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A estratégia adotada neste trabalho foi avaliar o impacto da interrupção de uma produção em campanha por tempo determinado, com a retomada de produção até a conclusão do número total de lotes previstos, e com isso, evidenciar que o período de interrupção não promove possíveis contaminantes para os lotes envolvidos no processo. O estudo foi realizado em uma linha de embalagem de comprimidos em uma empresa farmacêutica da região oeste paranaense. Foi identificado o produto mais crítico para a execução da validação de limpeza e foi definido que seriam analisadas três campanhas produtivas, sendo cada uma delas composta por vinte lotes, com tempo de parada dentro da campanha produtiva de no mínimo quarenta e oito horas. Foram realizadas coletas nos tempos e nos pontos pré-determinados e as mesmas foram analisadas quanto à detecção de resíduos da substância ativa, presença de microrganismos e a presença de produtos de degradação. Após a produção dos lotes foi possível identificar o tempo de interrupção padrão entre as campanhas e o tempo total (em dia) de duração de uma campanha. Os resíduos dos possíveis contaminantes no equipamento após a limpeza geral foram inferiores aos limites dos critérios de aceitação admitidos para o estudo. Mesmo com a interrupção do processo, o emprego da produção em campanha e o tempo total de processo, o procedimento de limpeza estabelecido foi eficiente quanto a remoção dos resíduos microbio

The AAMI working group ST/WG 93 is finalizing a standard (AAMI ST98) for the cleaning validation of reusable medical devices based on guidance from the technical information report AAMI TIR30:2011/(R)2016. A number of analytical best practices are being considered for this new standard. Test method suitability for processing cleaning validations historically has been established using one positive control and performing an extraction efficiency. The new cleaning validation standard is proposed to require a change from only one replicate test sample to three when performing method suitability. This change will affect manufacturers; therefore, the value of and consideration for performing these additional replicates requires explanation. This article discusses how variation of validation parameters can affect the accuracy and precision during method suitability testing. Multiple replicates are needed to understand the variability of method extraction and impact on cleaning validations of reusable medical devices.

Cleaning validation is a prominent and ideal practice which is employed in industrial aspects to provide utmost shielding to develop drug products, so that a cleaning practice removes the particulate matters, chemicals, as well as the contaminant pathogens reside in active ingredients of drug product in a piece of apparatus, which are produced or being manufactured. The cleaning validation is established as the pre-eminent process that ensures the efficiency, safety, consistency of pharmaceutical equipment and manufactured product of assured quality. The utmost cleaning practice during manufacturing of drug substances affords the appropriate operator safety measures, organized calibration, description and routine monitoring of equipments, Sampling procedures, acceptance criteria’s and detection limits of analytical methods. This also lead to systematic data analysis for estimating of probable contagions in product batches builds up. Abortive cleaning may lead to adulterated product that may be originated from preceding batches, clean-up agents or other superfluous materials produced during methodology. Hence to avoid the harmful contamination, sources, safety measures clean-in-practice is highly recommended as per regulatory and stability point of view. The present review intensifies the current challenges, basic mechanisms and future implication of cleaning validation in various analytical development firms and research organizations. Keywords: Validation, Sampling, Clean in Practice, Acceptance limits, Quality by Design.

Risk in general means exposure to harm or a factor that can contribute towards bringing harm to a system. Almost every operation in the pharmaceutical industry is susceptible to risks. There is a need to overcome risks and them to prevent unwanted changes in product quality and safety. This prevention can be done by carrying out quality risk management (QRM) that facilitates the proper of risks, risk analysis, risk assessment to control and reduce risks. ICH Q9 guidelines explain quality risk management and its applications in the pharmaceutical industry. Cleaning validation is performed to verify and evaluate the efficacy of cleaning procedures used to clean the equipment after production and to prevent cross-contamination between products that are manufactured in the production facility. current study on reviews of quality risk management and cleaning validation policies. By incorporating QRM in the quality policy, companies can look to improve the modern Approach towards facing risks related to the issues that affect the product quality, safety and compliance concerning the cleaning of equipment used in manufacturing and supporting operations in the industries.

Quality is the primordial intention of any industry and its products manufactured. Multiple views on obtaining such quality are the current interest in the pharmaceutical industry, and it has been maintained by validation. Validation is documented evidence that provides a high degree of assurance. Validation has become one of the pharmaceutical industries’ most recognized subjects. This article provides detailed information about pharmaceutical validation and its importance. Quality is always an imperative prerequisite when we consider the product. In this article, we discuss the types of validation, process validation, equipment validation, cleaning, and analytical method validation. Validation is the process that is used to confirm that the analytical procedure employed for a specific test is suitable for the intended use.

Current bacterial endotoxin testing systems can be labor-intensive and time-consuming, involving several manual pipetting steps. In our quality control laboratory, annually, we test about 15,000 samples of different grades of purified water, WFI and water samples taken to validate cleaning procedures for endotoxins. We are currently using the Kinetic-QCL™ assay which is a pharmacopeia method that provides reliable results. We compared this assay with another Limulus amebocyte lysate (LAL)-based assay (Endosafe®-MCS) and an alternative endpoint fluorescent recombinant Factor C (rFC) assay (ENDOZYME II GO®). Both these assays have been developed to reduce analyst preparation time. Our objective was to assess if they could increase the throughput of our testing while maintaining low rates of invalid results. The results demonstrated that the two most appropriate methods for rapid endotoxin detection in water are our current assay, K-QCL, and the rFC-based assay, ENDOZYME II GO. This latter assay was found to be less sensitive to interference than our current assay, particularly in cleaning validation water samples. It also showed better performance, accuracy, repeatability and had a shorter time-to-results. ENDOZYME II GO assay allows quick testing of large numbers of samples with reliable results and is a good alternative for conventional LAL assays.

Objetivo: Discutir os aspectos que devem ser considerados na validação concorrente da limpeza no Centro de Materiais e Esterilização (CME). Método: Revisão narrativa da literatura científica, legislação e normatização pertinentes. Resultados: A validação da limpeza na rotina deve considerar: o design dos produtos, a definição e a exequibilidade dos procedimentos operacionais padrão, além da estrutura do CME, dimensionamento, seleção e treinamento de pessoal, registro e interpretação dos resultados obtidos pelos testes químicos na rotina. Conclusão: A validação concorrente da limpeza dos produtos para saúde no CME imprime a cultura da valorização dessa etapa do processamento entre todos os colaboradores do setor, de tal forma que a limpeza passa a ser, de fato, o núcleo central do processamento.

A novel, simple, precise, accurate and reproducible RP-HPLC method for cleaning validation and assay for simultaneous estimation of perindopril and amlodipine in tablet dosage form has been developed and validated. The chromatographic separation was performed on WATERS SHERISORB CN column (250mm × 4.6mm,5μm) in an isocratic mode utilizing di-potassium hydrogen phosphate buffer (pH 6.5 with OPA): methanol: acetonitrile (70:20:10, v/v/v) as mobile phase, at a flow rate of 1.3 ml/min. Detection was carried out at 210 nm. The method was validated as per ICH guidelines for specificity, linearity, precision, accuracy, robustness, LOD and LOQ. The developed cleaning validation method was applied for the analysis of marketed formulation of the drugs. The retention times of perindopril and amlodipine were found to be 3.260 and 4.153 min respectively. The method was found to be specific as there was no swab interference. The Beer Lambert's law was obeyed in the concentration range 0.5–10 μg/ml for both perindopril and amlodipine. The mean % recoveries at 100% level and % RSD were within acceptance limits for both perindopril and amlodipine. The limit of detection (LOD) and limit of quantitation (LOQ) for perindopril and amlodipine were found to be 0.2 μg/ml and 0.5 μg/ml respectively. The method was found to be robust. Assay of marketed tablet formulation gave assay results within acceptable levels.

Dietary supplements as pharmaceutical dosage forms, can be found commercially available in online pharmacies, drugstores and other establishments. They represent foods that supplement the normal diet and are concentrated sources of nutrients (vitamins, minerals, and other nutrients or physiological effects), marketed in dosage forms designed to be taken in prescribed amounts (capsules, tablets, drops, etc.). The purpose of this paper is to validate the cleaning process of the production line for the production of solid pharmaceutical forms. The aim of the research is to determine the effectiveness of the proposed measures by the validation of the cleaning process from the microbiologic perspective, as well as to define the time of the status of "clean" equipment, i.e. reliable and safe work on multifunctional equipment, a process in which there is no cross-contamination of one product with residues of another. The validation has clearly and unequivocally demonstrated that one production line for the production of solid pharmaceutical preparations may produce more products on the same line even if it also produces probiotic preparations which are normally considered believed to require a separate production facility. Continuous monitoring of the effectiveness of the validated cleaning procedure should be carried out at defined intervals after production of the selected product.

Cleaning verification and validation is a requirement in the pharmaceutical industry. Due to the limited number of mobile devices that do effective and accurate onsite cleaning verification, it is mostly done via lab-based quality control techniques. These techniques, such as high-performance liquid chromatography (HPLC) or total organic carbon, often lead to extending the validation of cleaning by days. The void of more sensitive, accurate, and portable instruments to verify cleaning onsite has to be filled. The article discusses the use of deep ultra violet (DUV) laser-induced fluorescence for detecting carryover of active pharmaceutical ingredients (APIs) and detergents onsite. A modified spectrometer was used as an offsite bench type prototype for analyzing trace samples of API and cleaning detergents with various substrates. Even if the API to be detected has a low fluorescence efficiency, the specificity of the technique allows API traces having concentrations as low as ≈0.20 μg/cm2 to be identified. The work also shows the possibility of using a probe for validating cleaning of hard to reach areas using DUV laser-induced fluorescence. DUV laser-induced fluorescence of trace API over any polymer/glass substrate has better signal to background ratio (SBR) compared to FTIR absorption techniques. Processing times of DUV laser-induced fluorescence trace detection are shown to be much less than swab based methods.

In this study, the HPLC and Total Organic Carbon (TOC) analysis methods have been developed and validated for the determination of the amount of Mometasone furoate and CIP100 residues on the surface of production equipment and to confirm the efficiency of the cleaning procedure. Mometasone furoate and CIP100 have been chosen based on the worst case assessment approach. The limit of mometasone furoate contamination that has been determined is 100 ug/swab and the specified limit of CIP100 contamination is 100 ug/swab which should not be exceeded during sequential cleaning of the equipment. Mometasone furoate shows good linearity in the range 0.1-1.0 ppm for the HPLC method and CIP100 2.0-10.0 ppm for TOC Analysis. The percentage of recovery from stainless steel plates using swab sampling techniques was found in the limits of 95.12% and 99.93% respectively in the HPLC and TOC methods. Both methods are simple, inexpensive, short analysis time and high sensitivity for quantitative determination of Mometasone furoate and CIP100 on the surface of manufacturing equipment well below the contamination limit. The validated method meets the requirements for demonstration of the validation of residual cleaning of mometasone furoate and CIP100 on the surface of production equipment

The main objective of the cleaning validation procedure is to verify the effectiveness of the cleaning procedure for removal and minimising the risk of cross-contamination, a topic that has become ...

The interest in Risk Management for validation activities has an impact on validation of training. Similar to process validation, cleaning validation, or sterilization validation, in training it is important to identify the requirements, the design of the means for testing against those requirements, the acceptance criteria, and documentation of the results. Training is an important aspect of the pharmaceutical process, crucial to every step and a factor in compliance with cGMPs, safety, productivity and customer satisfaction. Testing is a subcomponent of the validation of training, a component that has not been utilized for a variety of reasons but nevertheless a component central to the validation process. Validation should be performed on training because it is good business as well as required by regulations. Training validation will have a Requirements phase identified using a Needs Assessment evaluation, a Design phase, an Execution phase, and an Evaluation phase.

A cleaning validation for a family of compounds utilizing swab sampling and rinse solution procedures, and high performance liquid chromatography for separation and detection of the analytes was performed.Effective parameters on recovery including sampling method, swab characteristics, solvent, swabbing technique, and material substance of product contact surfaces within the manufacturing equipment for swab and rinse sampling method, quantitative cleaning verification method, and active pharmaceutical ingredient (API) level and nature have been studied.The limit of detection and the limit of quantitation for the HPLC method were determined to be 0.0198 µg/mL, and 0.0495 µg/mL of the analyte, respectively. The linearity on replicate injections of the standard prepared in the range of 0.78, 1.55, 3.1, and 6.2 µg/mL, and relative standard deviation (R.S.D.) found to be 1.2, 1.0, 0.9, and 0.6, respectively with correlation coefficient of R2 = 0.9999. Recovery coverage for each type of surface was acceptable, ranging from 63.88% for swab sampling of stainless steel to 97.85% for rinse sampling of PVC. The acceptance criteria for precision on replicate injections of the analyte prepared in three concentration levels covering the specified range of 50, 100, and 200% was successfully accomplished R.S.D. lower than 15% for recovery results.Thus, choosing the appropriate sampling method, swab type, and surface condition can affect and increase recovery rate determination efficiency.

Background A fresh selective, rapid, accurate, precise and RP-HPLC stability-indicating method was developed and validated for the quantitative simultaneous determination of dolutegravir and lamivudine in the bulk as well as pharmaceutical dosage form. A chromatographic separation was done by using Inertsil ODS 3V (250 × 4.6 mm, 5 μm) column and mobile phase composed of phosphate buffer, pH 3.0:acetonitrile:methanol (50:20:30% v/v/v) with flow rate of 1.0 mL/min, and the detection of eluents was carried out at a wavelength of 257 nm utilizing a PDA detector. The drugs, dolutegravir and lamivudine, were subjected to varied conditions like base hydrolysis, acid hydrolysis, oxidation, thermal, photochemical and UV. The suggested method was analysed statistically and validated to fulfil requirements of International Conference on Harmonisation (ICH) and the validation covered accuracy, precision, linearity, limit of detection (LOD), limit of quantification (LOQ), robustness, ruggedness and specificity. Results The retention time of dolutegravir and lamivudine were observed to be 6.36 and 2.16 min, respectively. The method was found to be linear within the range of 14.98 to 91.25 μg/mL for lamivudine and 2.54 to 15.35 μg/mL for dolutegravir. The percentage recoveries (accuracy) for dolutegravir and lamivudine were in the range of 98.35 to 102.14% and 98.01 to 101.5%. The computed relative variance (%RSD) was within the suitable criterion of less than 2.0. Conclusion The suggested method was set to be precise as well as stability-indicating since no interfering degradant peaks and excipients were evident. All the peaks of degradation were successfully resolved by the use of the developed analytical method with altered retention times. Results obtained were analysed statistically and found to be acceptable in line with the ICH guidelines. Hence, such method is often employed successfully for routine analysis of active analytes in the bulk as well as pharmaceutical dosage form. It is going to be extended to review for its estimation in plasma and other biological fluids and may even be employed for quality control stability sample estimation and in cleaning method analysis during cleaning validation.

Objective: This study describes a new, simple, precise, accurate, and reproducible reversed-phase high-performance liquid chromatography (RP-HPLC) cleaning validation method for simultaneous estimation of rosuvastatin and aspirin. Methods: The proposed RP-HPLC method was carried out on AGILENT-ZORBAX RP-Inertsil column (250 mm × 4.6 mm, 5 μm) in an isocratic mode utilizing potassium dihydrogen phosphate buffer (pH 2.5 with OPA):acetonitrile (50:50,v/v) as mobile phase, at a flow rate of 1.5 ml/min. Detection was carried out at 243 nm using UV detector. Results: The method was found specific as there was no swab interference. The Beer–Lambert’s law was obeyed in the concentration range of 0.5–20 μg/ml for both rosuvastatin and aspirin. The mean percentage recoveries at 100% level were 89.4% for rosuvastatin and 82.1% for aspirin. The limit of detection and limit of quantification for rosuvastatin and aspirin were 0.03 μg/ml and 0.1 μg/ml, respectively. The method was found to be robust and precise with percentage RSD

Cleaning and cleaning validation remain major concerns both for product quality and from a regulatory perspective. This chapter discusses the concepts involved in cleaning chemistry, cleaning systems, and the validation of cleaning processes. Cleaning has both a direct and an indirect effect on product quality. The obvious direct effect is contamination. The cleaning approaches for equipment used in the biopharmaceutical industry have been derived from methods developed in the traditional pharmaceutical industry. Clean-in-place (CIP) is the preferred method of cleaning for both traditional pharmaceutical and biopharmaceutical industries. CIP is preferred because it is relatively easily automated, and automation implies that control is repeatable. The development of a cleaning validation plan is one of the most valuable activities for ensuring the success of a cleaning validation effort. Traditionally, validation protocols come in at least three categories: installation qualification, operational qualification, and process or performance qualification.

1. Abstract: Cross contamination is a major concern in pharmaceutical industry, especially with long term dosing and accumulative possible effects. The risk is dependent on many factors that can be divided into three main groups: - 1.1. Individual related - starting from the genomic makeup, age, gender, environment, even their diet and psychological state, which in return, alters the individual response to contamination and to any pharmaceutical API. 1.2. Formulation related: - like it`s clean-ability, solubility of the API, batch size, maximum daily dose or inactive materials and most importantly the PDE (permitted daily exposure) of the API/s, which covers the toxicological profile of this API, including its genotoxic, reproductive toxicity, sensitizing potential or any adverse effects that would result from long or short term cross contamination. 1.3. Facility related - As the machine SSA (Shared Surface area between product (A) as the contaminant and Product (B) as the contaminated). The following approach is based upon EMA recommendations on health based exposure limits. It aims to address all the three groups mentioned above to give a scientific rational, on how to evaluate the cleaning process efficiency. Keywords: - Cleaning validation; Cross contamination risk assessment; health-based exposure limits; Chemical swab limits; Chemical contamination. Abbreviations:- PDE( Permitted daily exposure), MACO( Maximum allowed carryover), SAL( Surface area limit), SSA(Shared surface area, ICH( International committee of harmonization), API( Active pharmaceutical ingredient)

Pharmaceutical product and active pharmaceutical ingredients (APIs) can be contaminated by other pharmaceutical products or APIs, by cleaning agents, by microorganisms or by other materials e.g. air borne particles, dust, lubricants, raw materials, intermediates, etc. In the manufacturing of the pharmaceutical products, it is a must to reproduce consistently the desired quality of product. Residual material from the previous batch of the same product or from different product may be carried to the next batch of the product, which in turn may alter the quality of the subjected product. An effective cleaning shall be in place to provide documented evidence that the cleaning method employed within a facility consistently controls potential carryover of product including intermediates and impurities, cleaning agents and extraneous material into subsequent product to a level which is below predetermined level The purpose of this review is to provide information about importance of cleaning validation of API in pharmaceutical industry and this information is in accordance with the regulatory guidelines

Food recalls due to undeclared allergens or contamination are costly to the food manufacturing industry worldwide. As the industry strives for better manufacturing efficiencies over a diverse range of food products, there is a need for the development of new analytical techniques to improve monitoring of the presence of unintended food allergens during the food manufacturing process. In particular, the monitoring of wash samples from cleaning in place systems (CIP), used in the cleaning of food processing equipment, would allow for the effective removal of allergen containing ingredients in between food batches. Casein proteins constitute the biggest group of proteins in milk and hence are the most common milk protein allergen in food ingredients. As such, these proteins could present an ideal analyte for cleaning validation. In this work, molecularly imprinted polymer nanoparticles (nanoMIPs) with high affinity toward bovine α-casein were synthesized using a solid-phase imprinting method. The nanoMIPs were then characterized and incorporated into label free surface plasmon resonance (SPR) based sensor. The nanoMIPs demonstrated good binding affinity and selectivity toward α-casein (K

The cleaning procedure must be validated, so special attention must be devoted to the methods used for determination of trace amounts of drugs. A rapid, sensitive, and specific reverse phase high-performance liquid chromatographic (HPLC) method was developed for the quantitative determination of fenspiride hydrochloride residues on pharmaceutical manufacturing equipment surfaces. The calibration curve was linear over a concentration range from 1.0 to 100.0 μg/ml with a correlation coefficient of 0.99994. The detection limit and quantitation limit were 0.41 μg/ml and 1.25 μg/ml, respectively. The developed method was validated with respect to specificity, linearity, limit of detection, accuracy and precision.

Cleaning validation acceptance criteria in multiproduct facilities are established using maximum allowable carryover calculations. Carryover calculations incorporate the shared equipment surface area between two products to ensure that an acceptable limit for residue from the previously manufactured product to the subsequent product is determined. The shared surface area can be limited to areas where carryover presents the highest risk to product quality or patient safety. In these cases, specifically for biologic drug substance manufacturing, the shared surface area is limited to equipment after the purification process based on the assumption that the purification process would remove potential product fragment residues from the previous product. Until now, this assumption has been based on empirical knowledge without experimental data quantifying the clearance or removal of potential residues. We present a three-part study that determined the effects of cleaning conditions on selected monoclonal antibodies (mAbs) and the generation of degraded fragments and evaluated the clearance of both the degraded mAb1 in a laboratory setting and the degraded fragments in the presence of a subsequent product, assessing the risk of co-purification. Several analytical techniques were used, including gel electrophoresis, capillary zone electrophoresis/laser-induced florescence detection, and liquid chromatography-mass spectrometry. Protein fragment generation was demonstrated for five different mAbs from different immunoglobulin G subclasses. The clearance of the degraded fragments in the absence and presence of the subsequent product was demonstrated by calculating fold clearance and log reduction value (LRV) for each chromatography step. The data showed that the fragments generated during cleaning could be removed by the purification process. The fold clearances were determined to be values of 5400 (3.7 LRV) in the absence of subsequent product and 4428 (3.6 LRV) in the presence of subsequent product. The results supported the removal of product residues from shared surface areas by the purification process in multiproduct biologic drug substance manufacturing facilities.

In the pharmaceutical industry, cleaning criteria are required for multipurpose manufacturing facilities. These Health Based Exposure Limits (HBELs), also called permitted daily exposures (PDEs) values, are derived from toxicological and pharmacological evaluation of the active pharmaceutical ingredients (APIs). The purpose of this publication is to show an example of how authors from different companies evaluate a generic drug, paracetamol, and discuss different approaches and relevance of the nonclinical studies for deriving PDEs. PDE limits of 25 mg/day for the oral route, and 20 mg/day for the intravenous (i.v.) and inhalation (inhal.) routes, respectively, were established herein. However, it has been already recognised that there are acceptable differences in the PDE calculations, which may be based on data accessibility, company-specific science-policy decisions or expert judgments. These differences can cause up to a 3-fold lower or higher values. If unnecessarily high factors are applied, this would result in a very conservative PDE value and unneeded additional cleaning and higher manufacturing costs. The PDE values presented are considered to be protective against adverse and pharmacological effects observed in clinical trials and in this case, a very long postmarketing period of paracetamol.

Validation and verification of cleaning and inspection methods are essential to prevent the spread of allergens via cross-contact. Among the hygiene monitoring tests used on-site, the ATP test is rapid and provides quantifiable results. Nevertheless, because a wide variety of foods contain significant amount of ADP and/or AMP due to the degradation of ATP, the ATP+ADP+AMP (A3) test is preferred for detecting food debris. Hence, the A3 test may be valuable in screening food debris that may contain residual allergens. In this study, the detection limits of the A3 test for 40 foods that are regulated in several countries as allergenic were compared with those of the other hygiene monitoring tests used on-site: the conventional ATP test with similar sensitivity for ATP, the protein swab test that detects as little as 50 μg of protein, and the lateral flow immunoassay (LFI). The A3 test demonstrated lower detection limits than did the ATP test. The detection sensitivity of the A3 test was greater than that of the protein swab test except for its use on gelatin (extracted protein). The cleaning validation performance using a stainless steel model in fish and meat revealed that the A3 test is efficient in verifying the levels of remaining food debris. Although LFI displayed the best sensitivities for 10 of 14 foods, it is not commercially available for some specific allergens; however, the A3 test can detect such food debris. Moreover, the detection limits of the A3 test were preferable or comparable to those of LFI for crustacean shellfish and for processed grains, with the exception of wheat flour and buckwheat. A field study in a food processing plant demonstrated that the amount of both A3 and milk protein (enzyme-linked immunosorbent assay) considerably decreased as the cleaning steps progressed. Therefore, the A3 test is effective in detecting the risk for allergen cross-contact after inadequate cleaning. HIGHLIGHTS

The primary aim of this chapter is to outline the significance of equipment cleaning as a process involving the development of cleaning procedures, their validation, and application. However, changes in an equipment cleaning process (ECP) are seldom pursued as the procedures are often set in stone. This chapter is aimed at helping practitioners develop, utilize, and maintain cleaning validation programs so that they can reduce process variability. To achieve this goal, we discuss important aspects, principals, and guides for cleaning validation that have gained traction in recent years due to the implementation of a risk-based life cycle approach. It is evident that a process validation life cycle approach with its use of statistics is applicable to ECP validation. Risk and knowledge management methodology help us understand our ECP process, identify the products of the processes (e.g., a clean surface), highlight variables, and ultimately gives us confidence during the commercial production of parenteral pharmaceutical products. The chapter concludes with a discussion on how the utilization of statistics and statistical process controls are essential for effective and efficient ECP postperformance qualification monitoring programs.

A detailed overview is provided for the possible patient exposure to highly potent active pharmaceutical ingredients (HPAPIs) from potential cross-contamination through the lyophilization process. The intent of this paper is to raise awareness of the risk(s) to patients and stimulate the implementation of adequate risk-based controls, such as containment process(es), use of adequate surrogates in cleaning validation/verification, and test method-sensitivity-based cleaning validation acceptance conditions. Although lyophilizers are considered to be nonproduct-contact surfaces because their surfaces and fixtures do not usually come into direct contact with the product, product contamination can occur at critical locations within a lyophilizer and/or during the unloading process. Contamination of the air because of released product particles can also create a risk. Therefore, special attention should be paid to HPAPIs, as the permitted daily exposures (PDEs) for patients are particularly low. During a lyophilizer cycle, areas of concern are spreading of the lyophilizer HPAPI powder because of air turbulence, contaminated plates, mechanical transfer systems, and spreading because of damaged vials or contaminated stainless steel or plastic surfaces. Specific considerations for contamination containment for the lyophilizer unloading process are presented. Suggestions are provided for the prevention of patient exposure through cross-contamination via direct-contact areas and prevention of manufacturing personnel exposure via non-direct-contact areas. A surface limit(s) of 1 PDE per square decimeter for nonproduct-contact surfaces inside a lyophilizer is proposed. Risk-based cleaning validation/verification strategies are discussed, with specific consideration of the quality control test method sensitivity expectations and use of suitable surrogates for lyophilized products in the cleaning verification studies. LAY ABSTRACT: This paper provides an overview of important points to consider during the manufacture of highly potent active pharmaceutical ingredients (HPAPI) with the intention to limit patient exposure and/or manufacturing personnel exposure to these highly toxic HPAPIs. HPAPI can potentially be spread during the freeze-drying process (lyophilization) and may cross-contaminate products. Manufacturing personnel and patients taking other freeze-dried products made in the same lyophilizer could be contaminated. It is therefore necessary to implement rigorous contamination controls. Within the lyophilizer, areas of concern are spreading of the lyophilizer HPAPI powder because of air turbulence, contaminated plates, mechanical transfer systems, and spreading because of damaged vials or contaminated stainless steel or plastic surfaces. Cleaning validation/verification studies, intended to demonstrate sufficient cleanability of the freeze-drying process as well as the recommended test method sensitivity to detect these highly toxic HPAPIs, are reviewed. Limits for the relevant production surface areas where cross-contamination and/or personnel exposure (through direct contact) could occur are proposed in this paper.

Cleaning validation is the documented evidence that shows the effectiveness of cleaning procedures for the removal of product residues and other contaminants. The cleaning procedures must be validated and methods to determine trace amounts of drugs have to be considered with special attention. An ultra-high-performance liquid chromatography-ultraviolet (UHPLC-UV) method for the determination of mometasone furoate residues on stainless-steel surfaces was developed and validated in order to control a cleaning procedure. The chromatography separation was achieved on a Waters Acquity UPLC HSS T3 column (50 × 2.1 mm, 1.8 µm) at 40°C using acetonitrile and water (1:1, v/v) as the mobile phase at a flow rate of 0.5 mL/min. The injection volume was 2 µL, and the detection was performed at 254 nm. The swab and rinse procedures were optimized in order to obtain a recovery higher than 90% of mometasone furoate from stainless-steel surfaces, using ethanol as the extraction solvent. The method was validated in the range of 0.2–2.6 µg/mL and showed appropriate selectivity, limit of detection and quantification, linearity, precision, accuracy, and robustness. This method was found to be simple, fast, and sensitive for determination of mometasone furoate residues and, therefore, can be used for cleaning validation analysis.

In order to ensure compliance with the current Good Manufacturing Practice (cGMP), cleaning process of pharmaceutical manufacturers should be validated. This study was aimed to utilize a reusable flat-membrane in the electromembrane extraction (EME) for isolation of tamsulosin hydrochloride (TMS) from rinse samples of sterile production of pharmaceutical line. Moreover, validation of mentioned method was done. The residual concentration of TMS was determined by RP-HPLC. Effective parameters such as pH, applying voltage and extraction time were optimized individually. Optimum conditions were found 12, 100 V and 10 min for pH, applying voltage and extraction time, respectively. Figures of merit were calculated under optimum conditions, therefore, linear range and limit of detection (LOD) were obtained 0.5-1000 ng mL−1 with a good coefficient of determination (R2=0.9901) and 0.05 ng mL−1, respectively. Last but not least, RSD of determination was found 0.67% which shows a satisfactory repeatability. According to the obtained results, proposed method is a precise, accurate, relatively fast and applicable route to determine TMS concentrations in rinse samples.

Cleaning validation for pharmaceutical production equipment is a documented proof of the efficient cleaning, and one of prerequisites of good manufacturing practice in medicine production. Successful validation confirms the efficiency of the procedures of cleaning, washing, and disinfecting of the manufacturing equipment, and records results of the chemical and microbiological analyses, which are a prerequisite for a safe final dietary product. The main goal of this study was to improve the cleaning process of the production equipment by using cleaning validation procedures on the solid form production line (capsules) in the Abela Pharm d.o.o. The validation principles that are used in manufacturing of medicines can be applied to determine more efficient cleaning methods that will ensure longer periods of the status clean in the production of dietary supplements. The outcome is a practical analysis of the production equipment in view of regulatory demands, confirming that the cleaning validation measures ensure prevention of unwanted microbial growth or removal of contamination from the production equipment in order to preserve the activity, efficacy, and safety of the final dietary product.

The Acceptable Daily Exposure (ADE) derived for pharmaceutical manufacturing is a health-based limit used to ensure that medicines produced in multi-product facilities are safe and are used to validate quality processes. Core to ADE derivation is selecting appropriate point(s) of departure (PoD), i.e., the starting dose of a given dataset that is used in the calculation of the ADE. Selecting the PoD involves (1) data collection and hazard characterization, (2) identification of "critical effects", and (3) a dose-response assessment including the determination of the no-observed-adverse-effect-level (NOAEL) or lowest-observed-adverse-effect-level (LOAEL), or calculating a benchmark dose (BMD) level. Compared to other classes of chemicals, active pharmaceutical ingredients (APIs) are well-characterized and have unique, rich datasets that must be considered when selecting the PoD. Dataset considerations for an API include therapeutic/pharmacological effects, particularities of APIs for different indications and routes of administration, data gaps during drug development, and sensitive subpopulations. Thus, the PoD analysis must be performed by a qualified toxicologist or other expert who also understands the complexities of pharmaceutical datasets. In addition, as the pharmaceutical industry continues to evolve new therapeutic principles, the science behind PoD selection must also evolve to ensure state-of-the-science practices and resulting ADEs.

Objectives Our pharmacy works in accordance with the Good Manufacturing Practice in the area of multidose individual blister repackaging. This required validating the cleaning procedure of the blister machines accounting for the characteristics of our setting and investigating worst possible production scenarios. Methods Visual clean: After machine cleaning we inspected surfaces for visible residues. Cross-contamination: A tablet vulnerable to contamination was analysed after blister packaging for residues of a medication with high contamination risk using. Critical medications in the machine were identified by their dust formation potential. Placebo tablets were blister-packaged and analysed for residues of these critical medications using mass spectrometry. We assessed pharmacological relevance of contamination from these two analyses by the dose criterion. Validity of results: Comparing production conditions and technical construction of the blister machines, validity of the validation results for the whole setting was investigated. Results After cleaning no residues were visible on the machine. No contamination was detected on the vulnerable tablet. In 80% of 280 analysed placebo tablets contamination was not measurable or below 1% of the cut-off limits according to the dose criterion, the highest value being 8.5%. Production volume and cleanability were comparable in the other machines. Conclusions Blister machine cleaning was successfully validated: visual cleanliness was achieved; contamination values were clearly below the cut-off limits, ruling out relevant cross-contamination of copackaged drugs. The results proved valid for the whole site. The study contributes evidence to safety and quality of blister repackaging and may serve as reference for similar settings.

The Cleaning Validation protocol plays an important role in the field of pharmaceutical industries its main task is the verification of cleaning procedures to ensure that complete removal of product residues degradation products preservatives excipients cleaning agents and cross contamination of the previous active ingredients A new RP HPLC method is evaluated for determination of Amoxicillin AMO residues in NICOMAC coating machine using Betabasic C mm x mm micro m or equivalent mobile phase of a mixture of M sodium dihydrogen phosphate methanol v v adjusted to pH with orthophosphoric acid at a flow rate of mL min injection volume mu L and UV detection at nm The retention time of AMO is min and the total run time is min A Linear relationship is obtained in the range to ppm with a correlation coefficient of limit of detection mu gmL and limit of quantitation of mu gmL The overall recovery is plusmn the relative standard deviation for precision and intraday precision is less than The validation of the method is performed according to ICH guidelines and USP requirements for new methods which include accuracy precision specificity LOD LOQ robustness ruggedness linearity and range

Chromatography resins used for purifying biopharmaceuticals are generally dedicated to a single product. In good manufacturing practice (GMP) facilities that manufacture a limited amount of any particular product, this practice can result in the resin being used for a fraction of its useful life. A methodology for extending resin reuse to multiple products is described. With this methodology, resin and column performance, product carryover, and cleaning effectiveness are continually monitored to ensure that product quality is not affected by multiproduct resin reuse (MRR). Resin and column performance is evaluated in terms of (a) system suitability parameters, such as peak-shape and transition, and height equivalent theoretical plate (HETP) data; (b) key operating parameters, such as flow rate, inlet pressure, and pressure drop across the column; and (c) process performance parameters, such as impurity profiles, product quality, and yield. Historical data are used to establish process capability limits (PCLs) for these parameters. Operation within the PCLs provides assurance that column integrity and binding capacity of the resin are not affected by MRR. Product carryover defined as the carryover of the previously processed product (A) into a dose of the subsequently processed product (B) (COA→B), should be acceptable from a predictive patient safety standpoint. A methodology for determining COA→B from first principles and setting acceptance limits for cleaning validation is described. Cleaning effectiveness is evaluated by performing a blank elution run after inter-campaign cleaning and prior to product changeover. The acceptance limits for product carryover (COA→B) are more stringent for MRR than for single-product resin reuse. Thus, the inter-campaign cleaning process should be robust enough to consistently meet the more stringent acceptance limits for MRR. Additionally, the analytical methods should be sensitive enough to adequately quantify the concentration of the previously processed product (A) and its degradants in the eluent. General considerations for designing small-scale chromatographic studies for process development are also described. These studies typically include process-cycling runs with multiple products followed by viral clearance studies with a panel of model viruses. Small-scale studies can be used to optimize cleaning parameters, predict resin performance and product quality, and estimate the number of multiproduct purification cycles that can be run without affecting product quality. The proposed methodology is intended to be broadly applicable; however, it is acknowledged that alternative approaches may be more appropriate for specific scenarios. LAY ABSTRACT: Chromatography resins used for purifying biopharmaceuticals are generally dedicated to a single product. In good manufacturing practice (GMP) facilities that make a limited amount of any particular product, this practice can result in the resin being used for a fraction of its useful life. A methodology for extending resin reuse to multiple products is described. With this methodology, resin and column performance, product carryover, and cleaning effectiveness are continually monitored to ensure that product quality is not affected by multiproduct resin reuse. General considerations for designing small-scale chromatographic studies for process development are described. These studies typically include process-cycling runs with multiple products followed by viral clearance studies with a panel of model viruses. Small-scale studies can be used to optimize cleaning parameters, predict resin performance and product quality, and estimate the number of multiproduct purification cycles that can be run without impacting product quality. The proposed methodology is intended to be broadly applicable; however, it is acknowledged that alternative approaches may be more appropriate for specific scenarios.

In pharmaceutical industry there are some possibilities of contamination and cross-contamination because of improper cleaning of equipment, apparatus, processing area or the starting material, this can lead to severe hazards, therefore in pharmaceutical industry we can’t afford any contamination as well as cross contamination. This can be minimized by proper cleaning of equipment, apparatus as well as the processing area. TheIndustry wants to achieve these main goals with the help of GMP. This review focused on the different types of cleaning process adapted by pharmaceutical industry, how the process of cleaning validation is done. In the cleaning validation different critical parameter, factor, material and critical process are monitored and validated so that the cleaning consistency can be achieved and documented accordingly. Keywords: Cleaning validation, contamination, clean in place, clean out of place, swab sampling, worst case

Reusable medical devices (RMDs) must be reprocessed between uses to render them safe for each use and each patient. Cleaning used devices removes organic and inorganic soil making them either safe for reuse or ready for disinfection/sterilization depending on the device. Although cleaning is an important step in a RMD's life cycle, it is not always a priority during device design. In addition, when performing cleaning validation, it is recommended that the manufacturer takes into consideration, what the most appropriate or worst case conditions are in terms of type of soil or the presence of bacteria. This study compared the ability of three different cleaning/disinfecting agents (water, alcohol, and bleach) to remove bacteria and fecal test soil from two different polymers: polypropylene and ultrahigh molecular weight polyethylene (UHMWPE) with two different roughness. There were some differences in the effects of the cleaning/disinfecting agents, the materials, and the roughness depending on the particular circumstances. However, the most consistent effect on the removal of bacteria was the presence of soil, which protected the bacteria from being removed. Conversely, the presence of bacteria played little role in the removal of soil. Although the interactions between material type and roughness, soil type, and bacteria are complicated, they should be taken into account during device design and reprocessing validation to create a device that is easy and safe to use. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1706-1710, 2019.

Cleaning validation, a requirement of the current Good Manufacturing Practices (cGMP) for Drugs, consists of documented evidence that cleaning procedures are capable of removing residues to predetermined acceptance levels. This report describes a strategy for the selection of the worst case product for the production of lyophilized reagents (LRs) for labeling with 99mTc from the Instituto de Pesquisas Energéticas e Nucleares (IPEN-CNEN/São Paulo). The strategy is based on the calculation of a "worst case index" that incorporates information about drug solubility, cleaning difficulty, and occupancy rate in the production line. It allowed a reduction in the required number of validations considering the possible manufacturing flow of a given product and the subsequent flow, thus facilitating the process by reducing operation time and cost. The products identified as "worst case" were LRs PUL-TEC and MIBI-TEC. RESUMO A validação de limpeza é uma exigência dos atuais regulamentos de Boas Práticas de Fabricação de Medicamentos (BPF) e consiste na evidência documentada, que demonstra que os procedimentos de limpeza removem os resíduos em níveis de aceitação pré-determinados. Este estudo apresenta uma estratégia para escolha do produto "pior caso" da linha de produção de reagentes liofilizados para marcação com 99mTc do Instituto de Pesquisas Energéticas e Nucleares (IPEN-CNEN/São Paulo). A estratégia baseia-se no cálculo de um índice denominado "índice para pior caso," que utiliza informações de solubilidade dos fármacos, dificuldade de limpeza dos equipamentos e ocupação dos produtos na linha de produção. A estratégia adotada proporcionou a diminuição no número de validações necessárias, considerando-se as possibilidades de sequências de fabricação de um determinado produto e do produto subsequente, possibilitando a simplificação do processo e redução no tempo e nos custos das atividades envolvidas. Os produtos indicados como pior caso foram os reagentes liofilizados (RL) PUL-TEC e MIBI-TEC.

BACKGROUND: Cleaning of technical equipment should remove residues of products and cleaning agents, as well as avoid microbial contamination.(1) In hospital pharmacies multipurpose equipment is used for the manufacture of different pharmaceutical preparations. Suitable well-documented cleaning procedures are necessary to guarantee patient safety by avoiding cross-contamination of drugs. PURPOSE: Effective cleaning procedures should be developed and validated for multipurpose and drug-contaminated equipment used in the solution production e.g. stirrers, tanks, tubes and filling systems. As a final result the contamination risk of all possible production lines could be assessed. MATERIAL AND METHODS: Focusing on direct product contact our multipurpose equipment was grouped into nine critical and 11 uncritical systems. For seven of nine critical systems, a validated cleaning process did not exist and had to be developed. The validation covered the cleaning status immediately at the end of production (t(0)) and after a 24 hours’ dirty-hold time (t(24)). Naphazoline nitrate was defined as the worst case active component of our solutions portfolio. The analytical (1/1000 dose criteria) and microbiological residue limits were calculated.(1) The HPLC method for the quantitative analysis of naphazoline nitrate was validated.(2) Based on a risk assessment evaluating the potential of contamination, the number of validation runs for each unit of equipment was defined. The analytical and microbiological results were quantified for each system. To assess the whole process the residues of all production lines at t(0) and t(24) were summarised. RESULTS: An effective cleaning procedure was evaluated for each system and validated at t(0) and t(24). Each unit of equipment and all possible production lines met the analytical residue limits at t(0), and at t(24) with the exception of the tubes. The microbiological requirements were fulfilled for the clean-room zones D and C. CONCLUSION: The tube surface consists of polytetrafluoroethylene and has to be cleaned immediately after the end of the production (t(0)). All other systems are almost completely made of stainless steel and can be cleaned until t(24). The cleaning validation of the solution production was the first process in our hospital pharmacy which was completely validated including a dirty-hold time. REFERENCES AND/OR ACKNOWLEDGEMENTS: 1. GMP-Guideline, Annex 15: Qualification and Validation. 2. ICH-Guideline, Topic Q2(R1): Validation of Analytical Procedures. No conflict of interest

Objectives The United States National Institute for Occupational Safety and Health (NIOSH) is developing a protocol to assess the containment performance of closed system transfer devices (CSTDs) when used for drug preparation (task 1) and administration (task 2) and published a draft protocol in September 2016. Nine possible surrogates were proposed by NIOSH for use in the testing. The objectives of this study were to: (A) select the most appropriate surrogate; (B) validate the NIOSH protocol using this surrogate; and (C) determine the containment performance of four commercial CSTDs as compared with an open system of needle and syringe using the validated NIOSH protocol. Methods 2-Phenoxyethanol (2-POE) was selected as a surrogate based on its water solubility, Henry’s volatility constant, detectability by mass spectrometry, and non-toxicity. Standard analytical validation methods including system suitability, limit of detection (LOD), and limit of quantitation (LOQ) as well as system cleaning validation were performed. The amount of 2-POE released when the CSTDs were manipulated according to two tasks defined by NIOSH was determined using mass spectrometry coupled to thermal desorption and gas chromatography. This approach allows sensitivity of detection below 1 part per billion (ppb). Equashield, Tevadaptor (OnGuard), PhaSeal, and ChemoClave were assessed according to manufacturers’ instructions for use. Results 2-POE was tested and validated for suitability of use within the NIOSH protocol. A simple and efficient cleaning protocol achieved consistently low background values, with an average value, based on 85 measurements, of 0.12 ppb with a 95% confidence interval (CI) of ±0.16 ppb. This gives an LOD for the tests of 0.35 ppb and an LOQ of 0.88 ppb. The Equashield, Tevadaptor (OnGuard), and PhaSeal devices all showed average releases, based on 10 measurements from five tests, that were less than the LOQ (i.e. < 0.88 ppb), while the ChemoClave Vial Shield with Spinning Spiros showed average releases of 2.9±2.3 ppb and 7.5±17.9 ppb for NIOSH tasks 1 and 2 respectively at the 95% confidence level. The open system of needle and syringe showed releases, based on two measurements from a single test, of 4.2±2.2 ppb and 5.1±1.7 ppb for NIOSH tasks 1 and 2 respectively at the 95% confidence level. Conclusions 2-POE proved to be an ideal surrogate for testing of CSTDs using the NIOSH protocol. We propose that a CSTD can be qualified using the NIOSH testing approach if the experimental LOQ is less than 1 ppb and the release values are below the LOQ. Equashield, Tevadaptor (OnGuard), and PhaSeal meet these acceptance criteria and can therefore all be qualified as CSTDs, but the ChemoClave system does not and so would not qualify as a CSTD.

Environmentally friendly gallic acid coated magnetic nanoparticles (GA-MNP) have been synthesized and evaluated as a novel photocatalyst for degradation of meloxicam; a commonly prescribed nonsteroidal anti-inflammatory drug. The synthesized GA-MNP were characterized using transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopy and dynamic light scattering. Results showed the formation of core–shell MNP with a mean hydrodynamic diameter of 160.55 ± 5.02 nm and zeta potential of −42.4 ± 1.6 mV. A validated RP-HPLC stability-indicating assay was developed for monitoring of meloxicam concentration in the presence of its degradation products and for determination of the kinetics of degradation. Full factorial design (24) was employed in order to investigate the effects of pH, irradiation time, GA-MNP loading and initial meloxicam concentration on the efficiency of the process. The irradiation time was found to be the most significant parameter followed by initial meloxicam concentration and GA-MNP loading, respectively. At the optimized conditions, increasing GA-MNP loading to 5.00 mg mL−1 demonstrated superior photocatalytic activity when compared to bare MNP and TiO2NP. Meloxicam degradation was found to follow pseudo first order rate kinetics with Kobs and t0.5 of −0.0029 min−1 and 239 min, respectively. The protocol was successfully applied for treatment of incurred water samples collected during various cleaning validation cycles. A percentage degradation of 89.10 ± 0.13% was achieved upon irradiation of samples containing 64.57 ± 0.09 µg mL−1 with UV light (1012 µW cm−2, 8 h) in the presence of 5 mg mL−1 GA-MNP at pH 9.0 ± 0.05. It could be suggested that treatment of wastewaters collected during the cleaning validation of each pharmaceutical product, before pooling into the general waste pool, should improve the efficiency and economics of pharmaceutical wastewater treatment.

Managing allergen changeover in food production facilities can be exceptionally challenging, especially when different allergens are handled on the same line or piece of equipment. Allergen cross-contact can occur when allergen-containing and non-allergen-containing foods or ingredients are produced in the same facility or processing line and allergen controls are not properly implemented. Cleaning is an essential tool for preventing allergen cross-contact during storage, production, and transportation of food. Many factors must be considered when developing cleaning procedures for the purpose of controlling allergens. These include the soil type, the composition and type of food-contact surface, how the food was applied to the surface, the concentration of the allergen in the food, the type and age of the equipment, the length of the processing run, and the type of cleaning method. This chapter discusses the factors that affect removal of allergens from food-contact surfaces, the different approaches for removal of allergenic food soils from food-contact surfaces, best practices and procedures for verifying and validating cleaning treatments for allergen removal and the steps associated with developing an allergen cleaning program. More effective approaches are needed for removing allergens from food-contact surfaces, particularly in the low-moisture foods manufacturing environment. Development of statistically based sampling plans for obtaining samples for cleaning validation and verification activities, and rapid, sensitive, and inexpensive analytical methods for detecting multiple allergens in a single assay are also key research needs.

Due to newly introduced EU GMP (Good Manufacturing Practice) guideline for Medicinal Products for Human and Veterinary use, product specific permitted daily exposure (PDE) for toxicological evaluation in multi-purpose facilities are required within a documented process for risk assessment. European Medicines Agency (EMA) guidance on setting PDE limits so far focused on systemic administration routes such as intravenous (IV), oral or inhalation. This article provides guidance on setting PDE values for risk management purposes in multi-purpose facilities for active pharmaceutical ingredients (APIs) applied as topical otic drugs to the outer ear canal. The therewith determined PDE otic, is used for the calculation of maximum safe carry-over (MSC) in manufacturing scenarios where a topical otic product is manufactured followed by another topical otic product.

Limits for the carry-over of product residues should be based on toxicological evaluation such as described in the "Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities". The toxicological evaluation should be performed also for locally administered drugs to ensure patient safety. Currently, there is no guidance on setting PDE for ocular drug substances in particular. The purpose of this investigation was to identify and describe a method for calculating a PDE value for topical ocular drugs (PDE

A simple and reproducible, RP-HPLC cleaning validation method for the simultaneous estimation of Olmesartan and Atorvastatin has been developed. The chromatography was carried out on Phenomenex Synergi polar RP-80A column (250mm×4.6mm, 4μm) in an isocratic mode utilizing ammonium acetate buffer (pH 6.5): acetonitrile (65: 35, v/v) as mobile phase, at a flow rate of 1.5mL/min. Detection was carried out at Isosbestic point of 252nm. Retention times of olmesartan and atorvastatin were 3.847±0.2 min and 8.930±0.2 min, respectively. The method was validated as per ICH guidelines. The method was found to be specific as there was no swab interference. The Beer Lambert's law was obeyed in the concentration range 0.1–10μg/mL for both olmesartan and atorvastatin with Correlation Coefficient, r2 = 0.9999. The % RSD of six replicates and mean % recovery were found to be within acceptable limits for both the drugs. The LOD was 0.003μg/ml for olmesartan and atorvastatin and the LOQ was 0.1μg/ml for olmesartan and atorvastatin which showed that method was sensitive. The method was robust as observed from insignificant variation of analysis results by adopting minor changes in chromatographic conditions. Stability studies conducted on mixed standard solution kept on bench top and under refrigeration conditions showed that the solution was stable on benchtop for 2 h, while the refrigerated solution was stable up to 24 h.

Objective The purpose of this study was to evaluate the contamination rate of media-fill products either prepared automated with a robotic system (APOTECAchemo™) or prepared manually at cytotoxic workbenches in the same cleanroom environment and by experienced operators. Media fills were completed by microbiological environmental control in the critical zones and used to validate the cleaning and disinfection procedures of the robotic system. Methods The aseptic preparation of patient individual ready-to-use injection solutions was simulated by using double concentrated tryptic soy broth as growth medium, water for injection and plastic syringes as primary packaging materials. Media fills were either prepared automated (500 units) in the robot or manually (500 units) in cytotoxic workbenches in the same cleanroom over a period of 18 working days. The test solutions were incubated at room temperature (22℃) over 4 weeks. Products were visually inspected for turbidity after a 2-week and 4-week period. Following incubation, growth promotion tests were performed with Staphylococcus epidermidis. During the media-fill procedures, passive air monitoring was performed with settle plates and surface monitoring with contact plates on predefined locations as well as fingerprints. The plates got incubated for 5–7 days at room temperature, followed by 2–3 days at 30–35℃ and the colony forming units (cfu) counted after both periods. The robot was cleaned and disinfected according to the established standard operating procedure on two working days prior to the media-fill session, while on six other working days only six critical components were sanitized at the end of the media-fill sessions. Every day UV irradiation was operated for 4 h after finishing work. Results None of the 1000 media-fill products prepared in the two different settings showed turbidity after the incubation period thereby indicating no contamination with microorganisms. All products remained uniform, clear, and light-amber solutions. In addition, the reliability of the nutrient medium and the process was demonstrated by positive growth promotion tests with S. epidermidis. During automated preparation the recommended limits Conclusion Extensive media-fill tests simulating manual and automated preparation of ready-to-use cytotoxic injection solutions revealed the same level of sterility for both procedures. The results of supplemental environmental controls confirmed that the aseptic procedures are well controlled. As there was no difference in the microbial contamination rates of the media preparations depending on the extent of cleaning and disinfection of the robot, the results were used to adapt the respective standard operating procedures.