Estimation of the probability of passing the USP dissolution test

To ensure that a drug product will meet standards for identity, strength and stability as specified in the United States Pharmacopedia and National Formulary (USP/NF), it needs to pass a number of tests such as the content uniformity test and dissolution test at various stages of the manufacturing process. The sponsors usually have in-house specification limits based on some lower bounds of the probabilities of passing USP/NF tests to make sure that there is a high probability of passing the tests. Several probability lower bounds for dissolution test have been provided in the literature. In this paper, a method of calculating the probabilities of passing the dissolution tests is proposed. For the population mean and variance in some specified range, the probability derived from the methodology is very close to the exact probability. Therefore, the proposed method can provide an easy and accurate way to calculate the probability.     

Estimation of the Probability of Passing the USP Dissolution Test

To ensure that a drug product will meet standards for identity, strength and stability as specified in the United States Pharmacopedia and National Formulary (USP/NF), it needs to pass a number of tests such as the content uniformity test and dissolution test at various stages of the manufacturing process. The sponsors usually have in-house specification limits based on some lower bounds of the probabilities of passing USP/NF tests to make sure that there is a high probability of passing the tests. Several probability lower bounds for dissolution test have been provided in the literature. In this paper, a method of calculating the probabilities of passing the dissolution tests is proposed. For the population mean and variance in some specified range, the probability derived from the methodology is very close to the exact probability. Therefore, the proposed method can provide an easy and accurate way to calculate the probability.     

Probability lower bounds for USP/NF tests

In the pharmaceutical industry, a number of tests such as content uniformity and dissolution testing are usually performed at various stages of drug manufacturing process to ensure that the drug product meets standards for identity, strength, quality, purity, and stability of the drug product as specified in the United States Pharmacopedia and National Formulary (USP/NF). The USP/NF provides requirements for sampling plans, testing procedures, and acceptance criteria for these tests. To ensure that there is a high probability of passing the USP/NF tests, the sponsors usually establish in-house specification limits based on some lower bounds of the probabilities of passing USP/NF tests for future samples. In this article, we derive some probability lower bounds for USP/NF tests. It is shown that the proposed probability lower bounds are better than the existing ones and are very close to the true probabilities in a broad range of the population mean and variance of the test sample.     

Probability lower bounds for USP/NF tests

In the pharmaceutical industry, a number of tests such as content uniformity and dissolution testing are usually performed at various stages of drug manufacturing process to ensure that the drug product meets standards for identity, strength, quality, purity, and stability of the drug product as specified in the United States Pharmacopedia and National Formulary (USP/NF). The USP/NF provides requirements for sampling plans, testing procedures, and acceptance criteria for these tests. To ensure that there is a high probability of passing the USP/NF tests, the sponsors usually establish in-house specification limits based on some lower bounds of the probabilities of passing USP/NF tests for future samples. In this article, we derive some probability lower bounds for USP/NF tests. It is shown that the proposed probability lower bounds are better than the existing ones and are very close to the true probabilities in a broad range of the population mean and variance of the test sample.     

Central limit theorems for conditional efficiency measures and tests of the ‘separability’ condition in non‐parametric,two‐stage models of production

In this paper, we demonstrate that standard central limit theorem (CLT) results do not hold for means of non‐parametric, conditional efficiency estimators, and we provide new CLTs that permit applied researchers to make valid inference about mean conditional efficiency or to compare mean efficiency across groups of producers. The new CLTs are used to develop a test of the restrictive ‘separability’ condition that is necessary for second‐stage regressions of efficiency estimates on environmental variables. We show that if this condition is violated, not only are second‐stage regressions difficult to interpret and perhaps meaningless, but also first‐stage, unconditional efficiency estimates are misleading. As such, the test developed here is of fundamental importance to applied researchers using non‐parametric methods for efficiency estimation. The test is shown to be consistent and its local power is examined. Our simulation results indicate that our tests perform well both in terms of size and power. We provide a real‐world empirical example by re‐examining the paper by Aly et al. (1990, Review of Economics and Statistics 72, 211–18) and rejecting the separability assumption implicitly assumed by Aly et al., calling into question results that appear in hundreds of papers that have been published in recent years.     

Development of an inhalation unit risk factor for cadmium

An inhalation unit risk factor (URF) was developed for cadmium. The URF is based on excess lung cancer mortality in a key epidemiological study of cadmium smelter workers (Park et al., 2012). The Park et al. (2012) study is an update of the Thun et al. (1985) cohort that was previously used to derive a URF in USEPA (1985). Park et al. re-analyzed the cadmium smelter worker population (near Denver, CO) using more detailed work history information, a revised cadmium exposure matrix, a detailed retrospective exposure assessment for arsenic (potential confounder), and updated mortality data (through 2002). Grouped observed and expected number of lung cancer mortalities along with cumulative cadmium exposures were used in the current study to obtain the maximum likelihood estimate and asymptotic variance of the slope (β) for the linear multiplicative relative risk model using Poisson regression modeling. Life-table analyses were used to derive the final URF for cadmium of 4.9E-04 per μg Cd/m³. The corresponding lifetime air concentration at the 1 in 100,000 no significant excess risk level is 0.020 μg Cd/m³, which can be used to protect the general public in Texas against the potential carcinogenic effects from chronic exposure to cadmium and cadmium compounds.     

Content uniformity testing: suitability of different approaches for marketed low dose tablets

Context: Content uniformity (CU) testing was developed and improved to control the effectiveness and safety of dosage units. Many modifications of compendial CU test have been introduced and several alternatives have been suggested.

Objectives: This study aims to evaluate the degree of suitability of current USP CU test for low dose tablets and to compare the performance of the current test with that of the former USP27-NF22 and other alternatives for different sample sizes.

Methods: All locally marketed risperidone (RSP) tablets were analyzed using newly developed and validated isocratic UPLC method. The CU results were statistically analyzed in groups with sample sizes comparable to the USP sampling plans.

Results: Seven out of eleven products failed the different requirements of the former and current USP <905>chapters as well as of several alternative CU tests with several substantial deviations.

Conclusion: The current USP <905> chapter was found to have some deficiencies that allowed such failed products to exist in the market. The dependence of compendial CU test on two-staged sampling plan and the use of arithmetic mean to calculate the reference and acceptance values were obvious shortcomings.     

Particle Size and Content Uniformity

The requirements of the USP Content Uniformity test are translated into physical and mathematical parameters. Assuming spherical particle sizes with a log normal distribution, the mean particle size and particle size distribution required to insure a high probability of passing the content uniformity test are calculated. On the basis of these calculations it is shown that satisfactory tablets of low doses cannot be manufactured from a drug that does not meet certain particle size distribution specifications. It is recommended that particle size specifications for low dose drugs include a requirement for a limit to size distribution.     

基于蒙特卡洛的中美药典含量均匀度检查法的比较研究

目的 利用蒙特卡洛方法比较研究中国药典和美国药典的含量均匀度检查法,并提出改进思路。方法 以含量均匀度检查法准确率为性能指标,采用蒙特卡洛方法模拟药品质量的变化,并进行模拟抽样检查,比较中美药典含量均匀度检查法的性能;通过中心复合实验设计,考察中美药典含量均匀度检查法的检查参数对准确率的影响。结果 在不同均值和标准差情况下,中美药典的检查准确率无显著差异;中心复合实验设计的结果表明,中美药典含量均匀度检查法的参数均可进一步优化,从而提高检查准确率。结论 中美药典含量均匀度检查法的准确率基本一致,提出了优化含量均匀度检查参数的新思路。     

Asymmetry Effect of Particle Size Distribution on Content Uniformity and Over-Potency Risk in Low-Dose Solid Drugs

Most active pharmaceutical ingredients (API) exhibit particle size distributions with some degrees of asymmetry deviating from log-normality. A new log-skew-normal (L-S-N) distribution model is proposed for a systematic comparison of the asymmetry effect on content uniformity. The new model originated from the S-N model used by Azzalini gives a close approximation to real API particle size distribution. Monte-Carlo method was employed to simulate the dosage potency distribution. A high risk of over potency is uncovered when either the dose is low or API particle size distribution is positively skewed. This is due to the formation of pseudo heavy tail in potency distribution that decays slower than exponentially. Nomographs of API particle size versus dosage strength were constructed with a range of geometric standard deviations and asymmetry parameters with and without particle size cut-off (sieving) for a combined 99% pass rate against USP < 905 > Uniformity of Dosage Units. It was found that for a given specification of volume median and 90% diameters (d₅₀ and d₉₀), the dosage strength must increase by 10 times if the API asymmetry parameter changes from 1 (log-normal) to 1.1.     

Lack of medication dose uniformity in commonly split tablets

OBJECTIVE: To divide 11 commonly split tablets and evaluate the resulting half-tablets for content uniformity. DESIGN: Pre-post comparison. SETTING: Laboratory. Interventions: A trained individual split tablets of 11 products using a single-edged razor blade and 3 products by hand alone. MAIN OUTCOME MEASURES: The Uniformity of Dosage Units test published in the United States Pharmacopeia 24 (USP), which applies to whole tablets, was adapted liberally to assess the dose uniformity of the resulting split tablets. RESULTS: Of the 11 razor-split products, 8 failed the liberal adaptation of the USP uniformity test. No visible tablet features (e.g., scoring) predisposed a product's split tablets to pass or fail the uniformity test. All three hand-split tablets failed the uniformity test and yielded worse results than did razor-split tablets. CONCLUSION: The majority of the 11 drug products we tested, when assessed for their ability to be split into half-tablets of equal dose, failed a liberally interpreted USP uniformity test. The practice of dividing tablets to save costs or to improve a dosage regimen may not cause problems for patients using drugs with low toxicity and relatively flat dose-response relationships, but it is not recommended for patients using drugs with more substantial toxicity and steep dose-response efficacy curves.     

Investigation of the Performance of the Disintegration Test for Dietary Supplements

The aim of this study was to investigate how beaker size, basket assembly, use of disk, and immersion medium impact the disintegration time of dietary supplements. The disintegration times were determined for five tablet and two capsule products. A two-station disintegration tester was used with Apparatus A or Apparatus B as described in the United States Pharmacopeia (USP) chapters, <701> and <2040>. Two beakers complying with the harmonized specifications were used, one with a volume of 1,000 mL and one with a 1,500-mL volume. The disintegration data were analyzed using ANOVA for the following factors: beaker size, equipment (App A and B) and condition (with/without disk). Two tablet products were not sensitive to any changes in the test conditions or equipment configurations. One product was only partially sensitive to the test conditions. The other products showed impact on the disintegration time for all test conditions. The results revealed that these tablet products might pass or fail current USP disintegration requirements depending on the equipment configuration. Similar results were obtained for the two investigated capsule formulations. One product might fail current USP disintegration requirements if the large beaker was used, but might pass the disintegration requirements when the small beaker was used. Hydroxy propyl methyl cellulose capsules were mostly influenced if sodium instead of a potassium buffer was used as the immersion medium. The results demonstrate that the current harmonized ICH specifications for the disintegration test are insufficient to make the disintegration test into reliable test for dietary supplements.     

Development and Validation of a Stability-Indicating HPLC Method for the Simultaneous Determination of Sulfadiazine Sodium and Trimethoprim in Injectable Solution Formulation

A direct, precise, and stability-indicating HPLC method that is based on reversed-phase liquid chromatography (RP-HPLC) coupled with a photodiode array detector (PDA) was developed, optimized, and validated for the simultaneous determination of sulfadiazine sodium (SDZS) and Trimethoprim (TMP) in Bactizine® forte injectable solution. The separation was achieved using a C18 column (250 mm×4.6 mm i.d., 5 μm particle size) at room temperature, and an isocratic mobile phase that consisted of a trinary solvent mixture of water–acetonitrile–triethylamine (838:160:2, v/v) at pH 5.5 ± 0.05. The mobile phase was delivered at 1.4 ml/min and the analytes were monitored at 254 nm. The effects of the operational chromatographic conditions on the peak’s USP tailing factor, column efficiency, and resolution were systematically optimized. Forced degradation experiments were carried out by exposing SDZS, TMP standards, and their formulation to thermal, photolytic, oxidative, and acid-base hydrolytic stress conditions. The method was successfully validated in accordance to International Conference on Harmonization (ICH) and United States Pharmacopoeia (USP34/NF29) guidelines and found to be suitable for the quantitative determination and stability of SDZS and TMP in Bactizine® forte injectable solution.     

Novel system to investigate the effects of inhaled volume and rates of rise in simulated inspiratory air flow on fine particle output from a dry powder inhaler

This study evaluated the effect of inhaled volume and simulated inspiratory flow rate ramps on fine particle output from dry powder inhalers (DPIs). A simple, robust system was developed to account for “rate of rise” (ramp) effects while maintaining a constant air flow through a multi-stage liquid impinger (MSLI), used for sizing the emitted particles. Ramps were programmed to reach 30 and 60 L/min over 100 milliseconds; 500 milliseconds; and 1, 2, and 3 seconds. Rotahaler was chosen as the test DPI. Testing was done with simulated inhalation volumes of 2 L and 4 L. Testing was also carried out using the USP apparatus 4. At 30 L/min, for a 2 L volume, the amount of drug exiting the device in fine particle fraction (FPF) increased from 2.33 μg to 6.04 μg from the 3-second ramp to the 100-millisecond ramp, with 11.64 μg in FPF for the USP (no ramp) method. At the same flow rate, for a 4 L volume, FPF increased from 2.23 μg to 8.45 μg, with 10.25 μg for the USP method. At 60 L/min, similar trends were observed. In general, at both flow rates, an increase in FPF was noted going from the shallowest to the steepest ramp. However, there were no significant differences in FPF when a 2 L inhaled volume was compared with a 4 L volume at each flow rate. Overall, these data suggest that the existing USP apparatus may overestimate FPF at flow rates lower than those recommended by the USP.     

Application of Tunable Resistive Pulse Sensing for the Quantification of Submicron Particles in Pharmaceutical Monoclonal Antibody Preparations

Tunable resistive pulse sensing (TRPS, qNano Gold, IZON Ltd.) was investigated as a method to quantify submicron particles (SMPs) between 0.1 and 1 µm in solutions of biopharmaceuticals. To reduce sample dilution, a spiking-in approach was used to add the appropriate amount of electrolytes required for the measurement. For correct particle quantification, an electrolyte concentration of at least 50 mM sodium chloride was needed. Intra- and inter-nanopore variability were below 5% for size and below 10% for concentration measurements when analyzing polystyrene standard beads. Submicron particle counts in a stir stressed IgG1 monoclonal antibody formulation resulted in a non-symmetrical, almost bell-shaped size distribution with a maximum at 250 nm when using a NP300 nanopore (IZON Ltd.). It was shown that particle counts are heavily underestimated below 250 nm, and therefore it is recommended to quantify particle counts by TRPS in samples with heterogeneous particle size distributions (e.g., biopharmaceuticals) only starting from the maximum of the histogram towards the upper limit of detection.     

A revised amino group pKa for prymnesins does not provide decisive evidence for a pH-dependent mechanism of Prymnesium parvum’s toxicity

A reconsideration of the pKa values proposed by Valenti et al. (Theodore W. Valenti et al., A mechanistic explanation for pH-dependent ambient aquatic toxicity of Prymnesium parvum carter. Toxicon (2010) 55, 990-998) suggests that the ionization status of the C-14 amino group in prymnesins will not substantially influence the toxicity of these compounds over a pH range of 6.5-8.5. A revised pKa value and ionization state distribution for the prymnesins in aqueous systems is proposed.     

A Novel Use of Nanocrystalline Suspensions to Develop Sub-Microgram Dose Micro-Tablets

Developing solid oral drug products with good content uniformity (CU) at low doses is challenging; this challenge further aggravates when the tablet size decreases from a conventional tablet to a micro/mini-tablet (1.2–3 mm diameter). To alleviate the CU issues, we present a novel use of nanocrystalline suspension combined with high shear wet granulation for the first time. In this approach, nanomilled drug in the form of nanocrystalline suspension is sprayed onto the powder bed to ensure uniform distribution. The resulting granules had adequate particle size distribution and flow characteristics to enable manufacturing of micro-tablets with good weight uniformity and tensile strength. Nanomilled drug resulted in excellent content uniformity among individual micro-tablets even at a dose strength as low as 0.16 mcg, whereas micronized drug resulted in unacceptable CU even at 5x higher dose strength (0.8 mcg). Besides, the use of nanomilled drug has enhanced the dosing flexibility of micro-tablets and showed superior dissolution performance in comparison with micronized drug with no impact of storage conditions (40 °C/75%RH for six months) on their dissolution performance. The proposed approach is simple and can be easily incorporated into traditional high shear wet granulation process to develop sub-microgram dose solid oral drug products.