Consensus Statements on the Use of Novel Formulations of Isotretinoin: A Modified Delphi Process.

Oral isotretinoin remains a mainstay of treatment for severe, recalcitrant nodular acne. Novel formulations of isotretinoin have been developed over the past decade, including lidose isotretinoin and micronized isotretinoin. It is important to understand the differences between isotretinoin formulations to help guide clinical decision-making and selection of isotretinoin therapy. This study aims to provide evidence-based consensus statements regarding the use of novel formulations of isotretinoin for the treatment of moderate-to-severe acne. The Expert Consensus Group consisted of dermatologists with expertise in the treatment of acne. Voting members met in person to conduct a modified Delphi process; a maximum of 2 rounds of voting were conducted for each consensus statement. A total of 5 statements were generated regarding the use of novel formulations of isotretinoin, addressing the efficacy, tolerability, and side effects of novel isotretinoin formulations. All 5 statements achieved agreement with high consensus. The Expert Consensus Group agrees that individualized selection of isotretinoin therapy is important to maximize efficacy and minimize side effects. Compared to generic isotretinoin, micronized isotretinoin may require lower doses to achieve sufficient plasma concentrations. With the increased bioavailability of micronized formulation, there is no need to calculate cumulative dose; instead, the general recommendation with micronized isotretinoin is to treat for at least 5 months, or longer if needed to achieve clearance. Micronized isotretinoin can be taken in the fed or fasted state and has an acceptable safety profile. J Drugs Dermatol. 2024;23(6):429-432.     doi:10.36849/JDD.7971.

Characterization of Prototype Gummy Formulations Provides Insight into Setting Quality Standards.

Gummy formulations are considered suitable alternatives to traditional oral dosage forms like tablets and capsules due to their merits that include chewability, softness/flexibility, improved drug release, administration without water, appealing organoleptic properties, better patient compliance, easy preparation and usefulness for persons of different ages (e.g. children). Though there is increasing interest in gummy formulations containing drugs, measurable parameters, and specification limits for evaluating their quality are scarce. Quality check forms an essential part of the pharmaceutical development process because drug products must be distributed as consistently stable, safe, and therapeutically effective entities. Consequently, some quality parameters that could contribute to the overall performance of typical gummy formulations were investigated employing six brands of non-medicinal gummies as specimens. Accordingly, key physicochemical and micromechanical characteristics namely adhesiveness (0.009 - 0.028 mJ), adhesive force (0.009 - 0.055 N), chewiness (2.780 - 6.753 N), cohesiveness (0.910 - 0.990), hardness (2.984 - 7.453 N), springiness (0.960 - 1.000), and resilience (0.388 - 0.572), matrix firmness - compression load (2.653 - 6.753 N) and work done (3.288 - 6.829 mJ), rupture (5.315 - 29.016 N), moisture content (< 5%), weight uniformity (< 2.5 g; < 7.5% deviation), and intraoral dissolution pH (≥ 3.5 ≤ 6.8) were quantified to identify measures that may potentially function as specification limits and serve as prospective reference points for evaluating the quality of gummy formulations. Findings from this work contribute to ongoing efforts to standardize the quality control strategies for gummy formulations, particularly those intended for oral drug delivery.

[Overwiew of compounding oncology pharmacy in France in 2021]. / États des lieux de la pharmacotechnie oncologique en France en 2021.

The pharmacotechnical expert group of the French Society of Oncological Pharmacy presents the results of its national survey carried out in 2021 in the form of an inventory of pharmaceutical compounding units dedicated to oncology. Premises, equipment, controls, production flows and trends are described in this article, providing an overview of the sector at a time when the new Good Manufacturing Practices (GMP) are applicable. This overview will allow us to better address the needs and expectations of production pharmacists regarding the application of GMP and the development of their units.

Fouling Behavior during Sterile Filtration of Different Glycoconjugate Serotypes Used in Conjugate Vaccines.

PURPOSE: Sterile filtration can be a particular challenge when processing very large glycoconjugate vaccines. The objective of this study was to examine the sterile filtration performance of a series of glycoconjugate vaccines produced by coupling different polysaccharide serotypes to an immunogenic protein. METHODS: Sterile filtration was performed at constant filtrate flux using 0.22 µm pore size Durapore® polyvinylidene fluoride membranes. Glycoconjugates were characterized by dynamic light scattering, rheological measurements, and nanoparticle tracking analysis (NTA). Confocal microscopy was used to examine glycoconjugate capture profiles within the membrane. Transmembrane pressure data were analyzed using a recently developed fouling model. RESULTS: All glycoconjugates deposited in a narrow band near the entrance of the Durapore® membranes. The rate of fouling varied significantly for the different serotypes, with the fouling parameter correlated with the fraction of glycoconjugates larger than 200 nm in size. CONCLUSIONS: The fouling behavior and sterile filter capacity of the different glycoconjugate serotypes are determined primarily by the presence of large species (>200 nm in size) as determined by nanoparticle tracking analysis. The modified intermediate pore blockage model provides a framework for predicting the sterile filtration performance for these glycoconjugate vaccines.

Compounding for women's health: a compounder's perspective - need, regulations, and future.

Compounding medicine involves various health-care professionals working together to produce medications that treat patient conditions including menopause and other women's health-related illnesses. These medications are compounded under the standards and guidelines mandated by individual state pharmacy boards, the US Food and Drug Administration, and other professional organizations. Contrary to commercial medications, the personalized medicine aspect of compounding medications ensures that the patient's allergies, doses, and drug delivery preferences are addressed during formulation. In the foreseeable future, compounders will continue to formulate medications that are unavailable in the commercial sector, following strict safe-practice guidelines. More importantly, the application of pharmacogenomics and three-dimensional printing to compounding medications could revolutionize compounding formulations and generate new approaches for personalized medicine.

Bioidentical hormones.

After the results of the Women's Health Initiative trials were published, patient and clinician interest in potential alternatives to conventional hormone therapy (HT) has grown. A commonly used alternative therapy involves custom-compounded steroid hormone preparations, formulated by compounding pharmacies. Many postmenopausal women consider the hormones as natural or bioidentical, in contrast to hormones used in conventional HT, which they consider synthetic. In actuality, the chemical structures of many of the hormones used in bioidentical HT (BHT) are the same as those used in conventional HT. To customize formulations, compounding pharmacies frequently use saliva testing to measure hormones. However, there is a misconception that salivary hormone levels are equivalent to non-protein-bound (free) hormones in blood. Because hormonal custom-compounded formulations are not approved by the Food and Drug Administration (FDA), there are concerns regarding their purity, potency, and quality. Evolving regulatory guidelines by the FDA on oversight of these products should lessen the concerns regarding their safety and efficacy. This review addresses important misconceptions and uncertainties pertaining to BHT, the relationship between salivary and serum/plasma steroid hormone concentrations, the effect of topical progesterone creams on the endometrium, the variability in custom-compounded steroid preparations, and FDA oversight of custom-compounded products.

Standardization of conventional chemoembolization for hepatocellular carcinoma.

INTRODUCTION AND OBJECTIVES: Conventional transarterial chemoembolization (cTACE) has several limitations due to the lack of standardization. The aim of this study was to evaluate the chemical and physical characteristics and behaviors over time of emulsions for cTACE and to assess intra- and inter-operator variabilities in the preparation processes. MATERIALS AND METHODS: This in vitro study involved evaluation of emulsions for cTACE prepared using two methods: water-in-oil (WiO) and chemotherapeutic-in-oil (CiO). Three emulsions were prepared with each method and obtained after 20, 50, and 100 pumping exchanges. A drop from each final mixture was analyzed via light microscopy (time 1) and after 5, 10, 15, and 20min since the end of preparation. After 20min, all preparations were re-mixed and new drops were re-evaluated. The intra- and inter-operator variabilities were analyzed. RESULTS: The mean droplet diameter decreased non-significantly when the number of pumping exchanges increased and increased significantly over time for both WiO and CiO. The droplets returned to their initial diameters after re-mixing. There were no significant differences in the intra- and inter-operator variabilities (P>0.01). CONCLUSIONS: Any interventional radiologist, regardless of their experience, may prepare these emulsions. These data may represent a set of instructions to standardize cTACE.

Preparation and preliminary quality evaluation of aspirin/L-glutamate compound pellets.

L-glutamate is an important component of protein. It can prevent gastrointestinal damage caused by NSAIDs. We constructed two-phase enteric-coated granules of aspirin and L-glutamate compound by extrusion spheronization method and fluidized bed coating. The subliminal effective dose of L-glutamate is 100 mg/kg tested by model of gastric ulcer of rats induced by aspirin and drug administration. HPLC-UV and UV-Vis methods were adopted to determine content and cumulative release of aspirin and L-glutamate as quality analysis method indexes. The prescription and process optimization were carried out with yield, sphericity and dissolution. The two-phase compound granules have good sphericity of 0.93 ± 0.05 (aspirin pellets) and 0.94 ± 0.02 (L-glutamate pellets), content of salicylic acid (0.24 ± 0.03)%, dissolution of aspirin (2.36 ± 0.11)%. Quality evaluation and preliminary stability meet the commercial requirements. The stored environment of compound preparation should be sealed in a cool and dark place.

Approach to Establishment of Control Strategy for Oral Solid Dosage Forms Using Continuous Manufacturing.

As a result of the research activities of the Japan Agency for Medical Research and Development (AMED), this document aims to show an approach to establishing control strategy for continuous manufacturing of oral solid dosage forms. The methods of drug development, technology transfer, process control, and quality control used in the current commercial batch manufacturing would be effective also in continuous manufacturing, while there are differences in the process development using continuous manufacturing and batch manufacturing. This document introduces an example of the way of thinking for establishing a control strategy for continuous manufacturing processes.

A Review of the Main Considerations for Formulation Development in Preclinical Toxicology Studies.

The main considerations for the development of a formulation for preclinical safety assessment testing are explored. Intravenous, inhalation, oral and dermal dosing are given focus and although different dose routes do present their own individual challenges there are common themes that emerge. In each case it is necessary to maximise exposure to achieve high doses to satisfy regulatory requirements for safety assessment testing. This often involves producing formulations that are at the limits of solubility and maximum volumes possible for administration to different test species by the chosen route. It is concluded that for all routes it is important to thoroughly explore the stability of the test item in the proposed formulation matrix well ahead of dosing any animals, giving careful consideration to which excipients are used and what their underlying toxicity profile may be for the relevant preclinical species. In addition, determining the maximum achievable concentrations and weighing that against the maximum volumes that can be given by the chosen route in all the test species at an early stage will also give a read on whether it would be theoretically possible to achieve suitably high enough doses to support clinical work. Not doing so can cause delays in the development programme and may have ethical repercussions.

Establishment of an anti-inflammation-based bioassay for the quality control of the 13-component TCM formula (Lianhua Qingwen).

CONTEXT: Owing to the complexity of chemical ingredients in traditional Chinese medicine (TCM), it is difficult to maintain quality and efficacy by relying only on chemical markers. OBJECTIVE: Lianhua Qingwen capsule (LHQW) was selected as an example to discuss the feasibility of a bioassay for quality control. MATERIALS AND METHODS: Network pharmacology was used to screen potential targets in LHQW with respect to its anti-inflammatory effects. An in vitro cell model was used to validate the prediction. An anti-inflammatory bioassay was established for the quality evaluation of LHQW in 40 batches of marketed products and three batches of destructed samples. RESULTS: The tumor necrosis factor/interleukin-6 (TNF/IL-6) pathway via macrophage was selected as the potential target of LHQW. The IC50 value of LHQW on RAW 264.7 was 799.8 µg/mL. LHQW had significant inhibitory effects on the expression of IL-6 in a dose-dependent manner (p < 0.05). The anti-inflammatory biopotency of LHQW was calculated based on the inhibitory bioactivity on IL-6. The biopotency of 40 marketed samples ranged from 404 U/µg to 2171 U/µg, with a coefficient of variation (CV) of 37.91%. By contrast, the contents of forsythin indicated lower CV (28.05%) than the value of biopotency. Moreover, the biopotencies of destructed samples declined approximate 50%, while the contents of forsythin did not change. This newly established bioassay revealed a better ability to discriminate the quality variations of LHQW as compared to the routine chemical determination. CONCLUSIONS: A well-established bioassay may have promising ability to reveal the variance in quality of TCM.

[IMPACTCHIMIO: Development and multicentric validation of a tool for collecting pharmaceutical interventions carried out within chemotherapy reconstitution units]. / IMPACTCHIMIO : élaboration et validation multicentrique d'un outil de recueil des interventions pharmaceutiques réalisées au sein des unités de reconstitution de chimiothérapies.

OBJECTIVES: To develop and validate prospectively a specific tool for pharmaceutical interventions performed in centralized cytotoxic preparation units. METHODS: A pharmaceutical intervention is defined as a type of intervention performed in relation to a problem encountered. ImpactChimio is derived from the Act-IP® (SFPC) tool. The initial version (version 1) was developed from the pharmaceutical interventions collected over 1 year by the pilot centre. Its validation was carried out by the Delphi method via a prospective multicentric collection to assess its robustness (real life pharmaceutical interventions) and reproducibility (50 pharmaceutical interventions classified by pharmacists naive or not to the tool and study of classification divergences). RESULTS: The development of the tool (version 1) was based on the analysis of 412 pharmaceutical interventions. For its validation, 196 pharmaceutical interventions were provided by 6 centers for 5 months. The changes have been incorporated into the new versions of the tool (version 2 and version 3). Six naive and six non-naive pharmacists then tested reproducibility by reclassifying 50 selected pharmaceutical interventions into version 3. A total of 136 discrepancies (11.3 %) were found out of 1200 responses: 66 related to the problem encountered and 70 to the type of intervention. No statistically significant differences were found between naive and non-naive pharmacists. CONCLUSIONS: ImpactChimio is the first pharmaceutical interventions' specific tool for centralized cytotoxic preparation units, developed and validated by a multicentric study using the Delphi method. It makes possible to enhance the value of the analysis activity and to identify training areas for the teams.

A review of the clinical indications, general principles and techniques related to compounding.

Extemporaneous compounding is a means to tailor a medication to an individual patient's needs and may be required when no commercial product exists to meet that need. Compounded products range from buffered lidocaine to topical creams and ointments. This article outlines the clinical indications and general principles related to the manufacture of topical and common formulations.

Regulations, liability, safety, and economics related to compounding.

Extemporaneous compounding is a means to tailor a medication to an individual patient's needs and may be required when no commercial product exists to meet that need. Compounded products range from buffered lidocaine to topical creams and ointments. Recent heightened regulations have made compounding more challenging for dermatologists and prompted this review of regulations, liability, and safety related to compounding. With this information, providers may minimize liability and maximize safety while caring for their patients.

Evaluation of Physicochemical Properties Following Syringe-to-Syringe Mixing of Hyaluronic Acid Dermal Fillers.

BACKGROUND: Historically, soft-tissue hyaluronic acid (HA) fillers have been mixed with agents to reduce pain or alter physicochemical properties. OBJECTIVE: Evaluate the impact of dilution and mixing on HA filler physicochemical properties. MATERIALS AND METHODS: Crosslinked HA filler (VYC-20L, 20 mg/mL) was diluted to 15 mg/mL using saline through 5 or 10 passes between 2 syringes connected using a luer connector. Extrusion force, rheological properties, and microscopic appearance were assessed. Undiluted VYC-15L (15 mg/mL) served as the control. RESULTS: Average extrusion force was higher for diluted VYC-20L versus the control, with an increase in slope for gel diluted using 5 passes (0.65) and 10 passes (0.52) versus the control (<0.1). For diluted samples mixed with 5 or 10 passes, the rheological profile was different between the 2 halves of the syringe, with the second half more elastic than the first half, compared with the consistent profile of undiluted samples. Microscopically, diluted VYC-20L samples seemed more liquid near the luer and more particulate near the piston compared with the control, which was smooth throughout. CONCLUSION: In addition to potentially introducing contamination, diluting or mixing soft-tissue HA fillers yields a heterogeneous product with physicochemical characteristics that vary substantially throughout the syringe.

Assessment of unintended volume loss of six closed system transfer devices.

INTRODUCTION: Closed system transfer devices (CSTDs) are used to prepare and administer hazardous drugs. Previous studies have explored the vapor and fluid containment performance of CSTDs. A less obvious consideration is the effect of CSTD use on the intended dose for small volume administrations. We assessed six CSTDs to determine if they contribute to volume loss and delivery of less than the intended dose during simulated drug administration. METHODS: Using an analytical balance, we obtained the mass of each CSTD at four points during simulated drug preparation and subcutaneous administration using sterile water. We used the masses to determine the average volume loss (VL) for each CSTD. RESULTS: Using ANOVA, we identified significant differences in volume loss (VL) among the mean VL (F(6,59) = 18.45, p = 6.19 × 10-12) for the six CSTDs and control (no CSTD). Four CSTDs had a VL that was statistically different than the control (p < 0.05); the VL for two CSTDs was not statistically different than the control (p > 0.05). Volume loss did not depend on administration volume. CONCLUSION: Volume loss performance varied among CSTDs. Volume loss may be clinically significant for small volumes but is not likely clinically significant for larger volumes. It is the authors' opinion that 3 mL represents a reasonable administration threshold below which volume loss should be considered clinically significant. Users should consider volume loss in context of the tasks, drugs, users, and environments where CSTDs will be used. The United States Pharmacopeia (USP) General Chapter <800>: Hazardous Drugs-Handling in Healthcare Settings recognizes the lack of CSTD performance standards. USP <800> recommends independent performance evaluation of CSTDs based on peer-reviewed studies. Our study adds to the comparative performance evaluations of CSTDs available on the market at the time of this review.

Qualification of a chemotherapy-compounding robot.

KIRO® Oncology (Kiro Grifols, Spain) is a robotic system for automated compounding of sterile injectable drugs including intravenous cytotoxic treatments. The present article describes the qualification procedure applied prior to production phases. Peristaltic pumps which ensure the reconstitution of drugs were tested with water and NaCl 0.9%. The performance of the robot (accuracy and precision) to prepare bags, syringes and elastomeric pumps was evaluated with three placebo solutions (aqueous, foaming and viscous) using gravimetric controls. Microbiological controls were also performed. The pumps met the requirements set for volumes ranging from 5 to 100 mL. A total of 274 preparations was compounded. For the bags, the filling accuracy was within the limit of ±10% from 1 to 48 mL with aqueous solution, from 0.6 to 48 mL with foaming solution and from 5 to 48 mL with viscous solution. For all syringes and elastomeric pumps, it was within the limit of ±10%. The precision was validated for all preparations, except for bags and syringes prepared with 0.6 and 0.25 mL, respectively. The samples of surfaces and air complied with ISO 5 class environment. Among the 24 gloves tests performed, two presented microbiological growth. All Media fill tests were validated. The qualification procedure led us to exclude injections of any active principle volume strictly lower than 1 mL. The microbiological contamination of operators' gloves remains a critical point. Our operators will be made aware of the issue during the training period.

Contact haptens in emollients marketed in two European countries (Poland and Spain).

INTRODUCTION AND OBJECTIVES: Atopic dermatitis (AD) is the most common skin disease among pediatric patients, which affects up to 20% of children worldwide. Characterized by pruritus and eczema, it is also associated with improper skin barrier function and allergen sensitization. Here, we aimed to assess the presence of haptens in emollients marketed in two European countries: in Poland and Spain, as, firstly, these products are considered to be AD's basic therapy, and, secondly, frequent application of potent sensitizers on atopic skin may result in contact dermatitis. MATERIALS AND METHODS: We systematically searched for moisturizers explicitly described as "Atopic skin care" products in the most frequently visited online pharmacies in Poland and Spain. Subsequently, we created a database of all products and compared their composition with 139 contact haptens listed in the European Baseline Series (EBS), Fragrance and Cosmetic Series. RESULTS: As of December 2018, our list comprised 159 and 111 emollients available on the Polish and Spanish markets, respectively. There were no ingredients listed in 28 (17.5%) products in Poland and 24 (21.6%) in Spain. Only 23 (17.5%) and 13 (14.8%) products were hapten free. The pattern of most common haptens was similar in both countries, including phenoxyethanol, tocopherol and tocopheryl acetate, undefined parfum in Poland and tocopherol, phenoxyethanol, tocopheryl acetate and undefined parfum in Spain. CONCLUSIONS: This study shows that a vast majority of products taken into consideration contain at least one potential contact hapten. These findings indicate a need for patient education about potentially allergenic ingredients and stronger cooperation between academia and cosmetic manufacturers.

Determining the Sources of Variance in the Preparation of Analytical Standards for Chromatographic Analysis of a Lyophilized Peptide Drug Substance by Nested ANOVA Statistical Analysis.

Synthetic peptides used as therapeutic medicines is continuing to grow as an area of focus within the pharmaceutical industry due to specificity and potency. As such, quality control areas need to continue to advance their capabilities to ensure that appropriate analyses are being performed, and that the data generated are both accurate and precise. One area which poses a significant challenge compared with traditional small molecule drug products is having a highly robust, low variability method of quantifying the assay of the active substance. As many peptide therapeutics are formulated as liquid drug products for injection and preparation procedures to make these samples amenable to traditional chromatographic analysis are inherently low variability (i.e., a simple dilution), potential sources of variance derived from the preparation of the analytical standards used to quantify the assay of the product must be investigated. Here, a fully nested ANOVA experimental design was utilized to examine this process. Such a design allowed for multiple variables to be interrogated as well as the potential interplay of such differences. It was determined that sonication of the standards contributed the most variance, while the balance used and scale on which the standard preparation procedure was performed also contributed significantly. Finally, different procedures for introducing the material into a coulometric Karl Fischer (KF) titration device to quantify the water content of the drug substance were compared and showed that indirect quantification by anhydrous methanol extraction is a significantly more variable method than using an Oven KF autosampler.

Analysis of Extemporaneous Prescriptions Prescribed by Dermatovenerologists in Latvia and Comparison with Standardized Compounded Preparation Monographs of Germany and USA.

BACKGROUND AND OBJECTIVES: Even though many industrially manufactured medicines are available, extemporaneous preparations still have their niche in dermatology. In several countries, dermatovenerologists are one of the specialists prescribing extemporaneous medicines the most. In order to increase the quality of compounded medications and minimize risks to patient safety, several countries, for example, Germany and the United States of America (USA), created standardized compounded preparation monographs. Latvia, unlike these countries, does not have any officially approved standardized compounded preparation monographs. The purpose of this survey is to analyze the extemporaneous prescriptions prescribed by Latvian dermatovenerologists to identify the active ingredients, combinations of active ingredients, and excipients prescribed by dermatovenerologists the most often, and to find out how many active ingredients are most often compounded in different dosage forms. To understand whether the extemporaneous formulations used in Latvia for dermatological indications are evidence-based, they were compared with German and USA formulations. MATERIALS AND METHODS: A database was created entering data on all the prescriptions prepared in the selected pharmacies in 2017 to summarize information on extemporaneous prescriptions. The prescriptions prescribed by Latvian dermatovenerologists were selected and compared with German and USA formulations. RESULTS: Data from 17 Latvian pharmacies were collected, and 2521 extemporaneous formulations were analyzed. In preparation of semi-solid dosage forms, 25 bulk drug substances and 37 industrially manufactured preparations were used; in preparation of suspensions, 25 bulk drug substances and 10 industrially manufactured preparations were used; in preparation of topical solutions, 23 bulk drug substances and two industrially manufactured preparations were used; in preparation of topical powders, nine bulk drug substances were used; in preparation of oral solutions, five bulk drug substances were used. CONCLUSIONS: The analyzed prescriptions contained active ingredients used in Germany and the USA, as well as active ingredients, the use of which is limited in Germany and the USA. In Latvia, topical dosage forms containing two or more active ingredients are widely prescribed.