Influence of variability in starting materials quality on stability of finished drug products: a quality-by-design factor and response

The use of ill selected excipients in drug formulations can have a significant influence on the overall stability. Therefore, evaluation of chemical and physical excipient compatibility with the API has become a major part in the development of new drug products. Moreover, general and individual limits for excipient impurities have also been set by the Ph. Eur. However, batch to batch variability of these excipient impurities, although still Ph. Eur compliant, can cause significant variability in the stability profile of finished drug product. Recently, large manufacturer and batch to batch variability in hydroperoxide levels was documented in common used pharmaceutical excipients such as povidone, polysorbate 80, PEG 400 and hydroxypropylcellulose [1]. As a result, oxidation sensitive drugs, e.g. raloxifene HCl, can demonstrate inconsistent stability profiles when combined with aforementioned excipients [2]. Another example in which a miconazole-BHT adduct is formed, can be traced back to the petrolatum vehicle, containing BHT, used for topical application [3]. Note that no BHT limits are mentioned in the corresponding Ph. Eur. monograph. We evaluated the short-term storage stability of three triple intrathecal (Triple IT) solution batches under various conditions [4]. The Triple IT solution, containing cytarabine, methotrexate and methylprednisolone (21)-sodium succinate (MPSS), is used in the treatment of leukemia, lymphoma and brain cancers. Hydrolysis of MPSS to methylprednisolone was found to be the predominant degradation reaction. However, different MPSS degradation kinetics were observed. This observation was linked to the use of different batches of MPSS starting material, i.e. Solu-Medrol®, thus providing an inconsistency in the degradation profile. References [1] Wasylaschuk, W.R.; Harmon, P.A.; Wagner, G.; Harman, A.B.; Templeton, A.C.; Xu, H.; Reed, R.A. Evaluation of hydroperoxides in common pharmaceutical excipients (2006). Journal of Pharmaceutical Sciences; 96; 106-116. [2] Hartauer, K.J; Arbuthnot, G.N.; Baertschi, S.W.; Johnson, R.A.; Luke, W.D; Pearson, N.G.; Rickard, E.C.; Tingle, C.A.; Tsang, P.K.S.; Wiens, R.E. Influence of peroxide impurities in povidone and crospovidone on the stability of raloxifene hydrochloride in tablets: identification and control of an oxidative degradation product (2000). Pharmaceutical Development and Technology; 5; 303-310. [3] Zhang, F.; Nunes, M. Structure and generation mechanism of a novel degradation product formed by oxidatively induced coupling of miconazole nitrate with butylated hydroxytoluene in a topical ointment studied by HPLC-ESI-MS and organic synthesis. [4] D’Hondt, M.; Vangheluwe, E.; Van Dorpe, S.; Boonen, J.; Bauters, T.; Pelfrene, B.; Vandenbroucke, J.; Robays, H.; De Spiegeleer, B. Stability of extemporaneously prepared Triple inthrathecal solution of cytarabine, methotrexate and methylprednisolone sodium succinate (in press). American Journal of Health-System Phamacy

Pharmacopeial characterization of asparaginase

Asparaginase (ASNASE), an enzyme catalyzing the deamidation of asparagine, is therapeutically used for the treatment of pediatric acute lymphoblastic leukemia (ALL). Current administration protocols are exclusively using bolus injection. No information is available about other dosages, like slow intravenous administration, thus hampering the full clinical exploitation of the drug. Preliminary observation indicates inconsistent issue of incompatibility with the infusion solution, which seems dependent of i.a. the source and batch of asparaginase used. Therefore, a selective pharmaceutical characterization is urgently required, so that the right choices and use of ASNASE can be defined, extending the clinical use. We present our current results of the development and evaluation of (1) the enzymatic activity by determination of the formed ammonia by the Nessler reaction (see Figure 1) and (2) the amide-bond characterization (secondary/tertiary structures) by Fourier Transform Infrared Spectroscopy (FT-IR) and Circular Dichroism (CD). Different methods were selected for the ASNASE activity determination; whereof the Nessler assay was withheld for optimization. Using Design of Experiments (DOE) with four variables, i.e. CKI/CHgI2, CNaOH/CHgI2, CHgI2 final and reaction time in a D-optimal onion design space, a maximum enzyme activity response could be determined. For the characterization of the primary structure, peptide-mapping LC-MS method was adopted. The ASNASE amide-bond (secondary/tertiary structures) was characterized by FT-IR (see Figure 2) and CD. The secondary structure elements of the ASNASE are quantified by FT-IR, combined with mathematical deconvolution of the different amide peaks (mainly amide I, II and III bands). Using CD, the melting temperature (Tm) in relation with the enzyme stability is examined. Denaturation of the β-sheet is observed in a temperature range of 60-63°C, while the α-helix denaturated in 63-65°C

Successful treatment of adenovirus infection with brincidofovir in an immunocompromised patient after hematological stem cell transplantation

Immunocompromised patients, including hematopoietic stem cell transplantation (HSCT), HIV, and malnourished patients, are at increased risk for viral infections with high incidences of morbidity and mortality. In HSCT patients, the infection risk is increased until immune reconstitution is re-established. Therapy with standard of care antiviral drugs, for example Cidofovir, is expensive, requires prolonged administration, and has unfavorable toxicity profiles. Our case describes the successful use of Brincidofovir (CMX001), a lipid-conjugate of the nucleotide analog Cidofovir, in a 9-year-old post-HSCT girl with disseminated adenovirus infection. The increased efficacy of Brincidofovir (BCV) against multiple viral infections, limited toxicity, and oral-administered schedule opens options in different resource settings

Fused-core HPLC method development implemented in a short-term stability study of Triple IT solution

For the majority of children with acute lymphoblastic leukemia (ALL), treatment consists in part of a triple intrathecal (Triple IT) therapy, i.e. a combination of cytarabine (CB), methotrexate (MTX) and methylprednisolone sodium succinate (MPSS) [1]. This combination product is prepared ex-tempore. However, no in-use shelf-life under defined storage conditions has yet been established. During stability studies, a large number of samples are generated, thus creating the need for a fast, accurate and selective analytical method. In this study, a fused-core HPLC method was developed. This hybrid technology, consisting of a 0.5 µm thick porous shell fused to a 1.7 µm inert core, enables faster chromatographic separation with sufficiently high resolution. During method development, both stressed and unstressed solutions containing both single Triple IT components and the mixture thereof, were analyzed using different linear gradient times, ranging from 5 to 30 min. The mobile phase composition was fixed (A: 0.1% glacial acid in H2O; B: 0.1% glacial acid in ACN), starting with A:B (90:10, V/V) and ending with A:B (10:90, V/V). Method selectivity was evaluated based on the observed peaks in stressed CB, MTX and MPSS solutions, i.e. incubation at 40°C and 80°C. A balance between fast separation and sufficient resolution between the Triple IT components and related degradants, was found by setting the gradient time at 15 min. The Triple IT related degradation peaks were chromatographically separated from the remaining Triple IT components. Moreover, selectivity was supported by a peak purity analysis on the observed peaks. Linearity was demonstrated (R² > 0.999) for the three Triple IT components. Repeatability was evaluated by triplicate injections of 100% reference assay: relative standard deviation varied between 0.155% (MPSS), 0.464% (CB) and 1.352% (MTX) [2]. References [1] A. Ruggiero, V. Conter, M. Milani, E. Biagi, I. Lazzareschi, P. Sparano, R. Riccardi. Intrathecal chemotherapy with antineoplastic agents in children. Paediatric drugs 3(4) (2001) 237-246. [2] M. D’Hondt, E. Vangheluwe, S. Van Dorpe, J. Boonen, T. Bauters, B. Pelfrene, J. Vandenbroucke, H. Robays, B. De Spiegeleer. Stability of ex-tempore prepared Triple intrathecal solution consisting of cytarabine, methotrexate and methylprednisolone sodium succinate. American Journal of Health-System Pharmacy, submitted for publication

Rapid and sensitive plate method for detection of Aspergillus fumigattus

The routine identification of Aspergillus fumigatus in clinical samples involves, apart from direct examination, the isolation of the organism on a plate followed by its microscopic characterization. This approach lacks sensitivity, specificity, and speed. A new procedure has been developed combining microcolony formation on a nylon membrane filter at 45 degrees C with the detection of a specific 4-methylumbelliferyl-alpha-L-arabinopyranoside cleaving enzyme activity in digitonin permeabilized cells. The test takes approximately 14 h and has an efficiency of 98.2% and false-positive and -negative rates of 0 and 3.1%, respectively, When applied to 188 clinical samples taken from patients with proven or nonproven presence of Aspergillus species, a good agreement with the conventional plate-microscopy method was obtained

Drug shortages in a pediatric stem cell transplantation ward : challenges and implications : a 5-year bilan

This article describes the implications of shortages of pharmaceutical products used in conditioning and supportive care regimens of pediatric patients undergoing a hematopoietic stem cell transplantation in a tertiary care hospital. Between July 2011 and July 2016, a total of 84 individual shortages, affecting 22 different drugs (79.8% supportive care drugs; 20.2% chemotherapeutics) were detected with a mean duration of 85 days (SD 138) per individual drug shortage. Eighteen shortages were critical and very urgent. Sulfamethoxazol/trimethoprim, piperacillin/tazobactam, ranitidine, benzylpenicillin, ondansetron (supportive care) and methotrexate, melphalan (chemotherapeutics) had the longest supply disruptions. A variety of solutions could be identified including the purchase of a generic alternative (36.9%) for both oral and parenteral treatments (in a ratio 3:2). Urgent import from another (European) country was performed in 14 cases (16.7%). High impact solutions such as cohorting of patients and change of ongoing treatments (2.4%) were used for parenteral treatments only. Pharmaceutical modification was sometimes applied for oral treatments (2.4%). Due to persistent occurrence of these shortages, an efficient pharmacy workflow (electronic follow-up by end of 2016) and a multidisciplinary approach were needed

Clinical pharmacy in a multidisciplinar team for chronic pain in adults

The aim of this study was to evaluate the role and the impact of a clinical pharmacist as a member of a multidisciplinary pain team. Although physicians have a good knowledge of pharmacotherapy in the field of pain medication, pharmacy interventions were necessary to enhance the quality of prescribing. On a population of 93 patients, a total of 120 interventions were recorded. The different types of interventions included: provision of information (10.0%), clinical intervention (89.2%) and the provision of a specific product (0.8%). Out of the 107 clinical interventions, a total of 95.3% interventions were accepted, by the physicians. The results highlight the clinical importance of the pharmacy in optimizing drug therapy for adult patients with chronic pain