Here’s a familiar scenario: the Manufacturing Director approaches the Quality Director, wringing his hands in despair he says, “Oh no, the microbiology laboratory have told us of another set of unacceptable results with our environmental monitoring (EM) in the facility! What do we have to do to fix this issue?! Do you know what that is going to cost us?”
It may seem like the start of a bad joke but this type of conversation has been heard over and over again in pharmaceutical companies around the world. How do we address it?
The regulators expect pharmaceutical manufacturers to be in control of the environmental conditions within their manufacturing facility. Companies invest large amounts of time, resources and money to provide the regulators with what they believe the regulators want to see.
But wait a minute! The purpose of a good EM programme is not just to satisfy the regulators – it’s to provide assurance that the environment that the products are produced in is fit for use.
Manufacturers of products, especially of sterile products produced by aseptic processing, have a significant challenge to create and manage an effective EM programme, with their available resources.
So what’s the answer?
You may just have to go back to basics and make sure the foundations of a good EM programme are in place and maintained before you start chasing the root cause of the problem.
There are three key building blocks on which to base an effective EM programme, each with its own elements:
- Knowledge of the process, the facility and microbiology,
- Performance of personnel and equipment used in the monitoring programme,
- Appropriate Review of the results.
Let’s take a closer look at each one, as they all play a vital role in supporting the structure of your EM programme.
Know your process:
It is a regulatory requirement that a risk assessment is performed to determine which locations require EM. Mapping the manufacturing process will provide understanding and an opportunity to assess where the risk points are in the process, and help provide information for the most appropriate EM locations. This will help focus the effort on monitoring the areas that need to be monitored rather than those that do not.
Call on the right experience:
It is essential that a microbiologist is involved in establishing the EM programme, including reviewing results and trends.
Shop floor or direct manufacturing personnel can provide an insight into potential areas of concern.
For existing facilities, using past experiences adds to the knowledge. Make sure that issues of the past are well documented and available for review since they can provide insight into current and potential future issues.
Know your facility:
Understanding the facility, materials of construction, design and performance will aid understanding of factors that impact on the quality of the environment.
Perform testing to the established procedures but understand that conventional EM has limitations. EM is a sampling exercise. No one media type, set of incubation conditions or technique can detect all potential microorganisms.
Make sure your personnel have the required training in and knowledge of good aseptic practices.
Equipment must be fit for intended use. The equipment must be prepared and appropriately sanitised or sterilised, as required.
Technique and assessment:
Personnel should have their sampling technique assessed for their level of competence and consistency. This should be reviewed at a predetermined frequency.
Clear, unambiguous instructions are essential, not only for the EM practice itself but also to detail the designated sampling locations, sampling frequency, type of media used, incubation conditions, recording and assessment of results, acceptance criteria and any follow-up actions and reporting activities required.
Vital, but difficult to measure. Personnel who perform the EM tasks play a key role.
Media, equipment and samples need to be handled with appropriate care and processed in a timely manner.
If EM is not performed properly, the results obtained may be meaningless, and that may have significant consequences. For example:
- The testing doesn’t detect potential issues: you don’t recognise that there are quality issues with the environment. Compromised product could be released to the market.
- The results indicate a compromised environment, when the environment is actually acceptable: This results in additional monitoring, wasteful investigations, loss of time, money and resources, with potential rejection of “good” product and further regulatory impact.
Day to day:
Daily EM is a sampling exercise. Individual results are directly assessed against a specification or limit. This data is then used as the basis for trending.
Due to the limitations of conventional EM, it is essential that trending and review of the trends occurs on a regular basis. Monthly, quarterly, six monthly and yearly are typical review periods. Let the trend be your friend – it will provide evidence of the state of control of the manufacturing environment. It provides opportunities for improvement by identifying risk points. Trending can be of the process, environment, and personnel.
Although the focus here has been on microbiological monitoring, the principles can be applied to different monitoring processes, for example, non-viable particle monitoring.
The keys are to:
- understand your process
- monitor sampling points that will provide evidence of the true state of the environment
- select the appropriate monitoring process and perform the monitoring properly, with trained personnel
- provide staff with clear, unambiguous documented procedures
- record individual results, then review and trend them against predetermined criteria
- implement any corrective or preventative measures.
The challenge is to establish and execute an EM programme that meets the regulatory requirements and ensures the environment is suitable for producing and releasing quality product, while keeping an eye on the bottom line. Build the foundations first.
- PE 009-10 Guide to good manufacturing practices
- PE 009-10 Annex 1 Manufacture of sterile medicinal products
- PI 007-6 Recommendation on the validation of aseptic processes
- ISO 14644 series Cleanrooms and associated controlled environments
- ISO 13408-1:2008 Aseptic processing of healthcare products
- FDA guidance for Industry, Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice
- USP Microbiological evaluation of clean rooms and other controlled environments
- PDA Technical report No.44 Quality Risk Management for Aseptic Processes
- PDA Technical report No.13 (revised) Fundamentals of an Environmental Monitoring Program