By: Jeanne Moldenhauer - Excellent Pharma Consulting
Background
With the upcoming implementation of the revised Annex 1 of the European Union GMPs, many companies are developing contamination control strategies. For some, this is a newer experience, as the requirements apply to both sterile and non-sterile manufacturing operations. A key consideration in the development of a contamination control strategy is what happens if a contamination risk is detected. One would assume, that if a risk is identified, appropriate corrective actions should be taken to mitigate or eliminate the contamination risk.
When writing these types of requirements into Standard Operating Procedures (SOPs), it becomes important to understand how the individuals using these SOPs will determine what contamination risks are as well as how to correct them.
Figure 1 provides an example of a holistic contamination control program. When the various areas affected are reviewed, there are many job functions that may be affected by the strategy developed. Some of these individuals may have very limited background in understanding contamination control risks.
Types of Contamination
There are a several different types of contamination that need to be considered including for example:
- Microbial Contamination (bacteria, fungi, parasites, viruses, prions), allergens, and pathogens
- Particulate Contamination
- Foreign Material Contamination (Physical contamination), e.g., fibers, glass
- Chemical Contamination, e.g., product carryover, cleaning agent residues
- Other Foreign Matter, e.g., molds and animal contamination (e.g., insects, their eggs or larvae, spiders, rodents and excreta, and any other unwanted matter (like glass, metal, or plastic)
Depending upon the type of contamination, it may be different sources that are potential risks of contamination. Additionally, the appropriate corrective actions to mitigate or eliminate the risks are likely to be different.
Training of Employees
There are GMP requirements for training of individuals in pharmaceutical companies. Among the common topics, for manufacturing, quality, and laboratory personnel include the applicable regulatory GMP requirements, aseptic processes (if applicable), safety procedures that must be followed, hygiene, microbiology, and job-specific training.
The introductory microbiology activities, often include a few basic slides that talk about how microorganisms can be dangerous to the patients or product. Some information may be provided on types of microorganisms, but it is usually limited.
With the increased focus on contamination control, we likely need to significantly update training to provide specific instruction on how to assess contamination risks for specific actions and conditions and to provide guidance on appropriate corrective actions that should be taken to mitigate or eliminate the risks.
Development of Experts in Contamination Control
Another approach that may be taken is the development of subject matter experts (SMEs) in contamination control. This may not be as simple as we think. Looking at some of the types of contamination listed previously, the ideal SME may need to understand microbiology, chemistry, quality, entomology, and quality compliance, at a minimum. It may not be easy to find a person with all these skill sets. It is more likely, that we will have to develop groups of experts with different skills. It is likely, that our companies do not have experts in all the referenced subjects today. If something is not a common occurrence, perhaps we need to develop criteria of risks of some of the types of contamination and have available consultants to aid in the mitigation and/or elimination of risks. Review of many types of situations will need assessment by a team of individuals to assess all the contamination risks.
The Problem
Consider the following typical experience in a pharmaceutical company. John Doe comes into the plant on Monday morning and finds that the storms over the weekend resulted in a major water leak and in some places there is standing water. Inspecting the leak in the filling area and the laboratory storage area, John contacts his supervisor and they decide to generate a work order to “get it fixed.” (This results after deviations are written and actions taken to make changes.) In the background, they discussed how many products batches are scheduled for the day. In generating the work order and getting it approved, we “hope or believe” that the approvers can identify all the associated risks and specifying the appropriate testing or other corrective actions today. Often, we do not do as well as we should. Many companies do not understand the risk of mold and endotoxin contamination when evaluating the work orders or change requests. This shows up in subsequent issues with contamination, where experts are brought in to assess the root causes of the contamination that is currently causing an adverse trend. In this type of event, one often sees mold counts increase, or endotoxin levels higher than normal. It would be easy to assume that these are the only risks, but the reality is different.
If the leak is due to a breach in the facility, one could have issues with foreign matter of many different types, e.g., insects, spiders, animals and their excrement, material from the structure (gypsum, brick fragments, roof fragments, and the like. We rarely identify these risks commonly.
Complicating the problem, is that the reviewer/approvers of these types of documents may not know who is responsible for identifying these contamination risks and who is responsible for correcting them. Without defined job responsibilities being updated for contamination control activities, items are likely to continue to cause problems.
Resolving these issues at the company will also require that we provide sufficient training to change the mindset of workers from just doing their existing jobs to always thinking about the types of contamination that could occur and how to prevent it, mitigate it, or eliminate it.
Taking Action
There are several issues companies need to consider in preparation for the implementation of the contamination control strategy. Some examples are included below:
Changing Our Attitude to Prevention of Contamination Rather than Reaction to Contamination
Typically, companies work to react to problems that occur. We are not as diligent in working on prevention of contamination. Isolators significantly reduce contamination risks for aseptically processed products. Some advanced aseptic processes generate a risk of contamination close to the risk associated with terminally sterilized processes. Knowing this, however, the industry in the United States has been slow to implement these processes.
There are many newer products that can significantly reduce contamination from occurring, e.g., antimicrobial, or antifungal surfaces, antimicrobial paints, fungal barrier products, and treated building materials. We should be considering these types of approaches when we are building, remodeling, or fixing facilities.
We should be performing more frequent walk-throughs of the facility to look at the condition of the facility, equipment, and process. Is rust or damage present that could be eliminated to prevent subsequent contamination? Along with performing walk-throughs, we need to increase our awareness of these types of issues when we are in the production, storage, and laboratory areas.
Educating Employees in the Regulatory Requirements for Contamination Control – and How it Applies to Their Own Job
When individuals are not assigned the responsibility for a task, they tend not to be as involved in acting upon that responsibility. You cannot just “assume” that someone will identify all the associated risks, without developing their knowledge in the contamination risks.
Developing a Broad Scope of Contamination Risks
Often, we do not consider all the types of risks of contamination associated with an aberrant event. We may identify the biggest risk, or a few top risks, but we often do not consider risks of all the types of contamination occurring. This necessitates we broaden our scope of contamination risks. Figure 2 provides a sampling of potential contamination sources associated with pharmaceutical production.
Automating Detection Methods, When Possible
Today, many types of contamination detection can be automated. Often automated detection methods are more sensitive than manual inspection procedures. Additionally, the automated system looks at the product in the same way all the time, giving consistency of inspection. These systems often complete the inspection quicker, notifying one earlier of the problem. Early detection allows for early response to the corrective actions and may aid in finding the root cause.
The use of process analytical technology methodology like rapid microbiological methods can also provide for early detection of contamination, e.g., real time viable and non-viable particulate counters, in-line systems for determining contamination potential in water systems or fermentation tanks, and the like. While many of these methods have been in existence for over 20 years, pharmaceutical companies are still slow in implementing these systems for production use. An extensive listing of rapid microbiological methods can be found at RMM Product Matrix - Rapid Microbiology and Rapid Microbiological Methods (rapidmicromethods.com). Dr. Michael Miller maintains this site and provides useful information on the advances and disadvantages of many methods.
Subscribe to our e-Newsletters
Stay up to date with the latest news, articles, and events. Plus, get special offers
from American Pharmaceutical Review – all delivered right to your inbox! Sign up now!