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Cleaning Validation for the 21 Century: Acceptance Limits for Active Pharmaceutical Ingredients (APIs): Part I

Authors:
  • Center for Pharmaceutical Cleaning Innovation, LLC

Abstract

This article reviews the history of Cleaning Validation Acceptance Limits for Active Pharmaceutical Ingredients (APIs) and identifies where the currently used industry limits came from.
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... c. The following step is to determine the presence of active residues, if any, via the following steps [14]. ...
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In the pharmaceutical industry, cleaning is a vital area that needs special focus before, during, and after any batch of manufacturing to prevent contamination and cross-contamination of the product(s). Cleaning validation refers to that something has been cleaned and that the contamination levels have been reduced to a certain ratio or below a certain target level. The main aim of cleaning validation is to assure documented evidence that a cleaning procedure has and will consistently remove all possible contamination for chemical, detergent, and microbial load to an acceptable limit. Contaminant of different type i.e. active ingredient, by-product or excipients, dust particle, residual of cleaning agent, residual of rinse water as well as microbial contamination is also of concern. This article highlights cleaning validation as a basic requirement for pharmaceutical products with an emphasis on acceptance criteria, sampling, worst-case analysis during cleaning validation.
... c. The following step is to determine the presence of active residues, if any, via the following steps [14]. ...
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In the pharmaceutical industry, cleaning is a vital area that needs special focus before, during, and after any batch of manufacturing to prevent contamination and cross-contamination of the product(s). Cleaning validation refers to that something has been cleaned and that the contamination levels have been reduced to a certain ratio or below a certain target level. The main aim of cleaning validation is to assure documented evidence that a cleaning procedure has and will consistently remove all possible contamination for chemical, detergent, and microbial load to an acceptable limit. Contaminant of different type i.e. active ingredient, by-product or excipients, dust particle, residual of cleaning agent, residual of rinse water as well as microbial contamination is also of concern. This article highlights cleaning validation as a basic requirement for pharmaceutical products with an emphasis on acceptance criteria, sampling, worst-case analysis during cleaning validation.
... regulations and its authorities, food, beverage, healthcare research labs, business organizations, to obtain high assurance of product quality, integrity, batches integrity, minimization of costs quality, fewer down time, product batch failures and can function efficiently. 14,15 The schematic diagram elucidating various approaches of cleaning validations is depicted in Figure 1. ...
... Con el tiempo, se vio que el enfoque de Eli Lilly para establecer límites de validación de limpieza carecía de información toxicológica relevante, que resultaba en el establecimiento de límites más estrictos para algunos compuestos de bajo riesgo que para otros de alto riesgo 18 . Estas discrepancias conllevaban una imagen confusa del riesgo real de contaminación cruzada e, incluso, podría resultar que requirieran dedicación compuestos de bajo riesgo (por ejemplo, aspirina en dosis bajas). ...
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This is the Spanish version: Este artículo expone algo de la historia que inició el movimiento desde enfoques basados en el cumplimiento de los protocolos a los de validación de la limpieza por métodos científicos y de evaluación de riesgos introducidos en la H istóricamente, la industria farma-céutica ha enfocado principalmen-te la validación de la limpieza como un ejercicio de aplicación de protocolos. Como tales, estas actividades de validación de limpieza se establecieron generalmente en función de las expectativas reglamen-tarias de las observaciones durante las inspecciones y no en planes maestros con base científica o evaluaciones de riesgos. A principios de la década de 1990, la FDA, así como otras agencias reguladoras, comenza-ron a ver la limpieza como un proceso que requería validación. Por tanto, la validación de la limpieza se asoció estrechamente con la validación del proceso. La validación de limpieza se basó en el enfoque tradicional de validación de otros procesos, que utiliza protocolos preaprobados, con criterios de aceptación predeterminados y las tres ope-raciones estándar. Este enfoque se adoptó sin considerar si eran necesarios tres ciclos de validación de limpieza, si eran suficientes o si los criterios de aceptación predetermi-nados eran apropiados para este caso. Al mismo tiempo, la industria estaba discu-tiendo sobre cómo establecer estos criterios de aceptación predeterminados requeridos. Como parte de las GMP de la FDA para el proyecto siglo XXI, a partir de 2001 mu-chas nuevas iniciativas provinieron de las agencias reguladoras y de la propia indus-tria farmacéutica. Tres eventos importan-tes anteriores a este momento también Tabla 1. Eventos históricos relativos a la Validación de la Limpieza
... In order to determine whether the sampled equipment surfaces were clean or contaminated, the residue acceptance limit L was calculated. In light of the frequently used 10 ppm and 0.001 dose criterion [49,50] discussed in [51,52], the residue acceptance limit calculation was based on toxicological data [53]. It was performed for the swab (L Swab,E2 = 0.11 µg·mL −1 , L Swab,E3 = 9.9 µg·mL −1 and L Swab,IBU = 9.9 µg·mL -1 ) as well as the rinse tests (L Rinse,E2 = 0.015 µg·mL −1 , L Rinse,E3 = 3.1 µg·mL −1 and L Rinse,IBU = 15.6 µg·mL −1 ), similarly as in ref. [53]. ...
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To avoid any type of cross-contamination, residue-free production equipment is of utmost importance in the pharmaceutical industry. The equipment cleaning for continuous processes such as hot melt extrusion (HME), which has recently gained popularity in pharmaceutical applications, necessitates extensive manual labour and costs. The present work tackles the HME cleaning issue by investigating two cleaning strategies following the extrusion of polymeric formulations of a hormonal drug and for a sustained release formulation of a poorly soluble drug. First, an in-line quantification by means of UV–Vis spectroscopy was successfully implemented to assess very low active pharmaceutical ingredient (API) concentrations in the extrudates during a cleaning procedure for the first time. Secondly, a novel in-situ solvent-based cleaning approach was developed and its usability was evaluated and compared to a polymer-based cleaning sequence. Comparing the in-line data to typical swab and rinse tests of the process equipment indicated that inaccessible parts of the equipment were still contaminated after the polymer-based cleaning procedure, although no API was detected in the extrudate. Nevertheless, the novel solvent-based cleaning approach proved to be suitable for removing API residue from the majority of problematic equipment parts and can potentially enable a full API cleaning-in-place of a pharmaceutical extruder for the first time.
... This is not necessarily a common instrument in pharmaceutical analytical laboratories, but it is becoming more widely used. [15] Enzyme-Linked Immunosorbent Assay (ELISA) ...
... Specific limits have not been established for dissolution apparatus as they are not directly used in the manufacturing of drug products. The industry has used cleaning limits based on 10 ppm for finished drug manufacture, 50-100 ppm for API manufacture or dose, and maximum allowable carryover (MAC) calculations (35)(36)(37)(38). The idea behind GMP cleaning limits can be used as a justifiable detection benchmark for dissolution instruments. ...
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The regulatory expectations are changing day by day on the cleaning validation in Pharmaceutical industries, considering the patient safety and drug efficacy. Manufacturing of an Intermediate and Active Ingredient Pharmaceuticals involves many chemical syntheses and same equipment is being using for manufacturing of different product in multi-production facility. Equipment cleaning plays a key role in controlling the contamination, to control the potential carryover of the product, cleaning methods shall be designed effectively to reduce the previous product residue. The current good manufacturing practice regulations state that cleaning is a critical issue to ensure the product quality. Improper cleaning results the carryover of the previous product residue and leads to failure of the product, so adequate cleaning procedures should be in place to clean the equipment to provide the documented evidence. The established cleaning procedures and cleaning methods shall be validated, life cycle approach is considered for the cleaning validation process. The article discussed about the outlines of the life cycle approach for the cleaning validation.
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The design of a cheap, simple, and handy sensing system for rapid quantitation of pharmaceuticals is very mandatory to ease drug development procedures, quality control, health care, etc. This work describes a simple, innovative, and easily manufactured paper-based device using a correction pen as a plotter for hydrophobic/lipophobic barriers and the graphene quantum dots for recognition and quantification of the hemostatic drug, carbazochrome, via fluorescence turn-off mechanism mediated by the inner filter effect. A smartphone-based all-in-one device fitted with an inexpensive 365 nm flashlight as a UV light source and a free image processing software was developed for rapid and reliable interpretation of the fluorescence change from the paper-based device upon introduction of the drug. The simple and convenient steps permit the analysis of many samples in a very short time. The smartphone-based all-in-one device featured excellent sensitivity for carbazochrome with a limit of detection equals to 12 ng/detection zone and good %recovery (100.0 ± 0.4). The reliability of the device was ascertained by favorable statistical comparison with the analogous optimized conventional fluorimetry method and a reference HPLC method. The device has been successfully applied for versatile quantitation of carbazochrome in tablets and on manufacturing equipment surfaces with excellent recoveries. The device offers many green aspects that definitely assist the implementation of the sustainability concept to analytical laboratories. The cost-efficiency, reliability, and ease of fabrication as well as the greenness and user friendship qualify the device for wide application in low-income communities.
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The presence of active pharmaceutical ingredients (APIs) in adulterated or contaminated dietary supplements is a current product safety concern. Since there are limited guidelines, and no published consensus methods, we developed a tier-based framework incorporating typical lines of evidence for determining the human health risk associated with APIs in dietary supplements. Specifically, the tiered approach outlines hazard identification and decision to test for APIs in products based on criteria for likelihood of contamination or adulteration, and evaluation of manufacturer production standards. For products with detectable levels of APIs, a variety of default approaches, including the use of fraction of the therapeutic dose and the threshold of toxicological concern (TTC), as well as health-based exposure limits (HBELs) are applied. In order to demonstrate its practical use, as well as any limitations and/or special considerations, this framework was applied to five dietary supplements (currently available to the public). We found that the detected levels of APIs in some dietary supplements were above the recommended dose of the drugs, and thus, pose a significant health risk to consumers and potentially workers involved in manufacturing of these supplements. The results support the value of increased product quality surveillance and perhaps regulatory activity.
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The maximum acceptable carryover (MAC) criterion is widely used to set cleaning validation limits for contaminants. It is based on the assumption that all the residual contaminants in the cleaned equipment will carryover into the next batch that is manufactured in that equipment. Thus, the MAC criterion is based on a worst-case mass balance (WCMB) for the contaminant. This article demonstrates that the conventional approach for setting cleaning validation limits based on the MAC criterion is far more conservative than a WCMB. Consequently, it leads to acceptance criteria that are much more stringent than necessary. This often results in cleaning validation limits that are impractical to achieve. Additionally, in some instances the acceptance criteria can be well below the limit of quantification (LOQ) of the analytical method. An alternate approach for setting rational cleaning validation limits based on the MAC criterion and WCMB is described. The limits are used to derive more meaningful acceptance criteria for cleaning validation samples. For a typical pharmaceutical process, limits based on the proposed approach are shown to be about an order of magnitude higher than those based on the conventional approach. An important benefit of setting rational MAC-based limits is that higher acceptance criteria for cleaning validation samples can be justified. With higher acceptance criteria it is possible to replace complex product specific assays with relatively simple non-specific assays such as Total Organic Carbon (TOC).
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Pharmaceutical manufacturing requires validation of cleaning methods to ensure that the contaminants from one product to another are reduced to safe and acceptable levels. The current available methods for generating cleaning validation acceptance limits can be used effectively for both active pharmaceutical ingredients and finished products. A need still exists, however, for using these approaches rationally for topical formulations (TFs). The authors highlight the issues and challenges encountered when determining cleaning validation acceptance limits for TFs.
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Warfarin is an anticoagulant available as a racemic mixture. The R- and S-isomers differ with respect to relative plasma concentrations, clearance, potency, sites of metabolism, and cytochrome P450 (CYP) isoenzymes responsible for metabolism. S-Warfarin, the more potent isomer, is metabolized primarily by CYP2C9. Genetic polymorphisms resulting from single amino acid substitutions reduce the metabolic capability of 2C9. A reduction in warfarin metabolism due to genetic polymorphism may explain the increased warfarin response and bleeding episodes in some patients. Clinical studies showed an increased plasma level of S-warfarin, decreased clearance of S-warfarin, increased frequency of bleeding, and prolongation of hospitalization in patients with variant CYP2C9 alleles. Adverse outcomes associated with warfarin possibly could be avoided by identifying patients with variant alleles before therapy and starting therapy at low dosages.
Inc. Civil Action No. 92-1744, US District Court for the District of New Jersey: Acceptance limits for APIs 812 F. Supp. 458
United States vs. Barr Laboratories, Inc. Civil Action No. 92-1744, US District Court for the District of New Jersey: Acceptance limits for APIs 812 F. Supp. 458. 1993 US Dist. Lexis 1932; 4 February 1993, as amended 30 March 1993.
Drug Substance Manufacture and Control
  • H L Avallone
Avallone, H.L., "Drug Substance Manufacture and Control," Pharmaceutical Engineering, 1989, 9 (2), 37-40, 57, www. ispe.org/pe.
Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing Operations
  • G Fourman
  • M Mullin
Fourman, G., and Mullin, M., "Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing Operations," Pharmaceutical Technology, April 1993, www.pharmtech.com.