Quality Control Of Drug Products Research Articles

Measurement uncertainty arising from sampling and analytical steps of dissolution test of glyburide tablets

The dissolution test is an essential technique used in pharmaceutical research to assess the rate and extent of drug release from a dosage form into a dissolution medium. Accurate and reliable dissolution test results are crucial to ensure the quality and efficacy of the drug product. The aim of this study was to evaluate the measurement uncertainty arising from the sampling and analytical steps of the dissolution test for glyburide tablets. Dissolution test was performed using 900 mL of phosphate buffer pH 7.3 as dissolution medium and a dissolution apparatus equipped with paddles rotating at 75 rpm for 60 min. Quantification was performed by HPLC-UV. The uncertainty arising from sampling was estimated through classical Analysis of Variance (ANOVA), using 8-sampling targets, two samples for each sampling target and two replicas for each sample, totalizing 32 analyses. Uncertainty arising from analytical steps considered the uncertainty from dissolution step (estimated using Monte Carlo method and regression equation obtained using DoE) and uncertainty from quantification step. The overall uncertainty value was found to be 6.33 %. The sources of uncertainty contributing to the overall measurement uncertainty of the dissolution test were estimated to be 76.09 % from sampling, 22.15 % from the dissolution step, and 1.76 % from the quantification step. The study emphasizes the importance of evaluating measurement uncertainty in dissolution testing to ensure reliable and accurate drug product quality control. The results demonstrate that the dissolution test of glyburide tablets presented high sampling uncertainty and did not pass the dissolution test within the specified limits, probably due to glyburide’s low solubility. Univariate and multivariate rejection limits were calculated in order to ensure reduced particular and total producer’s risk, respectively. This study provides useful insights for pharmaceutical industries to optimize their quality control processes and ensure the efficacy and safety of their products.

ATR-FTIR Biosensors for Antibody Detection and Analysis.

Quality control of drug products is of paramount importance in the pharmaceutical world. It ensures product safety, efficiency, and consistency. In the case of complex biomolecules such as therapeutic proteins, small variations in bioprocess parameters can induce substantial variations in terms of structure, impacting the drug product quality. Conditions for obtaining highly reproducible grafting of 11-mercaptoundecanoic acid were determined. On that basis, we developed an easy-to-use, cost effective, and timesaving biosensor based on ATR-FTIR spectroscopy able to detect immunoglobulins during their production. A germanium crystal, used as an internal reflection element (IRE) for FTIR spectroscopy, was covalently coated with immunoglobulin-binding proteins. This thereby functionalized surface could bind only immunoglobulins present in complex media such as culture media or biopharmaceutical products. The potential subsequent analysis of their structure by ATR-FTIR spectroscopy makes this biosensor a powerful tool to monitor the production of biotherapeutics and assess important critical quality attributes (CQAs) such as high-order structure and aggregation level.

Application of capillary zone electrophoresis to determine second-generation H1 antihistaminic drugs, loratadine and rupatadine

The second generation of H1 antihistamines from the piperidine group are often used for treating allergic diseases due to their action on histaminic receptors, the primary mediator of allergy. Moreover, the antihistamines have anti-inflammatory action, mediated through platelet-activating factor blocking activity. A simple and rapid capillary zone electrophoresis method was developed and validated for the determination of loratadine (LOR) and rupatadine (RUP) in tablets. The analyses were carried out using a fused silica capillary of 50.2 cm (40 cm effective length), 75 µm i.d. The background electrolyte was composed of boric acid 35 mmol/L, pH 2.5. Voltage of 20 kV, hydrodynamic injection of 3447.3 Pa for 3s, temperature at 25 ºC, and UV detection at 205 nm were applied. Electrophoretic separation was achieved at 1.8 and 2.8 min for RUP and LOR, respectively. The method was linear for both drugs in a range of 50.0 to 400.0 μg/mL (r>0.99). The limits of detection and quantification were 46.37 and 140.52 μg/mL, for LOR and 29.60 and 89.69 μg/mL for RUP respectively. The precision was less than 5.0 % for both drugs. The average recovery was approximately 100 %. The proposed novel method can significantly contribute to the rapid detection of counterfeit products and in quality control of drug products containing antihistamines.

Evaluation of water induced phase transition of Fexofenadine Hydrochloride during wet granulation process using NIR and DSC techniques

The quality control of drug products during manufacturing processes is important, particularly the presence of different polymorphic forms in active pharmaceutical ingredients (API) during production, which could affect the performance of the formulated products. In this study, Fexofenadine Hydrochloride (FXD) Form I (anhydrous) was used as the starting material for pharmaceutical formulation, while FXD exhibited a polymorphic conversion to hydrate Form II in presence of water. It is necessary to monitor phase transition from Form I to Form II during wet granulation. The aim of this paper was to quantify the polymorphic forms of FXD during wet granulation process by NIR and DSC technique. Calibration models were developed and validated in binary mixtures of FXD polymorphs forms and multicomponent mixtures of FXD formulation. The NIR and DSC can be successfully employed to evaluate and quantify Form I during wet granulation. The Form I % determined was similar by NIR and DSC. The relationship between phase transition of FXD and water content was determined. In addition, the effect of various excipients on the phase transition of FXD was also evaluated by NIR. The understanding of the phase transition in wet granulation process of pure FXD, formulation and FXD-excipient mixtures provided directions for optimization of FXD manufacturing processes.

Solid Form and Phase Transformation Properties of Fexofenadine Hydrochloride during Wet Granulation Process.

The quality control of drug products during manufacturing processes is important, particularly the presence of different polymorphic forms in active pharmaceutical ingredients (APIs) during production, which could affect the performance of the formulated products. The objective of this study was to investigate the phase transformation of fexofenadine hydrochloride (FXD) and its influence on the quality and performance of the drug. Water addition was key controlling factor for the polymorphic conversion from Form I to Form II (hydrate) during the wet granulation process of FXD. Water-induced phase transformation of FXD was studied and quantified with XRD and thermal analysis. When FXD was mixed with water, it rapidly converted to Form II, while the conversion is retarded when FXD is formulated with excipients. In addition, the conversion was totally inhibited when the water content was <15% w/w. The relationship between phase transformation and water content was studied at the small scale, and it was also applicable for the scale-up during wet granulation. The effect of phase transition on the FXD tablet performance was investigated by evaluating granule characterization and dissolution behavior. It was shown that, during the transition, the dissolved FXD acted as a binder to improve the properties of granules, such as density and flowability. However, if the water was over added, it can lead to the incomplete release of the FXD during dissolution. In order to balance the quality attributes and the dissolution of granules, the phase transition of FXD and the water amount added should be controlled during wet granulation.

Advanced Formulation Design for Topical Creams Assisted with Vibrational Spectroscopic Imaging.

Vibrational spectroscopic imaging has become useful analytical tools for quality control of drug products. In this study, we applied microscopic attenuated total reflection (ATR)-IR and confocal Raman microscopy to elucidate microscopic structure of creams and for the formulation design in the development of semi-solid drug products. The model creams were prepared with prednisolone (PRD) and fluconazole (FLC) as active pharmaceutical ingredients and oily solvents such as mineral oil (MO), isopropyl myristate (IPM), benzyl alcohol (BA) and diethyl sebacate (DES). As a result of microscopic ATR-IR imaging, several domains indicating oily internal phase were observed, which had absorption around 1732 and 1734 cm-1 derived from MO, IPM and DES. In addition, domains of BA around 1009 cm-1 were observed at the complemental or similar position in the formulation with MO or DES, respectively. These results suggested that the creams were oil-in-water type and the distribution of domains would reflect the compatibility of the solvents. The contents of PRD and BA were determined quantitatively in each layer after the intentional separation of the creams and the results agreed well with the imaging analysis. Whereas, confocal Raman imaging allowed to visualize the distribution of the components in depth direction as well as two-dimensional plane. In particular, the Raman imaging would ensure the coexistence of FLC and BA as oily phase in the cream. From these results, the feasibility of spectroscopic imaging techniques was successfully demonstrated for the formulation design of semi-solid dosage forms.

A Biopharmetrics Approach for Drug Product Quality Control with Clinical Relevance

To exemplify a systematic and quantitative approach (Biopharmetrics approach) for product quality control with clinical relevance, the study utilized multivariate models to connect raw material attributes of a product to its dissolution obtained in a DOE (design of experiment) and further extended the connection to the in vivo exposures (AUC and Cmax) of the product using an available IVIVC (in vitro/in vivo correlation). Thus, a model for the relationship between in vivo exposure and raw material attributes of the product was established. Based on the model, the exposure ratios between future batches (with various raw material attributes) and the pivotal clinical batches (with confirmed clinical efficacy and safety) were predicted resulting in a set of contour lines in a graphical representation. Among these contour lines, the lines for exposure ratios of 0.8 and 1.2 were defined as lower and upper limits. With the failure edges defined, clinically meaningful limits for the raw material quality control were specified. If the raw material attributes in the future production conform to the specifications, the manufacturing would lead to products bioequivalent to the clinical batches. From these exercises, Biopharmetrics, a subdiscipline of biopharmaceutics, was introduced and its definition, scope, and characteristics were discussed.

Improving coverage probabilities for parametric tolerance intervals via bootstrap calibration.

Statistical tolerance intervals are commonly employed in biomedical and pharmaceutical research, such as in lifetime analysis, the assessment of biosimilarity of branded and generic versions of biopharmaceutical drugs, and in quality control of drug products to ensure that a specified proportion of the products are covered within established acceptance limits. Exact two-sided parametric tolerance intervals are only available for the normal distribution, while exact one-sided parametric tolerance limits are available for a limited number of distributions. Approximations to two-sided parametric tolerance intervals often use the Bonferroni correction on the one-sided tolerance interval calculation; however, this often incurs a higher coverage probability than the nominal level. Recently, the usage of a bootstrap calibration has been demonstrated as a way to improve coverage probabilities of tolerance intervals for very specific and complex distributional settings. We present a focused treatment on using a single-layer bootstrap calibration to improve the coverage probabilities of two-sided parametric tolerance intervals. Simulation results clearly demonstrate the improved coverage probabilities towards the nominal level over the uncalibrated setting. Applications to medical data for various parametric distributions also highlight the utility of constructing these calibrated tolerance intervals.

A NEW VALIDATED STABILITY-INDICATING DIRECT HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY METHOD FOR THE DETERMINATION OF ROSIGLITAZONE ENANTIOMERS IN THE PRESENCE OF ITS DEGRADATION PRODUCTS

Objective: In the present study, an isocratic chiral reverse-phase high-performance liquid chromatography method was developed and the resolution of the drug and complete separation from its degradation products were successfully achieved.&#x0D; Methods: An isocratic method developed with a Phenomenex Lux 5 μ Cellulose 1 (150 mm×4.6 mm i.d., 5 μ) using UV detector at wavelength of 220 nm, with a mobile phase consisting of methanol:0.1% diethylamine (60:40% v/v) and a flow rate of 1 ml/min. The drug was subjected to alkaline, acidic, neutral, oxidative, and photolytic to apply stress conditions. The stressed samples were analyzed by the proposed method.&#x0D; Results: The described method was linear over the range of 3–7 μg/ml for R-enantiomer and 9–21 μg/ml of S-enantiomer, respectively. The limit of detection and limit of quantification of R and S enantiomers were found to be 0.56 μg/ml and 0.18 μg/ml, respectively.&#x0D; Conclusion: The method provides good sensitivity and excellent precision and reproducibility. The developed method can be applied in the quality control of drug products.

Low-Field NMR in Nondestructive Quantitative Inspection of Drug Products

Batch-to-batch inference-based quality control of drug products has historically been very effective. However, infrequent incidences of drug defects may be missed by traditional batch-to-batch testing, especially for complex drugs, e.g. biologics. Compared to small molecule drugs, complex drugs have many more factors involved their production and manufacturing, and are more prone to degrade with temperature stresses or agitation during transportation and storage. Relying on batch testing, the sole inspection method of released drug products is human visual inspection. Here we investigate the use of low-field NMR (23 MHz) to inspect four types of drug products, each addressing a different potential quality control problem: 1. Novolog FlexPen® (wrong dosage), 2. Ferrlecit® vs. generic (false equivalence), 3. Alhydrogel® (uneven filling of alum adjuvant), 4. Daptacel®, Engerix-B®, and Vaqta® vaccines (freeze/thaw stress). In every case, during our experiments the product (vial or pen) remained sealed without any tampering; low-field NMR as a method for drug product inspection is non-destructive. The water proton transverse relaxation rate, R2(1H2O), was found to be sensitive to concentration changes in aluminum hydroxide adjuvants, and insulin protein. Furthermore, differences in brand name and generic drug products were detected by the R2(1H2O), where properties measured by other analytical methods failed to detect differences. These findings suggest that low-field 1H2O NMR could serve as a non-destructive inspection method for drug products, such as insulin pens and vaccines.

Correlation of dissolution and disintegration results for an immediate-release tablet

The drug release rate of a rapidly dissolving immediate-release tablet formulation with a highly soluble drug is proposed to be controlled by the disintegration rate of the tablet. Disintegration and dissolution test methods used to evaluate the tablets were shown to discriminate manufacturing process differences and compositionally variant tablets. In addition, a correlation was established between disintegration and dissolution. In accordance with ICH Q6A, this work demonstrates that disintegration in lieu of dissolution is suitable as the drug product quality control method for evaluating this drug product.

Main Reasons for Registration Application Refusal of Generic and Similar Pharmaceutical Drug Products by the Brazilian Health Regulatory Agency (ANVISA)

Objective. The marketing authorization of generic and similar pharmaceutical drug products involves the analysis of proposing company's administrative aspects as well as drug product technical description and scientific evaluations. This study evaluated the main reasons for registration refusal of generic and similar pharmaceutical drug products in Brazil. The aim is to help future applicants to better organize the proposal. Methods. A retrospective search of drug products registration processes was performed on the Brazilian Government Official Gazette from January 1, 2015, and December 31, 2015. Results. Drug product quality control, drug product stability study, deadline accomplishment, API quality control made by drug manufacturer, active pharmaceutical ingredient (API), and production report were the main reasons for marketing authorization application refusal of generic and similar pharmaceutical drug products in 2015. Conclusion. Disclosure of the reasons behind failed applications is a step forward on regulatory transparency. Sharing of experiences is essential to international regulatory authorities and organizations to improve legislation requirements for the marketing authorization of generic and similar pharmaceutical drug products.

Near infrared spectroscopy to monitor drug release in-situ during dissolution tests

Dissolution tests can be used to demonstrate suitable in vivo drug release through in vivo/in vitro correlations. This work explores the possibility of using near infrared spectroscopy (NIRS) to monitor in-situ dissolution tests. It aims at expanding surrogate methods in quality control of drug products. Laboratory designed tablets of an immediate-release formulation containing folic acid and four excipients were used as case study. The dissolution tests were performed on a 1L vessel filled with 500ml of Milli-Q water with a rotating paddle apparatus (apparatus 2, Ph. Eur.) at 50rpm and 37±0.5°C. Near infrared (NIR) spectra were acquired in-situ with a transflectance probe connected to a Fourier-transform near infrared spectrometer. NIR spectra were regressed against folic acid concentration by partial least squares (PLS) regression. Folic acid concentrations during dissolution tests were obtained by periodically sampling the dissolution vessel and resourcing to an UV method. The proposed real-time NIR method was tested on a validation run yielding a root mean squared error of 0.25μgml−1 (0.16μgml−1 for the calibration runs) and a R2 of 0.93 (0.95 for the calibration runs). The results suggest that NIRS is a suitable analytical technique for monitoring in-situ dissolution tests.

Investigation of the stabilizer elimination during the washing step of charged PLGA microparticles utilizing a novel HPLC-UV-ELSD method

Quantification of stabilizer content in microparticles and other products is of great importance for formulation development, drug product quality control as well as for reproducible manufacturing. A fast and sensitive HPLC method with evaporative light scattering detection (ELSD) capable of detecting docusate sodium (DOSS), poly (lactic-co-glycolic acid) (PLGA; Resomer RG 503 H) and R-1,2-dioleoyloxy-3-trimethylammonium-propane (DOTAP) in a single run was successfully developed. In contrast to previously described methods, hydrolysis of PLGA as pretreatment is not necessary, thereby enabling accurate quantification of stabilizer next to the intact matrix polymer.This method was used to investigate the impact of washing procedures of polymeric microparticles manufactured either with anionic stabilizer DOSS or with cationic stabilizer DOTAP. High amounts of DOSS were detected in the washing water. This finding was consistent with the result that no DOSS could be detected in the washed and dried microparticles (<limit of detection).In contrast, DOTAP was hardly measurable in the washing water during all washing cycles. However, DOTAP could be quantified in dried particles. The ratio of DOTAP to dry particle mass was approximately 1:10.This is most probably due to the different polymer surfactant interactions (e.g. charge) and the different hydrophilicity of the stabilizers used.

Using Tolerance Intervals for Assessment of Pharmaceutical Quality

In quality control of drug products, tolerance intervals are commonly used methods to assure a certain proportion of the products covered within a pre-specified acceptance interval. Depending on the nature of the quality attributes, the corresponding acceptance interval could be one-sided or two-sided. Thus, the tolerance intervals can also be one-sided or two-sided. To better utilize tolerance intervals for quality assurance, we reviewed the computation method and studied their statistical properties in terms of batch acceptance probability in this article. We also illustrate the application of one-sided and two-sided tolerance, as well as two one-sided tests through the examples of dose content uniformity test, delivered dose uniformity test, and dissolution test.

Application of LA-ICP-MS as a rapid tool for analysis of elemental impurities in active pharmaceutical ingredients

The control of inorganic contaminants in active pharmaceutical ingredients has a significant role in the quality control of drug products. The concentration limits for metal residues in drug products have been defined by various regulatory guidelines. Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) is a powerful and fast analytical technique for multi-elemental analysis. A disadvantage in using LA-ICP-MS method is the lack of matrix reference materials for validation and calibration purposes. This article focuses on the handling strategy of laboratory-made matrix calibration standards for the quantification of elemental impurities in an active pharmaceutical ingredient by LA-ICP-MS.

Impurity profile analysis of drug products containing acetylsalicylic acid: a chemometric approach

Abstract In this work attention is focused on impurity profile analysis in combination with infrared spectroscopy and chemometric methods. This approach is considered as an alternative to generally complex and time-consuming classic analytical techniques such as liquid chromatography. Various strategies for constructing descriptive models able to identify relations among drug impurity profiles hidden in multivariate chromatographic data sets are also presented and discussed. The hierarchical (cluster analysis) and non-hierarchical segmentation algorithms (k-means method) and principal component analysis are applied to gain an overview of the similarities and dissimilarities among impurity profiles of acetylsalicylic acid formulations. A tree regression algorithm based on infrared spectra is used to predict the relative content of impurities in the drug products investigated. Satisfactory predictive abilities of the models derived indicate the possibility of implementing them in the quality control of drug products.

Measurement of flowability of lubricated powders by the vibrating tube method

Background: The evaluation of lubricity or flowability of pharmaceutical powders is important for consistent production and quality control of drug products. However, there have been only a few studies on quantitative measurements of the properties of lubricated powders.Method: Magnesium stearate (MgSt) and sodium stearyl fumarate (SSF) were used as lubricants. Lubricated powders were prepared by adding lubricants to spray-dried lactose under different conditions. To evaluate flowability, the vibrating tube method was used. In this method, the vibration amplitude of the tube is increased at a constant rate, and the mass of the powder discharged from the tube is recorded. Flowability profiles, i.e. the relationships between the mass flow rate and vibration acceleration, were obtained experimentally. To characterize static and dynamic friction properties of powders, critical vibration acceleration required to make powder particles flow and the average mass flow rate were determined.Results: Addition of 0.5% MgSt was sufficient for the reduction of static friction between particles. Blending time of the lubricants had little effect on the average mass flow rate of lubricated powders. On the other hand, addition of SSF resulted in an increase in static friction at the beginning of blending, and after a certain blending time, flowability improved. The combination of MgSt and SSF improved both static and dynamic friction properties irrespective of the blending time.Conclusion: The vibrating tube method can be used to evaluate the flowability properties of lubricated powders, and the experimental results provide useful information on the production of pharmaceutical solid dosage forms.

A quantitative human monoclonal antibody immunoassay using anti‐idiotypic antibody as a membrane antigen surrogate with surface‐plasmon‐resonance detection

Biologically active membrane proteins are difficult to isolate. Very often the isolated membrane proteins have low binding affinity or no biological integrity at all. Despite some success in isolation, one has to overcome the hurdles of obtaining sufficient quantity of the proteins and maintaining biological activity upon coating them on surfaces for developing an ELISA. Thus an alternative approach may be useful. The present study describes a quantification assay method for a therapeutic hmAb-1 (human monoclonal antibody-1) that recognizes a cell-surface protein employing an anti-ID (anti-idiotypic antibody) to hmAb-1 as a surrogate antigen in an immunoassay format using surface- plasmon-resonance technology. This assay is applicable for quantification of hmAb-1 in process streams, final drug-product quality control, as well as low-concentration drug substances in intravenous-solution bags. The surrogate nature of the anti-ID was confirmed by demonstrating that the anti-ID displaced the interaction between the hmAb-1 and its membrane antigen in a FACS titration test. The assay format involves first capturing hmAb-1 on the flow-cell surface, which then binds quantitatively to anti-ID in a mixture of increasing quantity of hmAb-1 in solution. An inverse dose-response relation between this anti-ID bound signal (or resonance units) and hmAb-1 concentration was established. The dose-response range of the calibration curve for hmAb-1 was between 20 and 300 ng/ml. The precision, accuracy and specificity of the assay are reported in the present paper.

Determination of protamine peptides in insulin drug products using reversed phase high performance liquid chromatography

This paper describes the establishment and validation of a reversed phase HPLC (RP-HPLC) method for determination of protamine peptides in protamine sulphate raw material and insulin drug products, discusses the analytical results obtained for a number of protracted insulin formulations and the potential of the method in connection with protamine sulphate raw material and final drug product quality control.