The Importance of Microbiology in the Contamination Control Plan for Aseptic, Terminally Sterilized and Non-sterile Manufacturing

Introduction

The development of a contamination control program is critical to the effort to get a new facility qualified, and to maintain the facility in a state of control once qualified.   The design and successful execution of a contamination control program requires a plan. The creation of a specific document allows the company philosophy, goals, and expectations to be formalized and agreed to by all parties. It also provides the goals and metrics by which the state of control for the facility can be measured in the annual review. The business reasons for this are obvious in terms of reduced regulatory risk and reduction of rejected/recalled batches (Lowry 2001).
This plan is important no matter what type of facility is being developed. Although it is most frequently used in the Quality plan for commissioning an aseptic facility, this is also important and should be used for commissioning and controlling facilities using terminal sterilization, and for non-sterile manufacturing facilities.
Why be concerned with contamination control in a nonsterile manufacturing facility? In many ways contamination control is more of a concern in a non-sterile facility than in sterile product production facilities. The sterile production facility knows there is a problem with contamination and cross-contamination of batches, the non-sterile facility has a great temptation to belief they are not touched by these issues. This can lead to an extremely cavalier attitude about contamination control by the operators and management.
The non-sterile manufacturer is responsible for all aspects of his product, including any objectionable organisms present (Sutton, 2006) as described in a recent newsletter (PMF Newsletter v12 n7).
The API manufacturer is also concerned with contamination control. The FDA has explicit instruction on this score (FDA 1998) out of CBER. The EMEA guidance on API manufacture also includes guidance on control of bioburden and cross-contamination of batches (EMEA 2000).
This essay will not be able to provide more than an overview of issues in the space available this month. However, it is hoped that the need for an adequate contamination control plan for a facility will be made clear, and the beginnings of the content of such a plan explained. The interested reader is referred to the articles listed in the “References” and the “Further Readings” sections.

Scope

The Contamination Control Plan should be developed as part of the facility commissioning effort. As such, there will be four distinct phases of the facility operations that will need to be addressed:

1. 1. Commissioning and initial start-up
   2. Ongoing Operations
   3. Shut-down for regular maintenance
   4. Start-up after scheduled shut-down

These phases will not have the same level of contamination control. In fact, the third and fourth phases may well have different levels of control to be addressed. A good plan will discuss the concerns specific to each of these phases.
This program, and the protocol governing the program, are essential documents useful in documenting the rationale and methods used to accomplish three tasks:

• Minimizing the bioburden throughout the manufacturing processes
• Minimizing the level of batch residual cross-over contamination
• Minimizing the level of cleaning material residual contamination

As the SME (Subject Matter Expert) in microbiology, we will be most heavily involved in the first of these three tasks, minimizing bioburden. However, all three will be discussed (at least briefly) in this essay for context.

Minimizing Bioburden

Validated methods

All measures of bioburden in a facility will be indirect. We cannot count bacterial cells on a surface or in the air. We must transfer the microorganisms to an agar plate (or some other mechanism) and count colony forming units. If we make the assumption that the transfer of microorganisms from the air or from a surface to agar is consistent, then we can use these numbers to estimate trends over time. This assumes that the nutrient agar is capable of growing the microorganisms to visible colonies. As residual disinfectant on
a surface may impede the growth of microorganisms, neutralizers are frequently incorporated into the growth media (Dey-Engley agar, MCTA, etc.). All sampling methods must be validated for the conditions of use.
The facility should be disinfected regularly using validated sanitizers and sporicides. The contamination control plan should describe the methods for testing and rationale for acceptance of materials to be used in the ongoing program of disinfection. The plan should ideally describe the in vitro or laboratory tests to evaluate the sanitizers, including the identification of the most resistant microorganisms found in the facility as well as the most difficult-to-disinfect materials in the facility. This is also where the method for on-going evaluation of the sanitizers based on environmental monitoring data will be recorded. The choice of disinfection regimens should be reevaluated annually, and the contamination control plan should describe how this evaluation will occur.

Know the enemy

A successful contamination control program is geared to providing the most useful information on the microorganisms present while at the same time showing some fiscal responsibility. The FDA aseptic processing guidance document recommends genetic identification of all organisms isolated from the manufacturing environment on a regular basis. (FDA, 2004) This is a laudable goal, but few of us have anything near the required budget to accomplish this task, and in all honesty it is reasonable to wonder if it is really necessary. The numbers of CFU from validated sites (viable air and surface, non-viable) is sufficient to provide a measure of the state of control of the facility. However, periodic cataloging of the resident microflora will provide you with a good check on the continued effectiveness of the disinfectants in use. Shifts of bioburden to spore forming microorganisms will be strong evidence of the need for use of a sporicidal agent. Occasionally, this effort will also pick up shifts among non-spore-forming organisms – this is not due to “resistance” but rather ecological shifts towards species more naturally resistant to the disinfectant in use.

Control incoming bioburden

The first step in any control program is to control contamination at the very beginning of the process. This includes raw materials (excipients, API, water, etc) and the primary containers. All materials should be tested for incoming bioburden against documented acceptance criteria. Part of the incoming bioburden will also be any water used as an excipient to the process. A good guide for the water bioburden is the EMEA guidance on the subject (EMEA 2002).

Appropriate gowning

The gowning methods and materials are of critical importance to minimization of contamination. Although most attention is placed on aseptic gowning procedures, the appropriate use of gowning precautions will be a great boon to most non-sterile manufacturing facilities as well.   All personnel should be well-trained in appropriate gowning practice and behavior. The contamination control plan should describe the rationale for the level of gowning chosen, the frequency of gown cleaning, behavior and the acceptable gown materials for the type of manufacturing process.

Training

Operator training is critical to contamination control. No supervisor can be present at all locations at all times. Each operator must be aware of his or her role in contamination control and how to minimize the risk to batch integrity. The PDA has published a technical report that speaks to some of these training requirements from the microbiological perspective (PDA 2001).

Controlled Environments

Control and monitoring of the environment is another critical element of the contamination  control plan. Large portions of this can be addressed by the corporate Environmental Monitoring Master Plan (which provides rationale and consistency for a single EM  philosophy across the different facilities of the corporation) or the site Environmental Master Plan (which provides consistency and detailed instruction for the various manufacturing buildings at a given site).  However, the Contamination Control Plan should cite the relevant documents and their role in contamination control. Those interested in more on environmental monitoring should refer to the PDA’s treatment of the subject for a good overview (PDA 2001).
The appropriate Environmental Monitoring (EM) plan for non-sterile manufactures and for API manufacturers is not well-defined from a regulatory sense. There are no strong recommendations such as those seen for the environmental monitoring of aseptic facilities; however the absence of regulatory guidance is not the same thing as the absence of need for the activity. EM is useful for determining the state of control of the facility and so is an important part of the monitoring program for all manufacturers.

Well-defined and Understood Manufacturing Processes

The manufacturing process should be evaluated for its potential to limit or eliminate bioburden. The two common methods for performing this is either a HACCP-type (Jahnke and Kuhn 2003) or a FMEA approach. The use of organic solvents, heat, or other inhospitable activities can greatly reduce bioburden of a process. The contribution of compression (and associated shear), for example, should be evaluated for a potential reduction in risk of excessive microbial contamination (Blair 1991). The contribution of the finished product water activity should also contribute to this analysis (USP 2007).
Of particular importance in this evaluation for the potential for microbial contamination of the process are cleaning steps, equipment hold times, HVAC, control level of environments for critical tasks, open-system vs closed-system operations, and bioburden monitoring (among others specific to your process). As an example of the importance of the bioburden control point issue, there is a strong regulatory expectation in Europe that products sterilized by filtration should have a pre-filtration bioburden of not more than 10 CFU/100 mL immediately before the sterilizing filter (or be subjected to dual filtration in series).
Finally the Contamination Control Plan should cite the need clear SOPs on all aspects of manufacturing, monitoring and control. These SOPs are critical for training, documentation and batch release.

Minimization of Batch Residual Cross-over Contamination.

The contamination control plan should also address the potential for a batch to be contaminated by material from the previous batch manufactured using that equipment. Obviously, the contamination control plan should describe the methods by which this likelihood is minimized.
The concern over batch residual cross-over is most relevant when there is more than one product manufactured at a site. This concern has little to do with the sterility of the finished
product, and is relevant to sterile and non-sterile manufacture alike.

Minimization of Cleaning Material Residual Contamination

Validation of cleaning procedures is essential to demonstrate not only that the cleaning procedure effectively cleans and sanitizes the manufacturing equipment, but also that residual cleaning material is removed to prevent contamination of the next batch manufactured.

Conclusions

The Contamination Control Plan is an important document designed to formalize the rationale, methods and validation of contamination control procedures in a manufacturing facility. This plan is a valuable tool for pharmaceutical, medical device and personal product manufactures and should be written to address all phases of the facilities life cycle. The Contamination Control Plan should specifically address:

• Minimizing the bioburden throughout the manufacturing processes
• Minimizing the level of batch residual cross-over contamination
• Minimizing the level of cleaning material residual contamination

The microbiologist, as SME, has a critical role to play in the first of these three primary goals, and this essay has therefore been directed at that first topic. Minimization of bioburden in the manufacturing process occurs through (but is not limited to):

• Minimizing bioburden in the process
• Control incoming bioburden
• Appropriate Gowning
• Controlled Environments
• Well-defined Standard Operating Procedures; and
• Well-defined and understood manufacturing processes.

References

1. Blair, TC et al. 1991. On the Mechanism of Kill of Microbial Contaminants During Tablet Compression. Intl J Pharmaceutics. 72:111-115.
2. EMEA 2002. Note for Guidance on Quality of Water for Pharmaceutical Use. http://www.emea.europa.eu/pdfs/human/qwp/015801en.pdf.
3. EMEA 1996. CPMP/QWP/486/95 Note for Guidance on Manufacture of the Finished Dosage Form. http://www.emea.europa.eu/pdfs/human/qwp/048695en.pdf.
4. EMEA. 2000. CPMP/ICH.4106/00 Note for Guidance onGood Manufacturing Practice for Active Pharmaceutical Ingredients. (ICH Q7).   http://www.emea.europa.eu/pdfs/human/ich/410600en.pdf.
5. FDA. 1998. Guidance for Industry – Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients.  http://www.fda.gov/cber/gdlns/active.pdf.
6. FDA. 2004. Guidance for Industry – Sterile Drugs Products Produced by Aseptic Processing – Current Good  Manufacturing Practice.   http://www.fda.gov/cder/guidance/5882fnl.pdf.
7. Jahnke, M and K-D Kuhn. 2003. Use of the Hazard Analysis and Critical Control Points (HACCP) Risk Assessment on a Medical Device for Parenteral Application. PDA J Pharm Sci Tech. 57(1):32-42.
8. Lowry, S. 2001. Designing a Contamination Control Program.  IN Microbiology in Pharmaceutical Manufacturing R. Prince (ed) DHI/PDA Publ.   pp. 203-266.
9. PDA. 2001. PDA Tech Report #13 (Revised): Fundamentals of an Environmental Monitoring Program.
10. PDA. 2001. PDA Tech Report #35: A Proposed Training Model for the Microbiological Function In the Pharmaceutical Industry.
11. PIC/s. 2004 PI 006-2 Recommendations on Validation Master Plan: Installation and Operational Qualification – Non-sterile Process Validation, Cleaning Validation.
12. Sutton, S. 2006. The Harmonization of the Microbial Limits Tests. Pharm Technol. 30(12):66-73.
13. USP. 2007. <1112> Application of Water Activity Determination to Nonsterile Pharmaceutical Products.