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The ability to produce and isolate relatively pure amounts of relevant degradation products is key to several aspects of drug product development: (a) aid in the unambiguous structural identification of such degradation products, fulfilling regulatory requirements to develop safe formulations (International Conference on Harmonization Q3B and M7); (b) pursue as appropriate safety evaluations with such material, such as chronic toxicology or Ames testing; (c) for a specified degradation product in a late-stage regulatory filing, use pure and well-characterized material as the analytical standard. Producing such materials is often a resource- and time-intensive activity, either relying on the isolation of slowly formed degradation products from stressed drug product or by re-purposing the drug substance synthetic route. This problem is exacerbated if the material of interest is an oxidative degradation product, because typical oxidative stressing (H 2 O 2 and radical initiators) tends to produce a myriad of irrelevant species beyond a certain stress threshold, greatly complicating attempts for isolating the relevant degradation product. In this article, we present reagents and methods that may allow the rapid and selective enrichment of active pharmaceutical ingredient with the desired oxidative degradation product, which can then be isolated and used for purposes described above., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

During the past years, there has been an increasing focus on the presence of silicone oil as a contaminant in pharmaceutical formulations kept in prefilled syringes (PFSs). As the PFSs are coated on the inner wall with silicone oil (polydimethylsiloxane), there is a potential risk that the oil can migrate from the inner surface of the primary packing material into the aqueous solution. Several studies have demonstrated that presence of silicone oil as droplets in a high-concentrated protein formulation can cause protein aggregation. Hence, because the use of silicone-coated primary packing material for protein formulations are increasing, the call for an easy and quantitative method for determination of silicone oil and its degradation products in pharmaceutical formulations is therefore needed. Several analytical techniques have in the past been developed with the aim of detecting the presence of silicone oil and degradation products hereof. Most of these methods require hydrolyzation, derivatization, and extraction steps followed by, for example, gas chromatography-mass spectrometry analysis. Applying these methods can cause a loss in detection or an overestimation of the hydrolytic degradation products of silicone oil, that is, trimethylsilanol and dimethylsilanediol. The 2 silanols are highly hydrophilic and prefers the aqueous environment. Analysis of an aqueous formulation obtained from a PFS by 1 H-NMR spectroscopy provides data about the content and levels of silicone oil and the 2 silanols even in levels below 10 ppm. The 1 H-NMR method offers an easy and direct, quantitative measurement of samples intended for clinical use and samples kept at elevated temperature for a prolonged time (i.e., stability studies). The result of the study presented here showed dimethylsilanediol to be the main silicone compound present in the aqueous formulation when kept in baked-on PFSs. The degradation product dimethylsilanediol, in full accordance with expected hydrolytic degradation of silicone oil, increased during storage and with elevated temperature. In addition, the method can be applied to aqueous samples where polydimethylsiloxane has been added as, for example, the major constituent of antifoam., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

It was the aim of this study to incorporate a model peptide bivalirudin in self-emulsifying drug delivery system (SEDDS) and compare its storage stability with conventional aqueous solutions. Firstly, bivalirudin lipophilicity was increased via hydrophobic ion pairing using anionic or cationic surfactants. The chosen bivalirudin docusate complex (BIV/AOT) was incorporated into SEDDS composed of 40% (w/w) Cremophor EL, 20% (w/w) Capmul PG-8, and 40% (w/w) propylene glycol with a drug payload of 0.20% (w/w). SEDDS were stable over a wide pH range for at least 7 days at 37°C and showed an immediate bivalirudin release profile. Moreover, aqueous bivalirudin solutions were shown to be most stable between apparent pH 3 and 4. Furthermore, 94.39% and 72.66% of bivalirudin in SEDDS and 10% propylene glycol, respectively, remained intact after 90 days of storage at 25°C ± 2°C, whereas 99.12% and 80.54% were still intact in SEDDS and 10% propylene glycol at 5°C ± 3°C, respectively. Bivalirudin in reconstituted commercially available product Angiomax ® was, however, long-term unstable. According to these findings, SEDDS could be considered as a potential bivalirudin stabilization medium against chemical degradation., (Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Vial design features can play a significant role in heat transfer between the shelf and the product and, consequently, in the final quality of the freeze-dried product. Our objective was to investigate the impact of the variability of some geometrical dimensions of a set of tubing vials commonly used for pharmaceuticals production on the distribution of the vial heat transfer coefficients (K v ) and its potential consequence on product temperature. Sublimation tests were carried out using pure water and 8 combinations of chamber pressure (4-50 Pa) and shelf temperature (-40°C and 0°C) in 2 freeze-dryers. K v values were individually determined for 100 vials located in the center of the shelf. Vial bottom curvature depth and contact area between the vial and the shelf were carefully measured for 120 vials and these data were used to calculate K v distribution due to variability in vial geometry. At low pressures commonly used for sensitive products (below 10 Pa), the vial-shelf contact area appeared crucial for explaining K v heterogeneity and was found to generate, in our study, a product temperature distribution of approximately 2°C during sublimation. Our approach provides quantitative guidelines for defining vial geometry tolerance specifications and product temperature safety margins., (Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Although the impact of hydrogen peroxide (HP) on proteins in liquid solutions has been studied extensively, the impact during lyophilization has been largely overlooked. The purpose of this work was to investigate the effect of HP on lyophilized proteins and HP removal by lyophilization. A protein formulation at 5 mg/mL and its placebo were spiked with HP up to 5.0 ppm and then lyophilized. HP concentration, protein oxidation, and aggregation were monitored before and after lyophilization, as well as during storage at 25°C. The lyophilization process removed on average 94.1% of HP from protein formulation, but only 72.5% from the placebo. There were also significant increases in protein oxidization and aggregation. The oxidation increment correlated with the decrease of HP concentration in both the protein formulation and placebo at all temperatures. Protein oxidation at different freezing temperatures was also studied in follow-up studies. Data from these studies suggest that (1) HP has a significant impact on oxidation and aggregation of protein during lyophilization; (2) significant oxidation can occur even when the protein formulation is frozen; (3) the oxidized protein is more prone to aggregation during lyophilization process., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

A case study is presented for a vaccine drug product (DP) that showed variable re-dispersion times between syringes within a given DP lot and between different DP lots when shipped from the manufacturing site to the receiving site. A simulated shipping study was designed to understand the effect of individual shipping stresses on re-dispersion time and product quality. Shipping stresses simulating shock/drop, aircraft, and truck vibrations were applied separately to 3 syringe orientations, namely tip up, tip down, and tip horizontal (TH). Results from the simulated shipping study showed that shock/drop reduced re-dispersion time while truck and aircraft vibrations increased re-dispersion time in the tip down orientation. The dissimilar effects of different shipping stresses on re-dispersion resulted in the observed intra and inter DP lot variability in re-dispersion time. Shipping stresses did not impact re-dispersion in the TH or tip up orientation. No vaccine product quality attributes or physical properties were affected by shipping stresses. Actual shipping results correlated well with simulated shipping data. Because re-dispersion time was influenced mainly by shipping stress and syringe orientation, the mitigation measure to reduce end-user re-dispersion time was to implement the TH orientation for DP syringes during shipment and storage., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Oxidation of methionine residues is one of the well-known deteriorations in monoclonal antibody (mAb) therapeutics. Because methionine oxidation may affect their efficacy and pharmacokinetic profile, oxidation levels should be strictly controlled during their storage period. In this study, we revealed that when a therapeutic antibody was filled into a cyclo olefin polymer-based syringe and stored in a blister pack with an oxygen absorber, the methionine oxidation production under thermal or light stress was suppressed because of the reduction in the concentration of dissolved oxygen. Also unexpectedly, fewer amounts of the high-molecular-weight species and the acidic variants of the antibody were generated under thermal or light stress. Although the high-molecular-weight species contains methionine oxidants at similar levels to those in a monomer species, they were likely to be constituted from a higher amount of the oxidative species of internal disulfide linkage, tyrosine, or histidine. Because the dissolved oxygen could be readily removed from the mAb solution in the polymer-based syringe owing to its high gas permeability, this study shows the advantages of the polymer-based syringe with an oxygen absorber over glass syringes in terms of the suppression of the methionine oxidation and oxidative high molecular species., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Gelucire 50/13 alone and solid dispersions in this material containing two model drugs (10% w/w caffeine and paracetamol) have been studied with a view to establishing the mechanism underpinning changes in drug-release characteristics as a function of storage time and temperature. The lipid systems were fabricated into tablets and stored for up to 180 days at temperatures of 20 and 37 degrees C. The dispersions were studied using differential scanning calorimetry (DSC), scanning electron microscopy, and dissolution testing. DSC studies indicated that the Gelucire 50/13 exists in two principal melting forms (melting points 38 and 43 degrees C) that undergo transformation to the higher melting form on storage at 37 degrees C. Scanning electron microscopy studies indicated that the systems exhibit "blooming," with crystal formation on the surface being apparent on storage at both temperatures. The dissolution rate increased on storage, with the effect being particularly marked at higher storage temperatures and for the paracetamol systems. However, whereas these changes corresponded well to those seen for the morphology, the correlation between the changes in dissolution and those of the DSC profiles was poor. The study has suggested a novel explanation for the storage instability of Gelucire 50/13 whereby the change in dissolution is associated not with molecular rearrangement as such but with the gross distribution of the constituent components, this in turn altering the physical integrity of the lipid bases., ((c) 2004 Wiley-Liss, Inc. and the American Pharmacists Association)