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Sunday, March 12, 2017

What are the requirement s for PROCESS SIMULATION & TEST PROCEDURES ?


















PROCESS SIMULATION TEST PROCEDURES
General Comments:

The media fill should emulate the regular product fill situation in terms of equipment, processes, personnel involved and time taken for filling as well as for holding.

Where filling takes place over extended periods, i.e. longer than 24 hours, the process simulation test should extend over the whole of the standard filling period. In order to prevent excessively high numbers of units being filled it is usually acceptable to just run the machine for a reasonable time, if the validity of the simulation is not diminished by this procedure.
It should be considered that inert gases will prevent the growth of aerobic microorganisms. Therefore for process simulations sterile filtered air should be used instead of inert gases, also for breaking a vacuum. Where anaerobes are detected in the environmental monitoring or sterility testing, the use of an inert gas should be considered for a process simulation, as inert gas is supporting the growth of anaerobes.

Before enumerating the different process simulation test procedures some preliminary explanations are necessary for the preparation of liquid media as it is used for the majority of the process simulation tests. Where a liquid nutrient medium is used it should be prepared in a similar manner to the product. The medium should be dissolved in Water for Injection in a standard manufacturing vessel. If heat is required to dissolve it then only minimal heat should be used. The pH of the medium should be measured and, if necessary, adjusted to bring it into the required range. The medium should be aseptically filtered into an aseptic holding vessel using the normal production filter and processing procedure. In justified cases it may be also acceptable to sterilise the media. All aseptic holding vessels should be covered by a process simulation test on a regular basis unless a validated, pressure hold or vacuum hold test is routinely performed.

The following chapter illustrates the test procedures for the various simulation tests for aseptically produced solutions, lyophiles, suspensions, ointments and powders and summarises the considerations to be made.

Liquid Products

Vial Products

The liquid growth medium for the simulation test is prepared as above and kept in a sterile holding vessel for the maximum permitted holding time before starting the simulation test. If the bulk solution is stored under refrigerated conditions during the holding time then this should also be performed for the medium. Vials and closures should be prepared as in regular production.

Sterile Products in Plastic Containers

Ear and eye drops are typically marketed in plastic containers. Containers, inserts, closures and where applicable over seals are washed and sterilized as in regular production. Instead of sterilization with heat, irradiation or ethylene oxide are used.

Whilst clear plastic containers are frequently used for process simulation trials, the plastic is usually slightly opaque and thus hinders identification of contaminated units that show only a slight haze. In such case examination under natural or room lighting would not suffice. Where opaque containers are used for process simulation trials the whole contents should be removed for examination.

Ampoule Products

Open or closed ampoule types may be used. They should be sterilized by dry heat and afterwards used in the simulation test as per the regular production run.

Ampoules should be prepared as in regular production.

Injectable Powder Products

There are two possibilities for simulation of this process. Either by filling a sterilised liquid growth medium into the sterile container or adding a powder (inert or growth medium) before or after a sterile diluent (WFI or growth medium). Inert materials commonly used include: polyethylene glycol 8000 and carboxymethyl cellulose. These materials are usually sterilised by irradiation.

Suspension Products

This procedure is comparable to the filling of liquid products, except for the process step of maintaining suspension of the ingredients. The stirring or recirculation should be part of the simulation. If aseptic additions are made to the bulk solution these should be simulated by the use of inert sterile liquids/powders.

Freeze Dried (Lyophilised) Products

Crystallisation of the medium should be prevented because it may reduce the likelihood of recovery of organisms.

Two simulation methods are commonly used. In the first one a dilute medium is subject to a cycle that removes water until a determined medium strength is obtained, but is not subject to freezing. The second method uses full strength medium and requires only a partial vacuum be drawn whilst the chamber should be kept at ambient temperature. There is a risk that the medium may boil over and contaminate the chamber unless conditions are tightly controlled. The absence of boiling under the defined cycle conditions should be confirmed.

Semi-Solid Products (e.g. sterile ointments)

For this simulation test the liquid growth medium is thickened to the appropriate viscosity, used as in the routine production procedure. Suitable thickening agents are agar and carboxymethyl cellulose. Other agents would need to be validated with regard to lack of their bacteriostatic and fungi static properties. Metal and plastic ointment tubes prevent the examination of the medium in-situ. Usually the whole content of the tube should be examined and this is usually achieved by squeezing the contents into a plate (petri dish), and after whirling it is examined for turbidity and fungal colonies under defined light conditions or by performing a sterility test. If properly validated, an alternative method for detection of contamination of semi-solid products could be the use of media which changes color in the presence of contamination.

Clinical Trials Materials and Small Batch Size Products

As processes for smaller quantities (less than 3000 units) do not allow an interpretation according to chapter 5 of these Recommendations, any presence of microbial contamination should be regarded as an alert limit. Monitoring and test conditions, like incubation or media selection remain the same as for commercial production runs.

The size of media fills for small batch size products should at least equal the number of containers filled for the commercial product.

Biological and Biotechnology Products

The manufacture of these products varies, such that there is not one single process. It may be more practical to validate the various segments of the process individually. The frequency of the revalidation should relate to the one of regular, commercial production.

Sterile Bulk Pharmaceuticals 

Whenever possible a growth medium should be used and the process should be simulated as closely as possible to the normal route of manufacturing the sterile bulk drug substance.

The aseptic manufacture of sterile bulk drug substances is a difficult process, which may have numerous individual segments that need to be validated. The possibility of microbial ingress into the system has to be considered after each step of the routine production.


The validation may include segments, where the use of growth media is not feasible.

Author: Mahender Nagaraju
Source: PIC/S Guidelines

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