A Guide to GMP Regulations – Part 4: Minimising Contamination

10 March 2022

This is the final part in a 4-part blog series on A Guide to GMP Regulations. Part 1: What is GMP? Can be found here and Part 2: GMP Personnel and Documentation can be found here. Part 3: Quality Control can be found here. Also keep an eye out for our webinar version, available on our Resource Hub.

When manufacturing drug products, the environment in which aseptic operations are conducted must be controlled and maintained to ensure no contamination is present within the final drug product, or any containers or intermediates. Good Manufacturing Practices (GMP) guidance documents such as EudraLex Volume 4, and the CFR Title 21, provide detailed guidance about how to minimise contamination in the final drug product.

Aseptic processing

Aseptic processing is especially important for the manufacture of sterile medicinal products, as any contamination (either viable or non-viable) present in the final product can cause serious problems when the drug is administered. A product may be filter-sterilised prior to release, however contamination even in pre-filtered products can cause increased challenges to the sterilising filters and can also contribute impurities such as endotoxin to the drug product or lead to the degradation of the finished product.

Therefore, it is essential to maintain control of the environment, and controls should also be in place to minimise bioburden throughout the process. These controls are maintained throughout the manufacturing process by quality control departments and range from environmental monitoring of the facilities (including monitoring of both viable and non-viable contamination), to finished product sterility testing.

Facilities and operator monitoring

It is important that any manufacturing facilities are situated in environments which present minimal risk of causing contamination of materials and products. They should be designed in such a way that any components, materials, and drug products should have minimal risk of cross-contamination and laid out to allow high risk production operations to take place in a logical order. This refers to both the sequence of operations, and the required levels of cleanliness. Facilities and equipment should be designed so that it can be easily and thoroughly cleaned and disinfected in accordance with detailed cleaning and disinfectant procedures.

Operator activities and manipulation of the product and processes can increase the risk to product sterility. Procedures should be designed to minimise personnel intervention to decrease the risk of contamination, and operators should use aseptic technique at all times during aseptic processing.

Procedures for all stages of manufacture should focus on preventing microbial contamination, and any individual involved in the manufacturing process should be skilled in aseptic processes to minimise the risks further. Personnel entering clean environments should be appropriately qualified in gowning, with gowns being used to act as a barrier between the body and any exposed product materials or containers, protecting these from particles and microorganisms generated from the body. Gowning qualifications should be in place to assess the ability of operators to maintain the quality of the gown throughout procedures, and reassessment should be performed periodically to ensure confidence that gowning technique has been maintained.

Monitoring of operator gowning should also be performed throughout production processes – gowning contacts and finger dabs should be taken after interventions into clean areas, or upon exit from the manufacturing areas. This monitoring should be assessed through the quality risk management system. Additional monitoring should be in place for operators involved in labour intensive operations, and they should be representative – operators should not sanitise their gloves or gowns just prior to sampling, as this may prevent recovery of microorganisms present during aseptic manipulation. If operators exceed expected microbial levels, or show an adverse trend, investigation should be performed, and action may be required such as increased sampling, or re-training, or even disqualification from performing cleanroom activities.

Environmental monitoring

As well as contamination from operators, there is also the risk of contamination from the air. It is therefore essential to control air pressure and turbulence within cleanrooms. Rapid movement can create turbulence in the air, and this can disrupt the unidirectional airflow within critical areas. Therefore, operators should move slowly and carefully throughout the cleanroom.

Air quality should be controlled and monitored through both viable and non-viable monitoring, and the design of the cleanrooms and equipment should consider minimising contamination. Particles in the air can enter a product and this can cause issues whether they are biological or non-viable. Both turbulence and stagnant air can lead to increased contamination risks, and therefore the design of air handling systems can minimise risk of particle content within clean areas. These should be validated and maintained using well documented qualification studies.

The environmental monitoring program

“In aseptic processing, one of the most important laboratory controls is the environmental monitoring program.” – FDA Guidance for Industry (Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice)

The environmental monitoring program allows for the identification of potential routes of contamination to an aseptic area. The information produced from environmental monitoring also provides important information about the quality of the production environment, as well as of adjourning supporting areas. As well as monitoring during manufacture, environmental monitoring should occur during other production shifts, including prep and cleaning of the facilities and equipment. Monitoring should be performed for all floors, walls, and equipment surfaces, as well as the air and personnel within the cleanroom.

Detailed procedures should be written to include a list of locations to be sampled, the timing, frequency, and type of the sampling. These should all be determined based on risk management principles, and on their relationship with the operations being performed. The locations with the highest risk should be monitored the most frequently to ensure that aseptic conditions are maintained during activities performed here. It is especially important to monitor the air and surfaces where there is significant product exposure, and any critical surfaces which come into contact with the product.

When determining sampling regimes, consideration should be given to the criticality of the sample location, and also the impact the process may have should aseptic conditions be breached. These locations and frequencies should be justified as part of the environmental monitoring program.

Limits should be set for viable and non-viable monitoring levels, and these should be based on the level of cleanliness expected for the location. Areas where product is exposed (for example Grade A areas) should be free from microbial contamination, whereas areas for prep of equipment or changing rooms (for example Grade C and D areas) may have higher limits set as these are lower risk to the product. It should, however, be noted that, just because higher limits are set in these areas does not mean that contamination cannot be tracked from these areas into cleaner areas.

For more information about limit breaches and how to set them, see here.

So, what do you do with all of this data?

Environmental monitoring data should be monitored by the quality control department to detect limit breaches and shifts in trends of data. Trend reports should be generated regularly, and these should be produced by location, shift, operator, room, or any other parameter set out within the environmental monitoring program. Investigations should be carried out into specific data, such as the recovery of a particular isolate over a long period of time, to determine the impact of such events, and whether any follow-up actions are required.

Part of these investigations should include an assessment into the efficacy and suitability of disinfection procedures. If a high level or trend of certain microorganisms, or microorganism types is observed, it may indicate that a change in the disinfectant regime may be required. Investigation into the sensitivity of these microorganisms to the disinfectants should be performed.

Trending may also identify the migration of microorganisms from less controlled areas into aseptic processing areas. Identification of microorganisms from within these lesser controlled areas should be performed periodically to provide an understanding of the expected organisms in these areas, and to confirm whether any organisms detected in higher grade areas may have come from outside sources.

It is often difficult to analyse all of the relevant data when reporting on environmental monitoring conditions. Each area, room, operator, and time-period may show different data when analysed, and it is challenging for quality control leaders to review all of this data. This often leads to trends being missed, or detected long after the event, which can cause issues with the release of a product, or even potential product recall.

There are, however, systems in place which can help to effectively analyse all of this data easily without having to trawl through hundreds of data-points and numbers. SmartControl EM has been designed to analyse all of your data and look for any number of trends, with minimal input from quality control users. Once the users have set their trend “rules” within SmartControl EM, the software will analyse all data as it is stored, and all of the data already stored within the system and can therefore easily identify for example an increasing contamination rate, or high levels of a certain genus tracking through your environment.

Graphs can also be generated easily to perform analysis, and reports can be produced automatically, and all environmental monitoring data can be stored in one place, and easily filtered to find the relevant information.

Environmental monitoring is intended to monitor the state of microbial control within a production environment, and SmartControl EM can help to trend and analyse that data.

Download your SmartControl EM brochure here to learn more!