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

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

Impact of computerized physician order entry on medication prescription errors in the intensive care unit: a controlled cross-sectional trial

INTRODUCTION: Medication errors in the intensive care unit (ICU) are frequent and lead to attributable patient morbidity and mortality, increased length of ICU stay and substantial extra costs. We investigated if the introduction of a computerized ICU system (Centricity Critical Care Clinisoft, GE Healthcare) reduced the incidence and severity of medication prescription errors (MPEs). METHODS: A prospective trial was conducted in a paper-based unit (PB-U) versus a computerized unit (C-U) in a 22-bed ICU of a tertiary university hospital. Every medication order and medication prescription error was validated by a clinical pharmacist. The registration of different classes of MPE was done according to the National Coordinating Council for Medication Error Reporting and Prevention guidelines. An independent panel evaluated the severity of MPEs. We identified three groups: minor MPEs (no potential to cause harm); intercepted MPEs (potential to cause harm but intercepted on time); and serious MPEs (non-intercepted potential adverse drug events (ADE) or ADEs, being MPEs with potential to cause, or actually causing, patient harm). RESULTS: The C-U and the PB-U each contained 80 patient-days, and a total of 2,510 medication prescriptions were evaluated. The clinical pharmacist identified 375 MPEs. The incidence of MPEs was significantly lower in the C-U compared with the PB-U (44/1286 (3.4%) versus 331/1224 (27.0%); P < 0.001). There were significantly less minor MPEs in the C-U than in the PB-U (9 versus 225; P < 0.001). Intercepted MPEs were also lower in the C-U (12 versus 46; P < 0.001), as well as the non-intercepted potential ADEs (21 versus 48; P < 0.001). There was also a reduction of ADEs (2 in the C-U versus 12 in the PB-U; P < 0.01). No fatal errors occurred. The most frequent drug classes involved were cardiovascular medication and antibiotics in both groups. Patients with renal failure experienced less dosing errors in the C-U versus the PB-U (12 versus 35 serious MPEs; P < 0.001). CONCLUSION: The ICU computerization, including the medication order entry, resulted in a significant decrease in the occurrence and severity of medication errors in the ICU

Farmaco economie en geneesmiddelenbeleid

A

Economic impact of the preparation scenario for cytotoxic drugs: an observational study

Aim: To evaluate the financial impact of three different preparation and conservation scenarios for cytotoxic drugs. Method: In scenario one we discarded the residual fraction of the drug after each preparation. In scenario two we used the residual fraction of the vial until the end of the day. In scenario three we used the residual fraction of the vial until the chemical/physical expiry date. To analyse the economic impact of the three scenarios, we looked at 3,086 preparations during July and August 2006. Results and discussion: A major difference in cost was found between the three scenarios, namely: Euros 872,413, Euros 807,309 and Euros 754,442 for scenarios one, two and three respectively. Savings varied between a minimum of Euros 52,867 (7%) and a maximum of Euros 117,971 (15%) for the observation period of two months, or an average of Euros 17 to Euros 38 per preparation. Conclusion: When cytotoxic medicines are prepared under rigorous conditions, pharmacists can contribute to substantial economic savings