European Union Good Research Articles

TECHNOLOGICAL CHALLENGES IN STERILE PRODUCTOS MANUFACTURING: IS PHARMACEUTICAL INDUSTRY TRAINED?

Pharmaceutical industry, in addition to assuming the sanitary commitment, as has been demonstrated with the manufacturing of COVID-19 vaccines, must comply with the European Union Good Manufacturing Practices, for that reason it´s subject to a continuous updating demanded by the regulatory requirements. This commitment is even, if possible, greater for injectable drug’s manufacturing companies due to their intrinsic characteristics of safety for the patient, all this together with the maximum productivity objective. A review about the main challenges that the pharmaceutical industry must face for the manufacture of injectable products is carried out, that comprised the incorporation of new biological drugs and advanced therapies into the therapeutic arsenal, the increase in terms of the requirements in regulatory and inspection tasks by health authorities and the leading role that Contract Manufacturing Organisations are playing. On the other hand, issues such as the analytical methods used to evaluate product sterility validity, the impact of possible changes in the different processes and elements, especially in the case of aseptic manufacturing, and the evolution, with the implementation of Sterility and Quality by Design, of sterile products manufacturing science are discussed. Finally, the implementation of disruptive factors such as continuous manufacturing and robotization, which will have, with a high probability, a greater role in the not-so-distant future, is proposed. Key Words: Sterile Drugs, Inspection, Aseptic Manufacturing, Isolators, Good Manufacturing Practices, PAT, Pharmaceutical Industry

Structural Budget Balance as a Fiscal Rule in the European Union—Good, Bad, or Ugly?

The EU's Fiscal Compact requires member states to legislate structural budget balance rule(s) (SBR). We use elite interviews and government documents from Austria, Ireland, and Portugal to assess the extent to which SBRs are perceived to have resulted in improved accountability, coordination, and credible commitment on the part of elected officials. We find that establishing the SBRs in legislation has not resulted in domestic ownership on the part of the member states. Furthermore, SBRs do not appear to have improved accountability due to questions about their accuracy. There is some evidence that SBRs aid finance ministries' coordination efforts.

In-House Production of Dialysis Solutions to Overcome Challenges During the Coronavirus Disease 2019 Pandemic

In-House Production of Dialysis Solutions to Overcome Challenges During the Coronavirus Disease 2019 Pandemic

Data Mining to Determine the Influence of Fluid Properties on the Integrity Test Values.

Eudralex volume 4, Annex 1, the European Union Good Manufacturing Practice for sterile products, requires that "The integrity of the sterilised filter should be verified before use" (1). Implicit in this requirement for a PUPSIT is the rationale that the sterilizing filter could sustain damage during sterilization or use (i.e., subsequent to any pre-use test conducted prior to sterilization), causing a defect which would not be detected by the post-use integrity ("masked" during filtration). To assess whether a filter defect could be masked by partial filter plugging, we evaluated the impact of the bacterial challenge test (BCT) on the bubble point (BP) of the test filters. The BP tests that are conducted before and after the BCT have been collected and compared for 2086 filters (1571 × test filters and 515 × control filters), representing 531 BCTs on 518 different pharmaceutical products, buffers, and in-process fluids. These tests comprise a cross section of fluids from multiple firms spanning the pharmaceutical and biotechnology industry. A posttest to pretest BP ratio was calculated for each filter and the distribution of these ratios examined to determine whether there were cases of elevation of the BP because of bacterial loading to the point where masking of a filter defect could occur; that is, if a defective filter could pass integrity testing due to apparent reduction in filter pore size because of the bacteria retained during the BCT. Ratios were averaged across all tests for the same test fluid. The mean average ratio was 1.00 ± 0.15, indicating that on the average, elevation of the BP does not occur. To assess the risk of masking a filter defect, observed BP ratios were compared to the ratio of the minimum BP specification of a 0.2 μm filter to that of a 0.45 μm filter of the same membrane type. The lowest such ratio for any membrane type was 1.33. A BP ratio equal to or higher than this ratio was considered a risk for masking, because a 0.45 μm filter could appear to meet the specifications of a 0.2 μm filter. Out of 518 average BP ratios, only eight fluids (1.5%) produced BP ratios meeting this criterion for a masking risk. Potential risk factors associated with these cases are discussed. We conclude that filtration processes producing BP changes sufficient to present a risk of masking defects are not common, and are detectable during the routine BCT. The BP ratios observed during routine BCT are one means to assess the potential of a given filtration process to mask defects and can be considered when determining whether a PUPSIT should be implemented.

Validation of Quality Control Parameters of Cassette-Based Gallium-68-DOTA-Tyr3-Octreotate Synthesis.

Purpose of the Study:Gallium (Ga)-68-DOTA peptides targeting somatostatin receptors have been assessed as a valuable tool in neuroendocrine tumor imaging using positron emission tomography. However, at the moment, a specific monograph in the European Pharmacopoeia (Ph. Eur.) does exist only for Ga-68-edotreotide (DOTATOC) injection. Here, we report on the validation process of Ga-68-DOTA-Tyr3-octreotate (DOTATATE) cassette-based production and quality control (QC).Materials and Methods:Preparation of Ga-68-DOTATATE was performed according to the current European Union-good manufacturing practices, the current good radiopharmacy practice, the Ph. Eur., and the guidelines on validation of analytical methods for radiopharmaceuticals. Process was validated via three consecutive production runs to ensure that the methods are reproducible and reliable in routine use. The QC tests for Ga-68-DOTATATE were radiochemical purity (RCP – high-pressure liquid chromatography [HPLC]), radiochemical impurities 68Ga3+ (HPLC and instant thin layer chromatography [ITLC]), chemical purity (HPLC and gas chromatography [GC]), pH (pH-strips), radionuclidic purity (principal γ-photon), germanium-breakthrough (68Ge-content), Ga-68 half-life (γ-ray spectrometry), and sterility/endotoxin assay.Results:Radiolabeling procedure of Ga-68-DOTATATE fits all the applicable Ph. Eur. specifications. RCP measured via ITLC was >99% in the three validation batches. HPLC-measured RCP resulted 99.45%, 99.78%, and 99.75%. Germanium-breakthrough was far below the recommended level established in the Ph. Eur. Ga-68-DOTATOC injection (#2482). Residual ethanol tested with GC was less than 10%. All the batches were tested for endotoxin content, which always resulted lower than 17.5 EU/ml. All preparations passed the sterility tests. pH of the final product was 7 in all samples.Conclusion:Ga-68-DOTATATE fulfilled all the pre-set QCs and release criteria in the batches considered for this validation study. The results demonstrated a batch-to-batch reproducibility, ensuring that synthesis process leads to the expected final product in terms of yield, quality, reliability, safety, and efficacy.

GMP-compliant (68)Ga radiolabelling in a conventional small-scale radiopharmacy: a feasible approach for routine clinical use.

BackgroundThe number of routine care patient examinations with 68Ga radiopharmaceuticals is still relatively limited, probably caused by the presumed need for large investments in hot cells, automated synthesis modules, laboratory equipment and validation efforts. Our aim was to set up the preparation of 68Ga-DOTA-NOC in compliance with all current European Union-Good Manufacturing Practices (EU-GMP), current Good Radiopharmacy Practice (cGRPP) and European Pharmacopoeia (Ph. Eur.) guidance but without the availability of a hot cell and gas chromatography (GC), high-performance liquid chromatography (HPLC) and atomic absorption spectrometry (AAS) equipment.MethodsA risk-based approach was applied to align preparation conditions with applicable regulations, together with a validation of a thin-layer chromatography (ITLC) method to replace HPLC as modality for examining radiochemical purity.ResultsUsing an internally shielded labelling module for manual operation, a 68Ga-DOTA-NOC labelling procedure was set up that meets all applicable Ph. Eur. specifications. The applied ITLC method showed very good correlation with HPLC results (r = 0.961) and was able to detect relevant deviations in radiolabelling procedures. All identified quality assurance aspects were made compliant with EU-GMP and cGRPP guidance.ConclusionsWe consider the described configuration and validation approach feasible for many conventional small-scale radiopharmacies, something that could help to increase the availability of 68Ga radiopharmaceuticals to a large number of patients.

Functional characterization of alloreactive T cells identifies CD25 and CD71 as optimal targets for a clinically applicable allodepletion strategy

AbstractImmunotherapy with allodepleted donor T cells (ADTs) improves immunity after T cell–depleted stem cell transplantation, but infection/relapse remain problematic. To refine this approach, we characterized the expression of surface markers/cytokines on proliferating alloreactive T cells (ATs). CD25 was expressed on 83% of carboxyfluorescein diacetate succinimidyl esterdim ATs, confirming this as an excellent target for allodepletion. Seventy percent of CD25− ATs expressed CD71 (transferrin receptor), identifying this as a novel marker to target ATs persisting after CD25 depletion. Comparison of residual alloreactivity after combined CD25/71 versus CD25 immunomagnetic depletion showed enhanced depletion of alloreactivity to host with CD25/71 depletion in both secondary (2°) mixed lymphocyte reactions (P < .01) and interferon-γ enzyme-linked immunospot assays (P < .05) with no effect on third-party responses. In pentamer/interferon-γ enzyme-linked immunospot assays, antiviral responses to cytomegalovirus, Epstein-Barr virus, and adenovirus were preserved after CD25/71 allodepletion. CD25/71 ADTs can be redirected to recognize leukemic targets through lentiviral transfer of a chimeric anti-CD19ζ T-cell receptor. Finally, we have established conditions for clinically applicable CD25/71 allodepletion under European Union Good Manufacturing Practice conditions, resulting in highly effective, reproducible, and selective depletion of ATs (median residual alloreactivity to host in 2° mixed lymphocyte reaction of 0.39% vs third-party response of 62%, n = 5). This strategy enables further clinical studies of adoptive immunotherapy with larger doses of ADTs to enhance immune reconstitution after T cell-depleted stem cell transplantation.

The New European Union Good Agricultural and Collection Practice Rules—Are Good Practices Good Enough if They Do Not Result in Batch Consistency?

The New European Union Good Agricultural and Collection Practice Rules—Are Good Practices Good Enough if They Do Not Result in Batch Consistency?

The New European Union Good Agricultural and Collection Practice Rules: Are Good Practices Good Enough if They Do Not Result in Batch-to-Batch Consistency?

This article discusses the newly published European Union Points to Consider on Good Agricultural and Collection Practice for Starting Materials of Herbal Origin (hereafter called European Union GAP). It explains what good agricultural and collection practice is good for and provides an overview of the topics regulated by European Union good agricultural and collection practice. Because European Union GAP does not provide rules for standardization, there is no guarantee that the medicines made from starting materials cultivated or collected under these rules will be fully reliable. Examples will be given on content variation in opium and ginkgo leaf. Proposals are made to include additional rules for standardization. An example of the application of rules for standardization in the production of cannabis for medicinal purposes will be described.