formulation components on drug absorption. RESULTS: BioRAM yielded low scores for fluconazole absorption with respect to severity (risks of sub and supra-bioavailable drug products), probability of incidence of bioinequivalent results and capacity of detection. The results demonstrated that dissolution was highly influenced by the active pharmaceutical ingredient (API) polymorphism and the ratio of diluents. Process variables (mixing time, lubricant concentration, lubrication time and filling speed) did not impact the clinical outcome of the formulation with respect to dissolution and content uniformity. CONCLUSIONS: Understanding the clinical implications of the adopted formulation approach led to the construction of purposeful design space and control strategy.

Pharmaceutical product development: A quality by design approach.

The application of quality by design (QbD) in pharmaceutical product development is now a thrust area for the regulatory authorities and the pharmaceutical industry. International Conference on Harmonization and United States Food and Drug Administration (USFDA) emphasized the principles and applications of QbD in pharmaceutical development in their guidance for the industry. QbD attributes are addressed in question-based review, developed by USFDA for chemistry, manufacturing, and controls section of abbreviated new drug applications. QbD principles, when implemented, lead to a successful product development, subsequent prompt regulatory approval, reduce exhaustive validation burden, and significantly reduce post-approval changes. The key elements of QbD viz., target product quality profile, critical quality attributes, risk assessments, design space, control strategy, product lifecycle management, and continual improvement are discussed to understand the performance of dosage forms within design space. Design of experiments, risk assessment tools, and process analytical technology are also discussed for their role in QbD. This review underlines the importance of QbD in inculcating science-based approach in pharmaceutical product development.

Exploratory Investigation of the Limiting Steps of Oral Absorption of Fluconazole and Ketoconazole in Children Using an In Silico Pediatric Absorption Model.

Due to the higher total clearance of certain drugs in children than in adults, it is recommended that, in such cases, higher relative doses on a milligram/kilogram basis should be administered to children in order to achieve similar systemic exposure to adults. This is the case for fluconazole and ketoconazole. Even though the lower absorptive surface area and smaller volumes of intestinal fluids in children does not affect fluconazole absorption, cumulative fraction absorbed of ketoconazole seems to be dose dependent. A dose of 200 mg of ketoconazole, which belongs to the class 2a of the Developability Classification System (DCS) in adults, seems to be higher than the maximum absorbable dose in children, and ketoconazole absorption is expected to be solubility limited (i.e., DCS class 2b) in this population, indicating a DCS class migration. Therefore, extrapolating DCS and DCS drug classification from adults to pediatric groups does not seem to be straightforward and the development of specific pediatric classification systems should be a high priority.

Risk assessment for extending the Biopharmaceutics Classification System-based biowaiver of immediate release dosage forms of fluconazole in adults to the paediatric population.

OBJECTIVES: The paediatric population undergoes developmental changes in gastric pH, gastric emptying, intestinal transit time, membrane permeability, protein binding, body water, distribution and metabolism. It is widely recognised that changes in these parameters may result in an alteration of the plasma profile and thus in key bioequivalence parameters such as Cmax (maximum plasma concentration of drug) and area under the plasma concentration vs time profile curve. The aim of this work is to assess the risk of extending the biowaiver for immediate release dosage formulations of fluconazole from the adult to the paediatric population. METHODS AND KEY FINDINGS: Fluconazole exhibits good solubility and very rapid dissolution characteristics in various pH media. The absorption of fluconazole in children is known to be complete (over 90%) and not impaired by elevated pH, which is prevalent during the early days of life. Dose numbers calculated using body surface area are less than 1. Therefore, the risk to drug absorption due to differences in gastric pH, gastric emptying, intestinal transit, membrane permeability and metabolising enzymes between adults and children is considered low. CONCLUSIONS: Thus, it can be safely concluded that fluconazole meets highly soluble and highly permeable criteria in the paediatric population and can be allocated to class 1 of the Biopharmaceutics Classification System (BCS) for this population as well as in adults. Additionally, fluconazole has an excellent safety profile in children, similar to that in adults. The BCS-based biowaiver claimed in adults can be safely extended to the paediatric population provided that the requirements in excipient selection and dissolution profile comparison using BCS-based dissolution conditions as stated in the biowaiver monograph for fluconazole immediate release dosage forms in adults are fulfilled.

Biowaiver monograph for immediate-release solid oral dosage forms: fluconazole.

Literature data pertaining to the decision to allow a waiver of in vivo bioequivalence (BE) testing requirements for the approval of immediate release (IR) solid oral dosage forms containing fluconazole as the only active pharmaceutical ingredient (API) are reviewed. The decision is based on solubility, dissolution, permeability, therapeutic index, pharmacokinetic parameters, pharmacodynamic properties, and other relevant data. BE/bioavailability (BA) problems and drug-excipients interaction data were also reviewed and taken into consideration. According to the biopharmaceutics classification system (BCS), fluconazole in polymorphic forms II and III is a BCS class I drug and has a wide therapeutic index. BE of test formulations from many different manufacturers containing different excipients confirmed that the risk of bioinequivalence because of formulation and manufacturing factors is low. It was inferred that risk can be further reduced if in vitro studies are performed according to biowaiver guidelines. Thus, it is concluded that a biowaiver can be recommended for fluconazole IR dosage forms if (a) fluconazole is present as polymorphic form II or III or any other form/mixture showing high solubility, (b) the selection of excipients be limited to those found in IR drug products approved in International Conference on Harmonisation (ICH) countries for the same dosage form and used in their usual amounts, and (c) both the test and comparator dosage form are very rapidly dissolving, or, rapidly dissolving throughout the shelf life with similar dissolution profiles at pH 1.2, 4.5, and 6.8.