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Aaron Mertens is a Microbiologist and Technical Services Manager at STERIS Life Sciences.
Joe McCall, previously with STERIS, is the Associate Director of QA Technical Service at ADMA Biologics.
A well-defined contamination control program is essential to maintain quality through aseptic manufacture of parenteral drug products.
A robust contamination control program (CCP) does more than simply remove microbial contamination from cleanroom surfaces and equipment; a CCP ensures aseptic processes result in a sterile finished product. CCPs are critical to product and patient safety and must be multifaceted to consider all aspects of contamination to be effective. For pharmaceutical, biotechnology, and medical device manufacturing, CCPs are one of the foundational elements of a facility’s pharmaceutical quality system (PQS), as described in FDA Guidance for Industry, Q10 Pharmaceutical Quality System. The scope of International Council for Harmonization (ICH) Q10 includes the following systems, each of which is integrally related to CCP (1):
Assembling a multidisciplinary team to evaluate microbiological risk to the product identifies key areas of focus in the CCP including elements of the science-based assessment, policy-based management, and risk communication (2). This exercise provides direction and prioritization within the elements of the CCP.
ICH Q9, Quality Risk Management provides a framework for the risk management process within a pharmaceutical organization. The goal is to proactively identify and manage product risk as a continuous process. The Risk Flowchart within ICH Q9 details the quality risk management process, using risk management tools and risk communication (3).
The Microbiological Risk Analysis and Risk Flowchart are proven industry accepted tools to supplement the CCP. These tools create the link between the CCP and sterile products, ensuring risk of microbial contamination to the products is minimized.
To meet the quality system requirement detailed in ICH Q10 for a CCP, the following elements must be considered:
Best practices within these elements ensure the risk of a non-sterile product is minimized. Documentation within work instructions and/or standard operating procedures (SOPs) provides direction to trained staff, ensuring consistent execution of the best practices.
Environmental monitoring. Good EM practices demonstrate microbial control and identify adverse trends within the cleanroom environment. Data collected using an environmental particle counter over time validates the cleaning and disinfection process and gives evidence that the contamination control program is effective. Figure 1 shows an overview of points to consider when starting new or evaluating existing EM practices.
Gowning. The number one source of contamination in the cleanroom environment is people. Operators working in the cleanroom must adhere to strict gowning practices to ensure particulate and microorganism contamination stemming from the operator is kept to a minimum. Continued personnel training and monitoring is an essential part of the CCP. All operators should be included in a training program and undergo formal qualification (initial and periodic assessment of skill). Training should be conducted by subject matter expert(s) (SMEs), and employees should be restricted from cleanroom access until fully qualified.
Aseptic operators should be monitored at appropriate sites and frequencies (based on risk assessment). There should be an SOP-defined program for addressing poor performance, remediation, or removal of access based on test results.
Cleaning and disinfection. A cleanroom environmental CCP includes frequent scheduled application of a phenolic or quaternary ammonium disinfectant, followed by periodic routine use of a sporicide, and periodic residue removal using water for injection or alcohol. Table I shows details on rotation, residue removal, etc
Selection of agents
Formal program for qualification, use, and disposal of disinfectants. Disinfectants in the United States are Environmental Protection Agency (EPA) registered, with defined criteria for selection and suitability of agents (i.e., substrate compatibility, label claims, etc.)
More than one type; use of a broad-spectrum disinfectant with periodic use of sporicidal (frequency driven by environmental monitoring data), use of sterile 70% isopropyl alcohol (IPA) for aseptically gowned operators in ISO 5/ISO 7 zones (e.g., frequently on gloves, surfaces after interventions). Disinfectants have detergent capacity, or formal program exists for cleaning of surfaces prior to disinfection.
Frequency and method for rinsing is based on usage of disinfectant(s). Procedure is defined in standard operating procedures (SOPs); use of high purity water (United States Pharmacopeia purified water or water for injection) or 70% IPA for surface rinsing and residue removal. Formulated detergents used as needed, based on residue type and build-up.
Well defined in SOP (e.g., specify two or three bucket systems, stipulate mop type(s), hands-on operator training, periodic audit of program by QA to verify application technique and contact time.
Recovery from loss of control (planned or unplanned)
Formulated cleaner used to help remove debris and soil. SOP-defined plan for shutdown recovery (e.g., 3X Clean & Disinfection with final round of sporicidal). In-situ study performed (1x) to demonstrate ability to recover from loss of aseptic control. EM program used to generate in-situ data to demonstrate effectiveness, i.e., area mapping via contact plates after worst-case event; mapping done pre- and post-recovery to document ability to reestablish cleanroom conditions.
Disinfectant efficacy (DE) studies
Formal DE study performed using facility-specific substrates (surfaces) and microbial isolates. Substrates include all applicable facility surfaces: flooring, walls, equipment.
Wet contact time
Contact time is established in the DE study, and reflected in actual practice of disinfectant application in the facility
Stability of use-dilutions has been established via DE study.
Sterile vs. non-sterile
Selection is based on risk. If used in ISO 5 zone, solutions must be sterile-either purchased as sterile or introduced into ISO 5 zone via validated process (e.g., sterile filtration).
If not using RTU, then use-dilution is supported by DE study, with SOP preparation instructions including specified quality of water (e.g., USP Purified, WFI), method for accurate measurement, shelf-life.
Materials and equipment airlocks. The second highest risk of contamination to the cleanroom environment is from materials and equipment brought into the cleanroom from outside. Material-handling airlocks allow for contamination control, so decontamination practices should be used for these items prior to entry into the facility (see Table II).
Interlocking airlocks between entry points for classified areas of different grades (e.g., between ISO 8 and ISO 7).
Restricted and controlled access to aseptic processing areas (e.g., card readers).
Preventing ingress of spore formers
Disinfection of pass-through materials includes effective procedure for spores (e.g., use of sporicidal, double- or triple-bagged sterilized items).
Material pass-through process is well defined in SOP, with competency-based training program conducted by SMEs.
Ability of management or appropriate SME to assess pass-through technique and compliance with written procedures (e.g., CCTV, periodic audit or documented spot-check observations).
EM and cleaning supplies
Supplies for maintenance and monitoring should be autoclave sterilized into the cleanroom or decontaminated through the airlock. Material decontamination procedure should include a sporicidal treatment and/or removal of a layer of wrapping to ensure contamination is not brought into the cleanroom.
Sterilization. For sterile parenteral products, product contact surfaces must be sterilized, and careful consideration must be taken to protect these critical surfaces before, during, and after processing. Sterilization wrapping materials must be of high quality, with regards to microbial barrier and low particle generation (see Figure 2).
Figure 2. Pfroduct contact surfaces.
Parts and equipment use at filling line. To ensure the highest sterility assurance to the finished product, critical surfaces should be protected during storage in the cleanroom and until the time of use at the filling/manufacturing line. Critical product contact surfaces (i.e., product tanks, stopper bowls, filling needles) are covered and protected during installation and until time of use. Aseptic connections and manipulations should be minimized or performed in a way to prevent contamination (e.g., microbial, particulate, etc.). Additionally, cleaned equipment and parts should be dry and covered to avoid contamination. Hold time between cleaning, sterilization, and usage must be validated.
The following case study is an example of a failure in a contamination control program, as critical product contact surfaces were not protected from environmental contamination (4). A thorough multi-departmental investigation and root-cause analysis led to a simple solution. However, the root cause was identified, and preventive action was implemented after loss of product and significant production downtime due to the ongoing investigation.
Environmental contaminants (mold and Bacillus species) were repeatedly recovered from sterile bulk material and sterilized process equipment. Microbial analyses of the bulk material detected the presence of mold and Bacillus species. Investigational sampling via swabbing of the bulk tank’s interior surfaces also detected the same profile of contaminants. The specific species associated with the contamination events had no history of recovery by EM of the classified environments.
The root cause analysis followed a defined process with multiple disciplines involved. The CCP elements were reviewed within the team, using Figure 3 as a guide.
A review of the bulk tank preventative maintenance (PM) log showed that a rupture disc had burst prior to the onset of recovering mold and Bacillus species. Interviews with the technician revealed that the tank had been relocated to a non-classified area while a replacement rupture disc was ordered. No proactive measures were taken to protect the integrity of the tank while out of the controlled environment for several weeks. Upon reintroduction to the classified area, exterior surfaces of the tank were disinfected and treated with a sporicide. Clean-in-place (CIP) and steam-in-place (SIP) of the tank was performed; however, review of the tank’s SIP validation package showed that the interior area at the rupture disc connection proved to be a worst-case location for steam penetration. Investigational sampling in the unclassified area where the tank had been stored revealed the presence of genetically identical profile of mold and Bacillus species to that recovered from the tank interior.
A review of the bulk tank’s history through the equipment logbook showed the only significant event prior to the onset of the contamination was a burst rupture disc. Interviews with the manufacturing technician revealed that the tank had been relocated for several weeks to a non-classified area while a replacement rupture disc was ordered. Investigational sampling in the unclassified storage area revealed the presence of genetically identical profile of mold and Bacillus species, to that recovered from the bulk material and post-SIP tank interior. No proactive measures were taken to protect the integrity of the tank while it was held in an unclassified environment. Upon reintroduction to the classified area, exterior surfaces of the tank were disinfected and treated with a sporicide, and CIP and SIP cycles of the tank were completed. A concurrent review of the tank’s SIP validation package showed that although it passed validation criteria, the biological indicator (BI) located at the rupture disc connection was a worst-case location for steam penetration. The investigation logically concluded that the rupture disc zone of the tank had been exposed to the contaminating microorganisms while it was stored in the unclassified area, and that the ensuing CIP and SIP cycles were ineffective at removing surface contaminants from this specific area of the tank’s interior.
The resulting preventative action included a new policy to provide physical barrier protection of critical equipment and surfaces when moved to or stored in areas of lower classification. Figure 4 shows the location of the rupture disk on the tank). Figure 5 shows the good manufacturing practice (GMP) equipment cover being applied to protect the tank from potential environmental contamination.
GMP equipment covers manufactured using nonwoven spunbonded polyolefin material can protect equipment from particulate and microbial contamination during storage and when out of use. Regardless of how robust the CCP, environmental monitoring demonstrates that microorganisms are present at varying levels in any manned cleanroom environment. Additionally, aging facilities contribute to potential microbial risk to equipment in the cleanroom environment. It is important that barrier protection of critical surfaces be part of the CCP, especially during equipment staging and storage. Minimizing risk of microbial contamination, through prevention and protection of the product contact surfaces, should be the highest priority element in the CCP.
As part of a facility PQS, a robust contamination control program includes a diverse set of elements (e.g., EM, gowning, cleaning and disinfection, airlock and sterilization procedures, equipment use at the filling line) to minimize the microbial risk to the finished product, as well as to meet requirements in ICH Q10. Additional barrier protection increases sterility assurance of critical surfaces and further enhances the CCP.
The case study exemplifies how a simple solution like utilizing barrier protection over a bulk product tank would have prevented contamination of the bulk product. A proactive microbiological risk assessment in addition to the contamination control program will identify opportunities like this, where simple solutions minimize risk to the product. A holistic microbial risk assessment of all contamination control program elements ensures production of safe medicines and products.
1. ICH, Q10 Pharmaceutical Quality System (FDA, April 2009).
2. Quality Assurance and Food Safety, “Microbiological Risk Assessment,” Global Manager, Food Safety Services Innovation, June 2014.
3. ICH, Q9 Quality Risk Management (FDA, November 2005).
4. J. McCall, Case Study, unpublished manuscript, 2008.
Volumn 44, Number 5
When referring to this article, please cite it as A. Mertens and J. McCall, "How a Contamination Control Program Impacts Product Sterility," Pharmaceutical Technology 44 (5) 2020.