Assurance of sterility

EC verification provides an alternative to the model of establishing a certified production QA system. Independent testing of either all devices, or a statistically representative sample of each batch, is conducted by or on behalf of the Notified Body, which then issues a certificate of conformity for the tests conducted. This is not a popular option due to the costs involved. The procedure is not capable of providing adequate assurance as to the sterility of devices. Instead, an assurance of sterility must be based on the application of a production QA system to the sterilisation process. 

Lack of assurance of sterility in production or testing of sterile drug products. Discoloration. Counterfeit dosage form. 

Failed USP dissolution test requirements Microbial contamination of non-sterile products Lack of efficacy Impurities/degradation products Lack of assurance of sterility Lack of product stability Labeling Label error on declared strength Misbranded Promotional literature with unapproved therapeutic claims... 

Sterile radiopharmaceuticals may be divided into those which are manufactured aseptically and those which are terminally sterilized. In general, it is advisable to use a terminal sterilization whenever this is possible. Terminal sterilization is defined as a process that subjects the combined product/container/closure system to a sterilization process that results in a specified assurance of sterility [7], Since sterilization of solutions normally means autoclaving (steam sterilization), one must assure that the radiopharmaceutical product does not decompose when it is heated to temperatures above 120°C. Many radiolabeled compounds are susceptible to decomposition at higher temperatures. Proteins, such as albumin, are good examples of this. Others, such as 18F-fluodeoxyglucose (FDG), can be autoclaved in some formulation but not in others. 

The preceding relates solely to product quality attributes, based upon chemical or physical requirements. Assurance of sterility, the most critical of all the quality components for an aseptically filled sterile product relies on the following ... 

At present, the pharmaceutical industry regulatory requirements refer to isolators specifically in the context of the manufacture of sterile products. There is no reference to their role in broader areas of crosscontamination and operator safety control. Within Europe, the current EU GMP clearly states that isolators might produce improvements in sterility assurance of sterile products, and that aseptic processing manufacturing isolators should be placed in at least a Grade D surrounding environment. The Food and Drug Administration (FDA) requirements are less well defined, but it is likely that in equivalent circumstances, they would like to see an isolator located in a class 100,000 or M6.5 environment In Operation. ... 

Because of their small size many species of virus can enter the pores of filter membranes used for sterilization of liquids, but particle entrapment by the membrane is often achieved as a result of adsorption processes. As a consequence, substantial reductions in viral concentration can result from filtration through membranes of appropriate characteristics, and adequate assurance of sterility may be achieved provided that the pre-sterilization bioburden is carefully controlled (Chapter 20). 

Quality control and quality assurance of sterile products... 

The time lag in imposition of a legal requirement for sterility of ointments compared with solutions and suspensions was due to the absence of a reliable sterility test for the petrolatum-based ointments until isopropyl myristate was employed to dissolve these ointments and allow improved recovery of viable microorganisms by membrane filtration. Manufacturers found that, in fact, many of their ointments were sterile, but revised their manufacturing procedures to increase the assurance of sterility. 

Continued assurance of sterility for all sterile products can be assessed by a variety of means, including evaluation of the container and closure integrity by an appropriate challenge test or tests, or sterility testing as described in Section VII.C. Stability studies should evaluate product stability following exposure to at least the maximum specified process lethality (e.g., F, Mrads). 

The general point to be made is that delectable microbial growth in any test system is positive confirmation of nonsterility, but absence of growth can only give an assurance of sterility limited by the conditions of the test. It is fundamental that sterility for an hem can never be confirmed with 100% certainty by any test method. 

Autoclave Control Systems Modem production-scale autoclaves are usually computer controlled. Older models may be electromechanically controlled (hardwired). Manual control is rare, and much of the knowledge and many of the skills required in the past to operate autoclaves successfully are being lost to turnkey operation. In many respects this is a giant leap forward to more consistent assurance of sterility. A genuine concern is that some will think that com-puter[Pg.97]

For porous loads, two other monitoring techniques are in use to give assurance of sterility where there is a risk of air entrainment, superheating, etc. These are the Bowie-Dick test pack and the Lantor Cube. It should be emphasized that these are used in rather special applications and would be of little significance to fluid loads or nonporous solid loads. 

It is not possible to measure levels of sterility assurance (SALs) obtained with commercial systems of achieving sterility. The expected assurance of sterility is too high to be measurable by techniques that rely on detection of nonsterility in sampled items. With processes that involve microbiological inactivation, measurements of subprocess inactivation can be extrapolated to estimate process SALs. This not possible for aseptic filling. 

SALs obtained from aseptic filling processes have been modelled from theoretical considerations and are probably as good as 10 5 or better. The simulation trial is an insensitive tool that cannot within reasonable experimental dimensions confirm SALs better than 10. It is not to be assumed that an aseptic filling process is under control merely because a series of satisfactory simulation trials with less than one contaminated item in one thousand have been obtained. Adequate assurance of sterility can only be obtained by ensuring that all possible precautions against contamination are in place and that each one is performing in the manner intended. 

Aseptic manufacture is one of the most technically demanding operations in the pharmaceutical industry. To provide adequate assurance of sterility it is necessary to demonstrate that every critical mechanism and protective system consis-... 

It may he obvious that a containment system has failed to maintain sterility. The contents of a broken ampoule have no assurance of sterility. A syringe received in an open package cannot be supposed to be sterile. Other deficiencies in containment systems may pose greater threats to the user of the medical or pharmaceutical product because they go unnoticed. It is these more subtle problems that demand serious consideration. 

To provide assurance of sterility, special precautions are necessary in the aseptic processing products. 

The utilisation of absolute barrier technology and automated systems to minimise human interventions in processing areas can produce significant advantages in assurance of sterility of manufactured products. When such techniques are used, the recommendations in these Supplementary Guidelines, particularly those relating to air quality and monitoring, still apply, with appropriate interpretation of the terms work station and environment . 

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