Pharmaceutical good manufacturing practice: Leuplin® production in Japan identifies major international shortcomings.

In Japan, the production of Leuplin®, a key drug for the treatment of prostate cancer and breast cancer, was temporarily suspended in 2020 by the manufacturer. The incident illustrated several significant failings, namely the lack of uniformity in international GMP (Good Manufacturing Practice) regulations, the lack of mechanisms to resolve disputes between PIC/S (Pharmaceutical Inspection Co-operation Scheme) member countries, and the importance of maintaining a stable supply of safe GMP-compliant essential medicines.

A short term quality control tool for biodegradable microspheres.

Accelerated in vitro release testing methodology has been developed as an indicator of product performance to be used as a discriminatory quality control (QC) technique for the release of clinical and commercial batches of biodegradable microspheres. While product performance of biodegradable microspheres can be verified by in vivo and/or in vitro experiments, such evaluation can be particularly challenging because of slow polymer degradation, resulting in extended study times, labor, and expense. Three batches of Leuprolide poly(lactic-co-glycolic acid) (PLGA) microspheres having varying morphology (process variants having different particle size and specific surface area) were manufactured by the solvent extraction/evaporation technique. Tests involving in vitro release, polymer degradation and hydration of the microspheres were performed on the three batches at 55°C. In vitro peptide release at 55°C was analyzed using a previously derived modification of the Weibull function termed the modified Weibull equation (MWE). Experimental observations and data analysis confirm excellent reproducibility studies within and between batches of the microsphere formulations demonstrating the predictability of the accelerated experiments at 55°C. The accelerated test method was also successfully able to distinguish the in vitro product performance between the three batches having varying morphology (process variants), indicating that it is a suitable QC tool to discriminate product or process variants in clinical or commercial batches of microspheres. Additionally, data analysis utilized the MWE to further quantify the differences obtained from the accelerated in vitro product performance test between process variants, thereby enhancing the discriminatory power of the accelerated methodology at 55°C.

Separation and identification of acylated leuprorelin inside PLGA microspheres.

Studies have shown that the N-terminus and lysine side residue of peptides are prone to acylation in poly(d,l-lactide-co-glycolide) (PLGA) microspheres. Peptides such as leuprorelin lack a free N-terminus or lysine and only contain serine, arginine, and tyrosine as nucleophilic residues. The purpose of this study was to detect potential acylation impurities and determine their corresponding acylation sites in commercial leuprorelin-loaded PLGA microspheres. Commercial samples from three vendors were selected as targets for our study. The high-performance liquid chromatography (HPLC) conditions of the European Pharmacopoeia were used to separate and collect impurities. HPLC-tandem mass spectrometry (HPLC-MS/MS) was applied to confirm both the structure and acylation sites of the impurities. Our study demonstrated that impurities originating from both degradation of microspheres and synthesis of leuprorelin were well separated and identified using these HPLC conditions. HPLC-MS/MS analysis of acylated leuprorelin showed that diglycoyl, lactoyl-glycoyl, dilactoyl, and monolactoyl groups were conjugated to serine in leuprorelin-loaded PLGA microspheres. This is the first report showing serine to be the acylation site in peptide-loaded PLGA microspheres. Separation and identification of acylated leuprorelin derivatives will assist in minimising acylation and guiding the development of quality control for commercial leuprorelin-loaded PLGA microspheres.

Prevention of menstruation with leuprorelin (GnRH agonist) in women undergoing myelosuppressive chemotherapy or radiochemotherapy for hematological malignancies: a pilot study.

Vaginal bleeding during aplasia can induce transfusion support, infection and discomfort. Oral and intramuscular hormonotherapy can be toxic and/or difficult to manage (mucositis). This single-center pilot study evaluated the efficacy and safety of leuprorelin (L) in preventing heavy vaginal bleeding in 20 nonmenopausal women with leukemia, lymphoma or myeloma and foreseable therapy-induced thrombocytopenia. Until platelet recovery, patients received subcutaneous injections of L, with concomitant nomegestrol acetate (NA) during the first 35 days to prevent flare-up. Median age was 33 years (18-48). Platelet nadir was < 20 x 10(9)/l in 17 patients; 103 L injections were performed (median per patient: 4 [1-14]). No moderate or severe adverse event was related to hormonal therapy. Seventeen patients did not experience any clinically or therapeutically relevant bleeding. Eleven spottings and 8 metrorrhagias (mean duration: 3 days) occurred in 11 patients, requiring enhanced NA in 3 cases (baseline platelet count was < 20 x 10(9)/l in 1 pt, premature termination of NA [the single platelet transfusion for metrorrhagia] in 1 pt, and endometrial hyperplasia (EH) in the third). In patients without EH, only 5 spottings were observed after the third injection, without neither clinical nor therapeutic impact (63 injections). In conclusion, leuprorelin administration is safe and effective in preventing vaginal bleeding. The sustained-release form and subcutaneous administration offer quality of life advantages.

Treatment of moderate and severe hirsutism by gonadotropin-releasing hormone agonists in women with polycystic ovary syndrome and idiopathic hirsutism.

OBJECTIVE: To compare the therapeutic effects of a GnRH-agonist (GnRH-a), leuprolide acetate (LA) depot, versus LA plus and oral contraceptive (OC) containing cyproterone acetate in the treatment of hirsutism. DESIGN: Randomized study. SETTING: Women addressed to the Department of Gynecological Endocrinology, University of Brescia, Brescia, Italy. PATIENTS: Thirty-two patients suffering from moderate and severe hirsutism secondary to polycystic ovary syndrome (PCOS) or idiopathic causes were selected. INTERVENTION: Leuprolide acetate was injected IM every 28 days in all patients; 16 women, randomly allocated, received LA plus OC. At the beginning and at the end of treatment hirsutism score and hair diameters were evaluated. RESULTS: Both treatment arms resulted in a decrease of hirsutism score and hair diameter, both in idiopathic hirsutism (16% to 31% versus 24% to 32%) and in hirsutism secondary to PCOS (23% to 33% versus 24% to 36%). CONCLUSIONS: Gonadotropin-releasing hormone agonist can improve moderate and severe hirsutism effectively. It is necessary to add an OC.

Efficacy of a low-dose leuprolide acetate depot in the treatment of uterine leiomyomata in Japanese women.

OBJECTIVE: To compare the efficacy of two different doses, 1.88 mg and 3.75 mg, of a monthly depot injection of a gonadotropin-releasing hormone agonist (GnRH-a) in the treatment of uterine leiomyomata. DESIGN: A prospective randomized study. SETTING: Hospital department of gynecology and obstetrics. PATIENTS: Forty-one premenopausal Japanese women, 25 to 53 years of age, with uterine leiomyomata. INTERVENTIONS: Depot type of GnRH-a, leuprolide acetate (LA) 1.88 mg or 3.75 mg was administered subcutaneously every 4 weeks for 24 weeks. MAIN OUTCOME MEASURES: Efficacy of treatment was assessed in terms of uterine volume, serum levels of estradiol (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and adverse symptoms during treatment. RESULTS: In both groups, a significant reduction in uterine volume, 52% in 1.88 mg group and 47% in 3.75 mg group, was obtained at week 24, with near maximal reduction (41%, 45%) apparent by 12 weeks. No significant difference was observed between the groups in percent uterine volume reduction at each treatment week. Both groups showed significant and equal suppression of serum levels of E2, LH, and FSH. In addition, the incidence of adverse symptoms was not significantly different between the two groups. CONCLUSIONS: Monthly injection of 1.88 mg or 3.75 mg LA depot has equivalent treatment efficacy in reducing uterine volume. Twelve weeks of treatment is enough to obtain near maximal reduction.