Background: The production of house dust mite (HDM) allergen products for allergy immunotherapy has traditionally been based on purified mite bodies or whole-mite culture, which are quite different source materials with a limited possibility for adjusting the chemical composition. The SQ HDM SLIT-tablet is a fast-dissolving pharmaceutical formulation that has been developed for sublingual immunotherapy (SLIT) of HDM respiratory allergic disease. Objective: The objective of the present study was to establish a process for the production of drug substances for the SQ HDM SLIT-tablet offering a high reproducibility and independent control of the major allergens. Methods: Process controls were documented in a comprehensive process parameter qualification. The analyses comprised composition by crossed immunoelectrophoresis, protein content by BCA, total IgE binding potency by Centaur assay, quantitative major allergen determination by radial immunodiffusion and ELISA, and the ranking of emPAI scores generated by mass spectrometry. Results: Analysis of 20 batches of final product yielded a normalized mean and standard deviation for IgE binding potency of 100 ± 4.5. The standard deviation in the contents of Der f 1 and Der p 1 were correspondingly 11.9 and 6.1, whereas the variation in the group 2 major allergen content was 6.4. All measured 95% confidence limits between batches were less than 12%. Conclusions: The production process for the SQ HDM SLIT-tablet based on the separation of source material into four fractions each enriched in one major allergen enables precise adjustment of the relative major allergen content and high reproducibility of the final product.

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RATIONALE: Labyrithine nasal passages, the narrow nasal valve and complex static and dynamic aerodynamics limit traditional intranasal steroids' (INS) ability to effectively deliver medication to superior/ posterior nasal regions. Exhalation delivery systems (EDS) exploit unique characteristics of nasal anatomy and aerodynamics to overcome these limitations and achieve superior/posterior drug delivery. We review published human in vivo gamma-scintigraphy deposition data for conventional INS (C-INS; e.g., Flonase/Nasonex), HFA-based pMDI's (e.g., QNASL/Zetonna), and EDS systems for liquids and powders. METHODS: Four recent gamma-deposition studies comparing different technologies for nasal delivery of topical steroids were included: (1) Conventional INS sprays (Flonase and Nasonex) versus pMDI (QNASL), (2) C-INS (Nasonex) versus pMDI (Zetonna), (3) C-INS versus EDSliquid, (4) C-INS versus EDS-powder and EDS-liquid. Data on regional deposition and clearance was compared. RESULTS: Qualitative deposition differences were large, though variability in segmentation methods prevents quantitative comparisons. In all studies, C-INS consistently deposit primarily anteriorly (in the valve region) with clearance along the nasal floor and little deposition in superior/posterior regions. Both pMDIs (QNASL/Zetonna) show a stationary ''hotspot'' in the non-ciliated vestibule, little delivery to superior/ posterior regions, and minimal clearance. EDS (liquid or powder) produce less deposition in the valve area and broad deposition to superior/posterior segments with a different clearance pattern. CONCLUSIONS: Human imaging data demonstrate poor drug deposition in superior/posterior sites with conventional nasal sprays, and greatly increased deposition throughout upper/posterior nasal passages with an EDS. In CRS, upper/posterior sites, including the middle and upper meatuses (ostiomeatal complex) where sinuses ventilate/drain and polyps originate, are the primary target for treatment.

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Sir, Human growth hormone (hGH) is a polypeptide hormone that is secreted by the anterior pituitary, and consists of a variety of molecular isoforms, the most prevalent in human serum being the 22 kDa (1). These diverse isoforms have different cross reactivity profiles in hGH immuno-assays contributing to the observed discrepancies between these (2). The present study was undertaken in order to evaluate the conformity of two hGH immunochemiluminometric assays (ICMA) (DPC Immulite ® and Nichols ® Advantage™) in serum hGH samples obtained from healthy male subjects exposed to the growth hormone secretagogue (GHS) tabimorelin (NN703) (3). The mechanism of action of GHS seems to rely on several factors, a direct effect on the GH releasing cells in the anterior pituitary, amplification of the effects of GHRH, and functional antagonism of somatostatin (4). The assays studied both utilise a primary monoclonal anti-hGH antibody, and a secondary polyclonal anti-hGH antibody, and GH is sandwiched in between these. The assays are calibrated against the same international standard (WHO 80/505), and the conversion factor in terms of the WHO IRP 80/505 is 1 mg = 2.6 IU.Following approval from the local ethics committee, the blood samples for the comparative study were obtained from 10 healthy male subjects enrolled in a double-blind, randomised, placebo controlled, cross-over study with NN703/placebo administration (3 mg/kg bw) investigating the pharmacokinetics and pharmacodynamics of NN703 administered as capsules. From the total hGH serum profile obtained in this study (0-6 hours post dose, 3 samples/hour analysed by Nichols ® Advantage™), blood samples from 3-6 hours in the periods where the subjects received active treatment (10 samples/subject -in total 100 samples) were chosen for the comparative assay evaluation and subjected to additional analysis by DPC Immulite ® . This time period was chosen in order to have a wide range of hGH levels, with the highest number of samples above the lower limit of quantification (following NN703 administration the median hGH t max was 3.67 hours with a range of 3.33-5.67 hours). The assay procedures were performed in accordance with the manufacturer's instructions. The inter-assay variability was 9.3-9.8% for the DPC Immulite ® , and 3.83-6.94% for the Nichols ® Advantage™ ICMA. The higher variability observed with the DPC Immulite ® , as compared to what has been reported with the United Kingdom National External Quality Assessment Scheme (UKNEQAS), is most likely due to the fact that non-processed pooled serum was used, rather than the processed controls used in the UKNEQAS (5). Of the original 100 samples, 16 samples were excluded from the statistical analysis due to being below the lower limit of quantitation (LLOQ) in one (n=13) or both assays (n=3) (In both assays the LLOQ was determined as the lowest point on the calibration curve, and was found to be 0.15 ng/ml for Nichols ® Advantage™, and 0.05 ng/ml for DPC Immulite ® ). In Figure 1 a Bland-Altman plot of the data is present...