What Is Sterilization-In-Place?
What is sterilization, and why is it essential for sterile products?
Sterilization keeps patients safe from toxins and microbial illnesses when therapies or devices are consumed or used. Sterilization is any process that removes, kills, or deactivates all forms of life. Under the strictest definition of sterility, an item or product is sterile when there is the complete absence of viable microorganisms (bacteria, yeasts, viruses, and molds). Sterility is defined by regulatory acceptance criteria based on calculated contamination probability. An acceptable level of contamination risk for most items is the probability of a single contaminated product out of a million manufactured products. However, sterility criteria may be more stringent or lax depending upon the intended use of the medical device or product. Commonly, sterile products undergo sterilization processes that utilize chemicals, heat, radiation, or filters. Sterilization kills any microorganisms products collect during manufacturing. A less common version of sterilization is vapor phase sterilization. This article covers sterilization-in-place (SIP), sterilization in place protocols, SIP systems, superheated water and sterilization in place for pharmaceuticals.
What is sterilization-in-place (SIP)?
Sterilization-in-place (SIP) protocols are in situ sterilization processes where a system or system element is sterilized without being moved. SIP protocols reduce or eliminate post-sterilization handling, thus providing aseptic connections between sterilized equipment.
The following sterilization techniques can be used for sterilization in place in pharmaceuticals or other products:
#1: Steam (Moist Heat)
Steam is the most common SIP method for large processing systems. Examples of pharmaceutical and medical product sterilization equipment that use steam sterilization in place protocols are bioreactors, sterile bulk production lines, holding tanks, and delivery lines. After the steam sterilization cycle, automated air removal, condensate discharge, and steam removal systems are essential to preventing contamination in processing systems post-SIP.
#2: Superheated Water
Superheated water is water heated above its boiling point, which is pressurized to maintain liquidity. Water for injection and purified water systems can be sterilized by circulating superheated water. Superheated water can also sterilize vessels, filters, and other wetted processing components simultaneously.
#3: Dry Heat
Dry heat is provided through HEPA filters and has been used for sterilization in place for pharmaceutical spray dryers.
#4: Gas (e.g., ethylene oxide)
A gas-phase sterilization in place protocol is used for non- and low-pressure processing equipment, such as freeze dryers and process vessels.
#5: Liquid
Liquid chemical sterilization can be used only for spaces where liquid sterilant toxicity is not an issue and where item surfaces can come in full contact with the liquid sterilant. SIP liquid chemical sterilization is like superheated water, except chemicals rather than heat are used to destroy microbes.
#6: Vapor
Sterilizing vapors (hydrogen peroxide and peracetic acid) have been used for SIP of the same equipment treated with sterilizing gases. If gas or vapor sterilants are used, it is imperative to ensure appropriate off-gassing so that toxic sterilants do not contaminate products during processing.
How do you design and perform a SIP process?
The following are items to take under consideration when designing and using SIP processes:
- SIP methods are traditionally used with closed systems.
- The process or equipment may need to be sterilized in sections or portions for large processing systems. When sterilizing in parts, individual sterilization processes should overlap so that all internal surfaces are sterilized effectively.
- Demonstration of sterilization lethality relies upon physical measurements and biological indicators. Sterilization confirmation should extend to the sterile boundary of the system, which includes vessel headspace, connections between vessels and equipment, and any other parts of the system. All interior surfaces of the process equipment should be sterilized and the sterility confirmed with an appropriate biological indicator.
- SIP validation is almost exclusively performed with an overkill approach to sterilization. Components within a closed system sterilized with SIP should be selected based on their ability to withstand necessary SIP sterilization conditions. Care must be taken with high-efficiency particulate air (HEPA) filters as filters are susceptible to damage during SIP.
- SIP systems are custom and typically cannot be purchased through a manufacturer like a steam sterilizer or a dry heat oven. Thus, SIP design, maintenance, and control systems require system-specific care and consideration.
- SIP systems must allow for efficient removal of the sterilization agent. Often a SIP sterilizing agent is introduced through a filter on the system that may also purge gas or provide filtered ventilation. Removal processes must consider the effects of sterilant residuals on SIP sterilized equipment and the materials to be processed.
- At the end of the sterilization process, the system should be pressurized with a purge gas (sterile air or nitrogen) to prevent the introduction of contaminants to the sterilized system.
- Process parameters critical to SIP success must be recorded as SIP occurs. Example parameters include temperature, pressure, concentration, flow rate, humidity, and dwell time.
What are closed systems, when are they used in drug manufacturing?
SIP procedures are used in closed system manufacturing. Drug pharmaceutical manufacturing utilizes closed systems for maintaining sterile materials (liquids or powders), manufacturing biological and synthetic active ingredients (especially where microbial absence is essential), and preparing processing equipment for use in sterile drug product manufacturing and filling. Closed systems are advantageous for aseptic processing since they provide excellent separation between sterile materials and potential environmental contaminants.
Summary
Overall, sterilization keeps patients safe from toxins and microbial illnesses when therapies or devices are consumed or used. Sterilization-in-place (SIP) is an in situ sterilization process where a system or system element is sterilized without being moved. SIP processes reduce or eliminate post-sterilization handling, thus providing aseptic connections between sterilized equipment. While steam is the most common mode of sterilization for SIP, five other methods may be used. These five methods are superheated water, dry heat, gas, liquid, and vapor sterilization. SIP methods are traditionally used with closed systems to maintain aseptic conditions during product manufacturing. All in all, ensure you choose a contract manufacturing organization that can support you with appropriate sterility testing and filling for your unique cosmetic or parenteral product needs.
MycoScience is a contract manufacturing organization specializing in Sterilization Validations. MycoScience also offers Preservative Efficacy Testing, Microbial Aerosol Challenge Testing, Bioburden Testing, Cleaning Validations, Accelerated Aging, Microbiology Testing, Cytotoxicity Testing, Bacterial Endotoxin Testing, EO Residual Testing, Package Integrity Testing & Environmental Monitoring services medical devices and allied industries. MycoScience is an ISO 13485 certified facility.
References
Michael J. Akers. Sterile Drug Products Formulation, Packaging, Manufacture, and Quality. Drugs and the Pharmaceutical Sciences. Informa Healthcare. 2010.
United States Pharmacopeial Convention. <1229.13> Sterilization-In-Place. Rockville, MD, USA. 2021. (USPC <1229.13>).
