Pharmaceutical pricing and reimbursement policies in Algeria, Morocco, and Tunisia: comparative analysis.

Objectives: In this paper, we outline and compare pharmaceutical pricing and reimbursement policies for in-patent prescription medicines in three Maghreb countries, Algeria, Morocco, and Tunisia, and explore possible improvements in their pricing and reimbursement systems. Methods: The evidence informing this study comes from both an extensive literature review and a primary data collection from experts in the three studied countries. Key findings: Twenty-six local experts where interviewed Intervieweesincluded ministry officials, representatives of national regulatory authorities, health insurance organizations, pharmaceutical procurement departments and agencies, academics, private pharmaceutical-sector actors, and associations. Results show that External Reference Pricing (ERP) is the dominant pricing method for in-patent medicines in the studied countries. Value-based pricing through Health Technology Assessment (HTA) is a new concept, recently used in Tunisia to help the reimbursement decision of some in-patent medicines but not yet used in the pricing of innovative medicines in the studied countries. Reimbursement decision is mainly based on negotiations set on Internal Reference Pricing (IRP). Conclusion: Whereas each country has its specific regulations, there are many similarities in the pricing and reimbursement policies of in-patent medicines in Algeria, Morocco, and Tunisia. The ERP was found to be the dominant method to inform pricing and reimbursement decisions of in-patent medicines. Countries in the region can focus on the development of explicit value assessment systems and minimize their dependence on ERP over the longer-term. In this context, HTA will rely on local assessment of the evidence.

Comparison of Three Complementary Analytical Techniques for the Evaluation of the Biosimilar Comparability of a Monoclonal Antibody and an Fc-Fusion Protein.

In this work, a monoclonal antibody, adalimumab, and an Fc-fusion protein, etanercept, were studied and compared to one of their biosimilars. Samples submitted to stress conditions (agitation and high temperature) were used for method development. The developed methods were also applied to samples reduced by beta-mercaptoethanol to evaluate their capability to distinguish the expected species. Capillary gel electrophoresis (CGE), reversed-phase liquid chromatography (RPLC), and size-exclusion chromatography (SEC) methods coupled with UV detection were used to analyze the biopharmaceuticals. Their complementarity was investigated. For further molecular weight determination, SEC-multi angle light scattering and RPLC-quadrupole time-of-flight were occasionally used. For adalimumab, a larger amount of fragments and aggregates was observed in the biosimilar compared with the reference product. For etanercept, more related species were found in the reference product. Those three separation techniques showed good complementarity. Indeed, RPLC enabled the separation of hydrophilic and hydrophobic degradation products. CGE provided good selectivity for several adalimumab fragments, and SEC was useful for the analysis of aggregates and certain fragments that cannot be separated by the other approaches. Moreover, those formulations were submitted to mild stress conditions (30°C, 300 rpm for 4 h) that mimic shipping conditions. No additional peak was found under these conditions for the two studied biopharmaceuticals.

Physical and chemical stability of cytarabine in polypropylene syringes.

BACKGROUND: Cytarabine is widely used to treat leukemia and lymphoma. Currently, Cyrabol®, powder for injection, is one of the specialties marketed in Tunisia. However, no stability data when diluted with 0.9% NaCl are available. The aim of this study is to evaluate the physical and chemical stability of cytarabine (Cyrabol®) solution after dilution in 0.9% NaCl (1 mg/mL, 5 mg/mL and 10 mg/mL) in polypropylene syringes under different storage conditions. METHODS: Cytarabine solutions (1 mg/mL, 5 mg/mL and 10 mg/mL) in 0.9% NaCl were prepared in polypropylene syringes and stored for 28 days under different conditions. Cytarabine preparations in glass containers were prepared as a control to detect any adsorption. Chemical stability was assessed by a stability-indicating high-performance liquid chromatography method. The stability-indicating capacity of the method was proved by forced degradation tests. Linearity, precision and limit of detection and quantification were performed according to the International Conference on Harmonisation recommendations. Physical stability was checked by visual inspection. RESULTS: The method was proven to be a validated stability-indicating assay. At 2-8°C, all tested solutions were chemically stable for 28 days. However, at 25°C, the main degradation product gradually increased during the study and the chemical stability of 1 mg/mL, 5 mg/mL and 10 mg/mL solutions was 14 days, 8 days and 5 days, respectively. Similar results were observed in the glass containers. CONCLUSION: The highest physical and chemical stability of cytarabine diluted in 0.9% NaCl in polypropylene syringes was observed at 2-8°C. At 25°C, better stability was found in the 1 mg/mL solution compared with those at higher concentrations (5 mg/mL and 10 mg/mL).

In-capillary derivatization with (-)-1-(9-fluorenyl)ethyl chloroformate as chiral labeling agent for the electrophoretic separation of amino acids.

An original micellar electrokinetic chromatography (MEKC) method using in-capillary derivatization with a chiral labeling reagent was developed for the separation of amino acid (AA) derivatives. The potential of (-)-1-(9-fluorenyl)-ethyl chloroformate (FLEC) as in-capillary derivatization agent is described for the first time. Several parameters for in-capillary derivatization and subsequent MEKC separation were systematically investigated using experimental designs. Firstly experimental conditions for in-capillary derivatization were optimized using face-centered central composite design (FCCD). Mixing voltage and time as well as concentration of the labeling solution were investigated. Efficient labeling was achieved by sequential injection of AAs and FLEC labeling solution followed by the application of a voltage of 0.2 kV for 570 s. The background electrolyte (BGE) composition was then optimized in order to achieve selectivity. A FCCD was performed with two factors, namely the sodium dodecyl sulfate (SDS) concentration and the percentage of propan-2-ol (IPA). The separation of 12 pairs of derivatized AA (FLEC-AA) diastereomers was achieved with resolution values comprised between 3 and 20. Furthermore, an efficient derivatization and separation of 29 FLEC-AA derivatives were achieved in a single run using a buffer made up of 40 mM sodium tetraborate, 21 mM SDS and 8.5% IPA. The method was successfully applied to the analysis of spiked artificial cerebrospinal fluid (aCSF) sample.

Chemo- and enantio-selective method for the analysis of amino acids by capillary electrophoresis with in-capillary derivatization.

A novel dual chiral CE method was developed for the separation of l- and d-amino acids (AAs), using in-capillary derivatization with 9-fluoroenylmethyl chloroformate (FMOC). Firstly, using pre-column derivatization, the enantioseparation of FMOC-AAs was optimized according to the nature of cyclodextrins (CD). A background electrolyte (BGE) composed of 30 mM ß-CD, 30 mM octakis(2,3-dihydroxy-6-O-sulfo)-γ-CD (OS-γ-CD), 40 mM tetraborate and 15% isopropanol (IPA) was selected and led to 17 baseline resolved pairs (R(s)=1.7-5.8) and two partially resolved pairs (Lys, R(s)=0.5 and Arg, R(s)=1.2). Experimental conditions for in-capillary derivatization were then optimized. Several parameters, such as mixing voltage and time, concentration of labeling solution and the length of the spacer plug were studied. The optimal conditions for in-capillary derivatization procedure were obtained using successive hydrodynamic injections (30 mbar) of AAs for 2s, borate buffer for 4s and 10mM FMOC solution for 6s, followed by a mixing at 3 kV for 72 s and wait time of 1 min. Moreover, a particular attention was paid to improve separation chemoselectivity. The effect on stereoselectivity and chemoselectivity of different factors, such as decrease of pH and tetraborate concentration and the addition of sodium dodecyl sulfate (SDS), was investigated using the in-capillary derivatization procedure. The best separation of a standard mixture of ten AA racemates was observed using a BGE containing 30 mM ß-CD, 30 mM OS-γ-CD, 25 mM SDS, 40 mM sodium tetraborate and 17% IPA.

Micellar electrokinetic chromatography systems for the separation of mixtures of charged and uncharged compounds.

In this study, the migration behavior of charged and uncharged analytes was investigated under different conditions. Effective mobilities - electrophoretic mobilities under the influence of micelles - of cations, anions, and neutrals were measured at neutral, basic, and acidic pH (7.5, 11, and 2.2) using background electrolytes containing different sodium dodecyl sulfate (SDS) concentrations (0-90 mM) and acetonitrile (ACN) proportions (0-75%). SDS concentration and ACN proportion were found to have a tremendous effect on the effective mobilities and migration order of the model compounds. Although the SDS micelles preferably interact with neutrals and cations, hydrophobic bonds can also occur with anions. Cations, anions, and neutrals having rather different migration behaviors, it is possible to considerably enhance the selectivity of the method by adjusting properly the SDS concentration and the ACN proportion. These observations confirm the interest of using micellar electrokinetic chromatography not only for the separation of neutral substances but also to analyze charged compounds.

Enantiomeric separation of acidic compounds using single-isomer amino cyclodextrin derivatives in nonaqueous capillary electrophoresis.

The enantiomeric separation of a series of acidic pharmaceuticals (mostly nonsteroidal anti-inflammatory drugs) has been investigated in NACE systems using single-isomer amino beta-CD derivatives. The first part of this study consisted of the selection of the basic experimental conditions to separate efficiently the enantiomers of acidic drugs. Several parameters, such as the nature of the ionic BGE components, were studied and a methanolic solution of ammonium acetate containing the cationic CD was selected as BGE. A D-optimal design with 20 experimental points was then applied and the nature and concentration of the CD were found to have a significant effect on the enantiomeric resolution for all studied compounds. Resolution (R(s)) values were always higher with 6-monodeoxy-6-mono(3-hydroxy)propylamino-beta-CD (PA-beta-CD) compared to those obtained with 6-monodeoxy-6-mono(2-hydroxy)propylamino-beta-CD (IPA-beta-CD). However, the latter led to shorter migration times. Generic NACE conditions were then selected by means of the multivariate approach in order to obtain the highest R(s) values in a minimum amount of time. Finally, dependence of separation selectivity, resolution, as well as mobility difference on chiral selector concentration was discussed and binding constants with PA-beta-CD were estimated for the two enantiomers of one of the model compounds, suprofen in these NACE systems.