Key Differences Between USP 1115, USP 1116 and USP 1211
What is environmental monitoring for medical products & medical devices?
Environmental monitoring is the tools and techniques used to observe an environment, characterize an environment’s quality, and ensure that an environment meets established acceptance criteria. Environmental monitoring for medical products and medical devices covers the acceptance criteria for the environments throughout the entire lifecycle of the product, from raw materials to end-use or expiration. Environmental monitoring is an important quality control metric. It is particularly critical to verify your medical device or product is devoid of microbes during various phases of manufacturing, packaging, transportation, and storage. USP 1115, USP 1116 environmental monitoring, and USP 1211 SAL (sterility assurance levels) all touch upon environmental monitoring to maintain manufacturing conditions for non-sterile and aseptic processes.
What is covered in USP 1115?
USP 1115 covers the bioburden control of non-sterile drug substances and products. If you have a non-sterile product, USP 1115 will support you with bioburden requirements.
What is covered in USP 1116?
USP 1116 covers the microbiological control and monitoring of aseptic processing environments. If you have a product that requires aseptic manufacturing, USP 1116 will support you with bioburden requirements.
What is covered in USP 1211?
USP 1211 covers sterility assurance. USP 1211 is important for both non-sterile and sterile products that are manufactured aseptically or undergo terminal sterilization processes.
What are the key differences between USP 1115, USP 1116, and USP 1211?
USP 1115, USP 1116, and USP 1211 all relate to bioburden and sterility assurance regulatory requirements. However, there are key differences between the materials covered in USP 1115, USP 1116, and USP 1211. USP 1115 covers non-sterile monitoring and manufacturing conditions that do not require the same restrictions and quality as the aseptic manufacturing conditions in USP 1116. USP 1211 covers the third type of sterilization process, terminal sterilization. Most terminally sterilized products do not undergo aseptic processing and instead meet the same sterility criteria as aseptically processed products through a final sterilization process that guarantees a quantifiable safety level. Terminal sterilization is much cheaper than aseptic processing. Thus, most products will meet FDA sterility requirements through non-sterile manufacturing followed by a terminal sterilization processing instead of aseptic processing.
USP 1115 Nonsterile Product Processing Summary
What are non-sterile processes?
Non-sterile processes are methods or procedures that are undertaken in an environment where bioburden is controlled to safety levels based on product attributes, route of administration, and target patient population. Non-sterile processes contrast with sterile processes, in which the bioburden is essentially eliminated. The non-sterile products listed below are ranked with respect to the potential risk of microbiological contamination (from high to low). The same list applies to medical devices for use in the same body areas (nasopharynx, vagina, skin, rectum, and mouth).
List of common non-sterile pharmaceutical products:
- Metered-dose and dry powder inhalants
- Nasal sprays
- Optics
- Vaginal suppositories
- Topicals
- Rectal suppositories
- Oral liquids (aqueous)
- Liquid-filled capsules
- Oral tablets and powder-filled capsules
Why is environmental monitoring for non-sterile processes important for your medical device or product?
Unlike sterile products, microbial content in nonsterile products is controlled to the level needed for patient safety within the parameters of product use. Excessive sterility or aseptic processing controls add complexity and cost without safety benefits. Eliminating unnecessary sterility or aseptic processing controls saves money for both manufacturers and patients. Non-sterile processing methods may be advantageous depending on your medical product’s end use. Nonsterile product manufacture and product microbe management are distinctly different from those required for sterile products. Sterile products are injected or applied topically to sensitive tissues with a high risk of infection, little to no microbial flora, and no barriers to infection. In contrast, nonsterile products are administered to regions of the human body that have a high density of natural microbial flora as well as physical and immunological barriers to infection. Even though the microbial requirements for sterile products are stricter, non-sterile products must still go through manufacturing processing that prevents excessive contamination of the product. Microbial growth in excipients, components, and drug substances is monitored in-depth and is among the greatest causes of concern for non-sterile products. Examples of common non-sterile products are listed below.
How are manufacturing environments monitored for non-sterile products?
The monitoring of manufacturing environments for microbes is a qualitative tool to minimize contamination risk in non-sterile products. A successful environmental monitoring program confirms the effectiveness of microbiological controls and detects unforeseen contamination issues early, saving time and money. Microbial methods and practices for aseptic facilities may be used but are not intended for nonsterile environments. Often the levels of transient contamination depend on the level of human activity and gowning requirements of the manufacturing facility. The above is true because most microbial contaminants in clean environments are from humans. Manufacturers expect controlled bioburden levels that will not present a risk to the end-user in nonsterile products. Thus, manufacturers need to establish acceptable levels of microorganisms within each product and perform regular production plant hygiene assessments to keep up the effectiveness of the facility’s microbial environmental controls. Hygiene assessments include microbial sampling, staff evaluations for the appropriate execution of gowning and standard operating procedures, raw material assessments, and evaluations of cleaning protocol effectiveness.
Once a product has been placed into a packaging container, microbial monitoring is not required. Products resistant to microbial colonization or that have microbiocidal characteristics will need little or no microbiological monitoring for non-sterile manufacturing. Additionally, environments for tablet and powder- and liquid-filled capsule manufacturing need no or infrequent monitoring. The microbial monitoring frequency reflects the potential risk associated with the dosage form. Manufacturing areas for higher-risk dosage forms, such as inhalant products, require more frequent monitoring and typically are manufactured in ISO level 8 classified rooms.
USP 1116 Aseptic Product Processing Summary
What are aseptic processes?
Aseptic processes are methods or procedures undertaken in a sterile environment (such as an isolator). The aseptic sterile environment is maintained through specialized equipment that prevents microbial material from technicians, raw materials, or machinery from contaminating medical devices or products.
The terms aseptic and sterile are not synonymous. While both sterile and aseptic products will prevent microbial contamination following use, the processes by which microbial contamination is prevented are different. The term sterile means a complete absence of viable microorganisms or microbes that have the potential to reproduce. Thus, sterile products are often chemically or heat sterilized after being placed in their final packaging. The chemical or heat sterilization kills any microorganisms inside the products (obtained during manufacturing and packaging). This chemical or heat sterilization process after final product packaging is known as terminal sterilization.
However, an aseptic process prevents contamination by the exclusion of microorganisms. Though the definitions for aseptic and sterile are not the same, sterile is used interchangeably with aseptic. Indeed, many products labeled as sterile are manufactured by aseptic processing rather than terminal sterilization.
What Are Examples Of Medical Products Manufactured In Aseptic Environments?
- Pharmaceutical sterile products
- Bulk sterile drug substances
- Sterile intermediates
- Excipients
- Medical devices
- Biologics
The USP guidelines referenced for microbiological evaluation should be applied only to ISO-classified clean environments, restricted-access barrier systems (RABS), and isolators used for aseptic processing. Other clean environments are not required to meet the levels of contamination control required for aseptically produced sterile products. For products, such as oral tablets, topicals, or nasal sprays, that require non-sterile processing, please see USP 1115.
Why Is Environmental Monitoring For Aseptic Processes Important For Your Medical Device Or Product?
Aseptic processing requires the exclusion of microorganisms from the manufacturing methods. Microorganisms must be prevented from entering open containers or product materials during processing. Thus, product bioburden and the bioburden of the manufacturing environment impact the risk of unacceptable microbial contamination. Since products made from aseptic processing will not undergo terminal sterilization, it is critical to keep aseptic processing environments free of microbes to alleviate the risk of patient infection following product use. In advanced aseptic processing, operators wearing cleanroom garments are not needed or permitted for aseptic processing. For more information on the top sources of microbial contamination in manufacturing environments, visit our article here.
What Do You Need To Evaluate For Environmental Monitoring For Aseptic Processes?
Microbial contamination is inevitable in environments with human operators. Even the most cautious clean-room environment design and fastidious operation will not eliminate the shedding of microorganisms if human operators are present. As a result, zero contamination at aseptic locations during every aseptic process is unrealistic.
There are no perfect means to verify that an aseptic processing environment and the product-contact surfaces within that environment are sterile all the time. Technically, monitoring results can neither prove nor disprove sterility. However, manufacturers should review environmental monitoring results frequently so that the facility operates in a validated state of control.
Due to monitoring limitations, manufacturers cannot rely on monitoring, statistics, or aseptic processing simulations to assure a sterility level. Sterility assurance is best created by focusing on human-borne contamination and designing the facility to mitigate risk from this contamination.
Microbial contamination risk is greatly mitigated by reducing or eliminating human interventions through proper equipment design and by providing sufficient air exchanges per hour for the personnel population within the facility. Effective movement of personnel and materials, the proper control of temperature and humidity, and periodic sanitization are other contamination risk mitigation factors that can interrupt the chain of infection. Table 3 of USP 1116 (reproduced as Table 1 below) gives the suggested contamination recovery rates in various aseptic environments.
USP 1211 Sterility Assurance Summary
What Is Sterility Assurance?
Sterility assurance is environmental monitoring that encompasses aseptic processing, post-aseptic fill terminal sterilization, and terminal sterilization.
What Is Terminal Sterilization?
Terminally sterilized products are subjected to a final sterilization process that guarantees a quantifiable safety level, unlike products aseptically manufactured. Thus, in terms of microbial risk, terminally sterilized products are the lowest risk sterile medical products. Terminal sterilization most often occurs through a heat-steam method. However, chemical sterilization and irradiation (such as gamma or e-beam technologies) can also be used for terminal sterilization. Sterility assurance for terminally sterilized products is defined as the probability of non-sterility (PNS). Terminal sterilization processes must achieve a PNSU of ≤ 1,000,000 (a probability of not more than one nonsterile unit in 1 million units produced.
What Is Post-Aseptic Processing Terminal Sterilization?
A post-aseptic processing terminal sterilization is a product manufactured through aseptic processes that are then terminally sterilized. Products manufactured with aseptic processing have control over the pre-sterilization bioburden, such that the subsequent terminal sterilization processing can be less harsh for the product or medical device. This could mean that products are exposed to lower temperatures, shorter cycle times, or reduced chemical exposure for the final sterilization process. For terminal sterilization of products that have been aseptically manufactured, the terminal sterilization cycle aims to kill low bioburden organisms rather than pass biological indicators.
How Do You Perform Environment Monitoring For Sterility Assurance?
Environmental monitoring for sterility assurance qualitatively assesses the effectiveness of a facility’s design and operational controls to provide sterile products. As detailed in Figure 1 below, many external factors influence product sterility. While environmental monitoring is important, it cannot substitute for good facility equipment, process design, and practices. Indeed, monitory only provides a snapshot of the actual environmental conditions occurring moment-to-moment in a manufacturing facility. Additionally, excessive environmental sampling can impair product safety and performance in critical anti-microbial areas. There are inherent limitations with all viable and non-viable monitoring forms in terms of sample size, sample location, and recovery capability. Sterility testing and aseptic process simulations also have their limits. However, viable monitoring, non-viable monitoring, aseptic process simulations, and sterility testing are all excellent methods to perform environmental monitoring for sterility assurance of manufactured medical devices and products. These techniques ensure that established performance criteria, according to the ISO classification of the room, are met.
Viable Monitoring
Viable monitoring involves microbial sampling techniques for detecting and estimating the level of culturable microorganisms in the air, on surfaces, and on personnel.
Viable monitoring sampling methods include:
- Active air sampling
- Passive air sampling
- Viable particle counting using fluorescence technology
- A contact-plate sampling of surfaces, gloves, and gowns
- Swabbing of surfaces
- Personnel monitoring
Non-Viable Monitoring
Non-viable monitoring measures the number and size of particulates (live or dead) present in the air with calibrated particle counters. Non-viable monitoring is used to initially classify the cleanroom by ISO 14644-1 and to assess routine manufacturing conditions periodically.
Aseptic Process Simulations
Process simulations evaluate the performance of an aseptic activity using a sterile growth medium. The sterile growth medium can be directly substituted for the product or added to it. Process simulations are fully representative of the current, new, or revised production processing conditions and activities. Aseptic process simulations are often performed prior to introducing a new or modified process component (new product, facility, equipment, personnel, etc.) to assess if the addition meets aseptic performance criteria.
Sterility Testing
Sterility testing is performed to determine if the material’s specifications are met. Lot-by-lot sterility testing for finished products must be completed unless parametric release testing is approved. The parametric release is a sterility assurance release program that demonstrates control of the sterilization process for consistent lot-by-lot sterility results. The parametric release is currently the most common mode of sterile product release.
Summary
Overall, contamination control in nonsterile product manufacturing (USP 1115) differs from contamination control for aseptically manufactured products (USP 1116). Further, products that undergo sterility assurance for terminal sterilization after nonsterile or aseptic processing (USP 1211) follow additional requirements. Sterile and aseptically manufactured products are injected or applied to sensitive tissues with a high risk of infection, little to no microbial flora, and no barriers to infection. In contrast, nonsterile products are administered to regions of the human body that have a high density of natural microbial flora as well as physical and immunological barriers to infection. Examples of non-sterile products include oral tablets, nasal sprays, topicals, and rectal suppositories. Unlike sterile products, which have a set microbial limit, the microbial content in nonsterile products is controlled to the level needed for patient safety within the parameters of product use. Eliminating unnecessary sterility or aseptic processing controls saves money for both manufacturers and patients. All in all, whether you need non-sterile or sterile processes for your medical device or product, ensure you choose a contract testing organization that can support you with appropriate sterility testing, sterilization validations, and environmental monitoring for your unique medical device or product needs.
Ethide Labs is a contract testing organization that specializes in Sterility Testing, Environmental Monitoring and Sterilization Validations. Ethide Labs also offers Bioburden Testing, Microbiology Testing, Bacterial Endotoxin Testing, Ethylene Oxide Residual Testing, Cytotoxicity Testing, & Package Integrity Testing services for medical device companies and allied industries. Ethide 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. <1115> Bioburden Control of Non-Sterile Drug Substances and Products. Rockville, MD, USA. 2021. (USPC <1115>).
United States Pharmacopeial Convention. <1116> Microbiological Control & Monitoring of Aseptic Processing Environments. Rockville, MD, USA. 2021. (USPC <1116>).
United States Pharmacopeial Convention. <1211> Sterility Assurance. Rockville, MD, USA. 2021. (USPC <1211>).
