Validation of an automated dispensing system for subsequent dose dispensing of different radionuclides.

BACKGROUND: Automated dispensing systems (ADSs) for radiopharmaceuticals have been developed to reduce the radiation exposure of personnel, to improve the accuracy of the dispensed dose and to limit the microbiological contamination. However, before implementing such systems, validation according to various applicable guidelines is necessary to ensure safety and quality. Here we present the selection, validation and implementation of the PT459R2 from manufacturer Lynax s.r.o. as a guidance protocol for validation according to GMP and GRPP guidelines. Validation included linearity accuracy and precision of the internal scintillation detector for different isotopes and microbiological validation for aseptic procedures. RESULTS: The ADS can dispense accurate doses in the following linear range: 1000-10,000 MBq for lutetium-177, 20-74 MBq for zirconium-89, 100-1000 MBq for gallium-68 and 100-2000 MBq for fluorine-18. The maximum bias is 2.35% and the maximum coefficient of variation is 3.03% which meets the acceptance criteria of < 5%. Furthermore, the ADS does not affects the GMP class A environment in a laminar airflow cabinet and can dispense aseptically. In addition, radiation exposure is acceptable and data integrity is preserved. CONCLUSION: The PT459R2 ADS met all the requirements from our performance qualification and is therefore suitable for daily routine use in our center. Our approach can be used as a guidance for PQ of an ADS in a Radiopharmacy according to GMP and GRPP guidelines.

Performance Qualification Testing Improves Processing of Lumened Surgical Instruments in Ultrasonic Cleaners.

The use of performance qualification (PQ) tests for ultrasonic cleaners leads to improvements in the quality of processing lumened surgical instruments. Evidence and national standards assert the need for health care facilities to implement a quality management system related to device reprocessing and testing the adequacy of mechanical cleaning processes. Testing includes showing that ultrasonic cleaners have properly functioning cavitation, soil removal, and lumen perfusion capabilities. This article summarizes survey responses from an audit of sterile processing personnel regarding ultrasonic cleaning units in health care facilities. The article also provides guidance to facilities regarding assessing installation, operational, and PQ related to ultrasonic cleaning equipment. Implementing PQ testing of ultrasonic cleaners in sterile processing units leads to a decreased risk of soiled instrumentation in the OR, which can reduce the risk of patient infection and adverse events.

Multisite Qualification of an Automated Incubator and Colony Counter for Environmental and Bioburden Applications in Pharmaceutical Microbiology.

Traditional microbiological techniques have been used for well over a century as the basis for contamination testing of pharmaceutical products and processes. With more recent focus on faster product release and concerns around the integrity of the test data, new technologies have been implemented to detect and enumerate organisms faster and provide paperless processes to minimize data integrity issues. Manual colony counting technologies, where incubation is performed in a standard incubator, and the plate is manually transferred to the colony counter for a single read at the end of incubation, have been used for many years to reduce the potential for human error; however, they pose validation challenges due to poor counting accuracy. Colony counters that automatically perform both the incubation and enumeration functions (multiple enumeration calculations through the incubation phase) have recently been implemented for quality control (QC) laboratory analytical processes, supporting a cGMP environment. This article summarizes the findings of eight companies demonstrating the qualification of an automated colony counter technology to perform the majority of microbial tests required for QC, environmental monitoring, and bioburden for in-process, bulk drug substance, and water system testing. Comparable analytical performance and time to result data generated during individual studies at all companies allows the system to be qualified and implemented for cGMP processes while reducing data integrity risks.

[Qualification of low temperature vaporized hydrogen peroxide sterilization: Towards greater harmonization of practices?] / Qualification de stérilisateurs à basse température au peroxyde d'hydrogène : vers une meilleure harmonisation des pratiques ?

OBJECTIVES: Comparing performance qualification procedures for low temperature vaporized hydrogen peroxide sterilization. Assessing conformity with draft standard ISO/DIS 22441. METHODS: Qualification reports from several providers have been compared according to specific criteria: choices of cycles, loads, sterile barrier systems, probes, biological and chemical indicators; checking of packaging integrity and exposure to sterilizing agent. RESULTS: Six out of 8 reports based on 4 distinct sterilizers have been performed by third-party providers. Routine and process challenge devices are respectively used in 6 and 3 of these reports. Sizes and masses are never mentioned whereas load configuration is always specified. All reports use at least one biological indicator and 50% of them use one chemical indicator at a minimum. Most frequent wrapping materials are Ultra® and Tyvek® bags (respectively 50% and 37.5% of reports). Each qualification monitors per process pression and temperature, and 37.5% of them also quantify hydrogen peroxide concentration. Packaging integrity and environmental exposure are checked in respectively 50% and 12.5% of all reports. All reports have received providers approval. CONCLUSION: Qualification procedure is based on steam sterilization NF EN 14937 standard, which seems unsuitable for low temperature process. The lack of autonomy, the heterogeneity of loads and measurement choices reveal a low harmonization of practices. New standard should dispel the doubts about this heterogeneity.

A Sensitive and Controlled Data-Independent Acquisition Method for Proteomic Analysis of Cell Therapies.

Mass spectrometry (MS)-based proteomic measurements are uniquely poised to impact the development of cell and gene therapies. With the adoption of rigorous instrumental performance qualifications (PQs), large-scale proteomics can move from a research to a manufacturing control tool. Especially suited, data-independent acquisition (DIA) approaches have distinctive qualities to extend multiattribute method (MAM) principles to characterize the proteome of cell therapies. Here, we describe the development of a DIA method for the sensitive identification and quantification of proteins on a Q-TOF instrument. Using the improved acquisition parameters, we defined a control strategy and highlighted some metrics to improve the reproducibility of SWATH acquisition-based proteomic measurements. Finally, we applied the method to analyze the proteome of Jurkat cells that here serves as a model for human T-cells. Raw and processed data were deposited in PRIDE (PXD029780).

Upstream cell culture process characterization and in-process control strategy development at pandemic speed.

As of early 2022, the coronavirus disease 2019 (COVID-19) pandemic remains a substantial global health concern. Different treatments for COVID-19, such as anti-COVID-19 neutralizing monoclonal antibodies (mAbs), have been developed under tight timelines. Not only mAb product and clinical development but also chemistry, manufacturing, and controls (CMC) process development at pandemic speed are required to address this highly unmet patient need. CMC development consists of early- and late-stage process development to ensure sufficient mAb manufacturing yield and consistent product quality for patient safety and efficacy. Here, we report a case study of late-stage cell culture process development at pandemic speed for mAb1 and mAb2 production as a combination therapy for a highly unmet patient treatment. We completed late-stage cell culture process characterization (PC) within approximately 4 months from the cell culture process definition to the initiation of the manufacturing process performance qualification (PPQ) campaign for mAb1 and mAb2, in comparison to a standard one-year PC timeline. Different strategies were presented in detail at different PC steps, i.e., pre-PC risk assessment, scale-down model development and qualification, formal PC experiments, and in-process control strategy development for a successful PPQ campaign that did not sacrifice quality. The strategies we present may be applied to accelerate late-stage process development for other biologics to reduce timelines.

Establishment of instrument operation qualification and routine performance qualification procedures for handheld near-infrared spectrometers used at different locations within a laboratory network.

Quality assurance of finished pharmaceuticals is a necessity in ensuring the safety of consumers. There is a need for low-cost and portable rapid screening methods of pharmaceuticals in resource limited areas. Recent advances in technology have made handheld and low-cost diffuse reflectance spectrometers available to the public. While these handheld spectrometers offer advantages over benchtop spectrometers, the accuracy and repeatability must be assessed before these instruments can be used for quality assurance screening. Here, five handheld spectrometers of the same model were purchased, where an in-house installation qualification and operational qualification (IQOQ) was subsequently established for the instruments. Wavelength and photometric accuracy (and repeatability), spectroscopic noise, stray light, and bandpass were assessed between instruments. Results were found to be consistent between the spectrometers, passing IQOQ procedures, and were determined to be ready for field use. Once the handheld spectrometer's performance was verified, a practical and low-cost daily performance verification was established using common high density polyethylene vial caps on location in South Africa, Thailand, and the United States. A Mahalanobis distance-based classifier found the five spectrometers to be in agreement.

Recommended Best Practices for Lyophilization Validation 2021 Part II: Process Qualification and Continued Process Verification.

This work describes the lyophilization process validation and consists of two parts. Part one (Part I: Process Design and Modeling) focuses on the process design and is described in the previous paper, while the current paper is devoted to process qualification and continued process verification. The goal of the study is to show the cutting edge of lyophilization validation based on the integrated community-based opinion and the industrial perspective. This study presents best practices for batch size determination and includes the effect of batch size on drying time, process parameters selection strategies, and batch size overage to compensate for losses during production. It also includes sampling strategies to demonstrate batch uniformity as well as the use of statistical models to ensure adequate sampling. Based on the LyoHUB member organizations survey, the best practices in determining the number of PPQ runs are developed including the bracketing approach with minimum and maximum loads. Standard practice around CQA and CPP selection is outlined and shows the advantages of using control charts and run charts for process trending and quality control. The case studies demonstrating the validation strategy for monoclonal antibody and the impact of the loading process on the lyophilization cycle and product quality as well as the special case of lyophilization for dual-chamber cartridge system are chosen to illustrate the process validation. The standard practices in the validation of the lyophilization process, special lyophilization processes, and their impact on the validation strategy are discussed.

Wavelength Calibration Uncertainty in Protein Circular Dichroism Data Bank Spectra.

Algorithms to objectively compare the circular dichroism spectra of biopharmaceuticals, as a measure of consistent higher order structure, are sensitive to errors in spectropolarimeter wavelength calibration. A public database, the Protein Circular Dichroism Data Bank contains 108 unique calibration spectra of d-camphor-10-sulphonic acid, mainly collected on synchrotron-based instruments. Deconvolution of these spectra and statistical evaluation of the peaks located near 290 and 190 nm shows significant mean peak wavelength differences between instruments, with data ranges of 1.8 and 2.3 nm. Peak positions and peak height ratios for individual instruments changed significantly through time, and the difference between wavelength maxima was instrument dependent.

Estudios dosimétricos de la calificación operacional y del comportamiento funcional de la instalación de irradiación semindustrial para la esterilización de un producto de uso médico / Dosimetric studies of the operational qualification and functional behavior of the semi-industrial irradiation facility for the sterilization of a product for medical use

Resumen En el presente trabajo se muestran los resultados obtenidos durante los estudios dosimétricos de las etapas de calificación operacional y del comportamiento funcional de la instalación de irradiación semindustrial de Cuba después de su remodelación y recarga, así como el proceso de radioesterilización de un producto de uso médico.

Abstract The present work shows the results obtained during the dosimetric studies of the operational qualification stages and the functional behavior of the semi-industrial irradiation facility in Cuba after its remodeling and recharging, as well as the radio-sterilization process of a product for medical use.

Method Verification Requirements for an Advanced Imaging System for Microbial Plate Count Enumeration.

The Growth Direct™ System that automates the incubation and reading of membrane filtration microbial counts on soybean-casein digest, Sabouraud dextrose, and R2A agar differs only from the traditional method in that micro-colonies on the membrane are counted using an advanced imaging system up to 50% earlier in the incubation. Based on the recommendations in USP <1223> Validation of New Microbiological Testing Methods, the system may be implemented in a microbiology laboratory after simple method verification and not a full method validation.LAY ABSTRACT: The Growth Direct™ System that automates the incubation and reading of microbial counts on membranes on solid agar differs only from the traditional method in that micro-colonies on the membrane are counted using an advanced imaging system up to 50% earlier in the incubation time. Based on the recommendations in USP <1223> Validation of New Microbiological Testing Methods, the system may be implemented in a microbiology laboratory after simple method verification and not a full method validation.

Performance qualification for reproducible Surface Plasmon Resonance analysis.

Surface Plasmon Resonance Biosensors (SPR) are one of the most powerful tools to characterize protein binding, e.g. for drug discovery, like target identification, ligand fishing, assay development, lead selection and manufacturing quality control. However, there is increasing concern about its reproducibility in the light of the reproducibility crisis. Therefore an appropriate analytical instrument qualification (AIQ) is required for quality assurance of SPR instruments. AIQ is a prerequisite for analytical method validation and it is consisting of four parts, Design Qualification (DQ), Installation Qualification (IQ), Operational Qualification (OQ) and Performance Qualification (PQ). PQ regularly executed is supposed to continuously control the performance of the instrument under actual running conditions. In this work a performance qualification method was developed for the SPR instrument Biacore X100. This method is suitable for the routinely control of the instrument performance for antibody-antigen binding measurements. Control charts were designed to get a clearly representable and easy implementable tool to check the critical parameters. These control charts and a straightforward protocol now allow the design and application of an individual performance qualification procedure that can be used in the laboratory routine. They serve as reference for individual standard operation procedures (SOPs).

Life cycle management of analytical methods.

In modern process management, the life cycle concept gains more and more importance. It focusses on the total costs of the process from invest to operation and finally retirement. Also for analytical procedures an increasing interest for this concept exists in the recent years. The life cycle of an analytical method consists of design, development, validation (including instrumental qualification, continuous method performance verification and method transfer) and finally retirement of the method. It appears, that also regulatory bodies have increased their awareness on life cycle management for analytical methods. Thus, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), as well as the United States Pharmacopeial Forum discuss the enrollment of new guidelines that include life cycle management of analytical methods. The US Pharmacopeia (USP) Validation and Verification expert panel already proposed a new General Chapter 〈1220〉 "The Analytical Procedure Lifecycle" for integration into USP. Furthermore, also in the non-regulated environment a growing interest on life cycle management is seen. Quality-by-design based method development results in increased method robustness. Thereby a decreased effort is needed for method performance verification, and post-approval changes as well as minimized risk of method related out-of-specification results. This strongly contributes to reduced costs of the method during its life cycle.

Stage 2 Process Performance Qualification (PPQ): a Scientific Approach to Determine the Number of PPQ Batches.

The approach documented in this article reviews data from earlier process validation lifecycle stages with a described statistical model to provide the "best estimate" on the number of process performance qualification (PPQ) batches that should generate sufficient information to make a scientific and risk-based decision on product robustness. This approach is based upon estimation of a statistical confidence from the current product knowledge (Stage 1), historical variability for similar products/processes (batch-to-batch), and label claim specifications such as strength. The analysis is to determine the confidence level with the measurements of the product quality attributes and to compare them with the specifications. The projected minimum number of PPQ batches required will vary depending on the product, process understanding, and attributes, which are critical input parameters for the current statistical model. This new approach considers the critical finished product CQAs (assay, dissolution, and content uniformity), primarily because assay/content uniformity and dissolution as well as strength are the components of the label claim. The key CQAs determine the number of PPQ batches. This approach will ensure that sufficient scientific data is generated to demonstrate process robustness as desired by the 2011 FDA guidance.

Evaluation verification of Mindary BC5390 hematology analyzer / 国际检验医学杂志

Objective To evaluate the performance verification of Mindary BC5390 hematology analyzer .Methods According to requirement of CLSI documents ,the precision ,accuracy ,linearity ,carryover were evaluated .Results The background counts all met the designed requirements of manufacturer .Precision ,accuracy ,linearity of the WBC ,RBC ,PLT ,Hb ,HCT ,MCV were good and the contamination carrying rates were low .Except for basophils ,the classification of leukocyte was well correlated with the artificial microscopy classification(r2 >0 .95) .Conclusion The BC5390 is a ideal automated hematology analyzer which has high precision and accuracy ,wide linearity ,low contamination carrying rate ,and it can be used for the blood samples analysis .

Evaluation of Hcy assay performance by circulating enzymatic method / 国际检验医学杂志

Objective To evaluate analytical performance of homocysteine (Hcy) by circulating enzymatic method .Methods Re‐ferring to CLSI evaluation project and pertinent literature ,and by combining our actual works .we designed a verification procedure and experimental method .By using these above ,the precision ,accuracy ,analytical measurement range ,clinical reportable range of Hcy by circulating enzymatic method were evaluated .Results would be compared with the declaration of the manufacturer (NingBo Medical System Biotechnology Co .,Ltd) or desirable specifications derived from biologic variation .Results The results showed that the within‐run CV were 1 .26% and 0 .84% ,and the total CV were 1 .36% and 1 .32% ,less than 10% of the manufacturer′s statement .The relative bias between the results measured for calibrator at tow levels and target value was 3 .69% and 0 .69% ,less 10% .AMR was 3 .38-51 .81 μmol/L ,and the most suitable dilution rate was 1∶3 ,so the CRR was 3 .38-155 .43 μmol/L .Con‐clusion The analytical performance of Hcy analyzed by circulating enzymatic method is consistent with the standards which manu‐facturers has proclaimed ,so it is conform to the requirements of clinical .

Performance validation of ABI ViiA 7 Taqman HBV-DNA detecting system / 国际检验医学杂志

Objective To verify the performance of the ABI ViiA 7 Taqman HBV-DNA detecting system for confirming its sta-bility,accuracy and reliability.Methods According to the evaluation protocols of Clinical and Laboratory Standards Institute (CLSI),the performance of ABI ViiA 7 Taqman HBV-DNA detecting system was assessed in the aspects of precision,accuracy,lin-earity and comparability;the quantitative detection limit validation experiments was performed by diluting specimen until quantita-tive detection limit is lower than the lower limit of detection,and the detection results were compared with the quality target re-quirements and the analysis capability declared by manufacturers.Results The CV in within-run precision of this detection system was 1.485%,1.990% and 0.932% respectively;the total CV was 1.876%,3.361% and 1.891%,respectively;the maximum devia-tion of accuracy was -6.8%;the linear correlation coefficient was 0.998 3;the regression equation was Y =0.974 8X +0.050 7. The linear range was 1.00E2 - 2.00E8;the quantitative detection limit was 100 IU/mL;the comparability of ABIViiA7 and ABI7500:P =0.115,r2 =0.994,the linear regression equation was Y =0.987 2X +0.051 7.Conclusion The ABI ViiA 7 Taqman HBV-DNA detection system has excellent precision,accuracy,sensitivity and linearity and has a good correlation with ABI7500, which can be used for the detection of clinical specimens.

Performance verification of Sysmex XTˉ2000i hematology analyzer / 国际检验医学杂志

Objective To perform the performance verification of the Sysmex XT-2000i hematology analyzer.Methods Accord-ing to requirements of NCCLS EP5-A2,EP15-A2,EP6-A2,EP9-A2 documents,the accuracy,precision and linearity of the Symex XT-2000i hematology were evaluated and the detection results were compared with those detected by the Sysmex XE-2100i which participated in the external quality assessment(EQA)of Ministry of Public Health for long time.Results The accuracy,precision, linearity and contamination rate all are within the permissible range.Conclusion The performance of Sysmex XT-2000i is good,the determination results are reliable.As a perfect hematology analyzer,it can satisfy the hematological analysis of hospital clinical la-boratory.