Preamble:
Definition:
“Sterility assurance is a level of confidence that a particular product or unit that is purported to be sterile is sterile.”➡️Sterility assurance is achieved through multiple practices and procedures. A different variables of contamination control that help to increase confidence in sterility assurance and sterile products.
➡️USP <1211> is a general information chapter on sterility assurance. The chapter states that “an item is deemed sterile only when it contains no viable microorganisms. Sterility testing described in USP <71> Sterility Tests.
➡️The test only indicates that the subset of articles from a lot that are tested are sterile. The test is destructive in that every unit that is tested is either consumed or no longer sterile after the test is performed. To help ensure consumer safety, additional measures must be put into place to add assurance that the entire batch or lot of products manufactured is sterile.
➡️Figure 1 shows several factors that influence sterility assurance. The factors listed in Figure 1 should be considered for their impact on the sterility of the final product.
Figure 1: Key elements to influence on Sterility Assurance
➡️ A sterility assurance program should be fit for purpose for the product or device that is being manufactured. A holistic sterility assurance program for an aseptic manufactured product could include the following components.
1. Personnel
1.1.Training
➡️ Personnel must be properly trained, educated, and/or supervised to be involved with aseptic processing. The training records must be maintained.➡️Training concepts should include the importance of proper aseptic technique and clean room behaviours. It must be recognised that humans are the primary source of contamination in the clean room environment.
➡️Retraining and qualification of personnel should be done on a routine basis to keep personnel sensitised to the importance of aseptic technique.
1.2.Personal Hygiene and Sanitation Practices
➡️It must be procedures and training that govern personnel hygiene, sanitation, aseptic technique, aseptic behaviour in the clean rooms and aseptic gowning practices.➡️Personnel must adhere to sanitation and health precautions designed to avoid contamination of the test, environment, and/or product. Personnel must also adhere to gowning and personal protective equipment procedures. If an employee is feeling ill, they must inform their supervisor of any health or medical condition that may have an adverse effect on a test, product, or environment.
➡️Personnel must also be monitored for microbial growth and undergo gowning qualification training to ensure aseptic status of the manufacturing or testing environment.
➡️To protect exposed sterilized product, personnel should to maintain gown quality and strictly adhere to appropriate aseptic techniques.
1.3.Personnel Flow
➡️It must be procedures and practices regarding personnel flow. Personnel must follow established entry and exit routes to prevent cross contamination.➡️The routes should include different levels of gowning for each grade of the clean room environment. These routes must also be established in standard operating procedures (SOPs) and understood by personnel.
2. Procedural Control
2.1 Cleaning Process
➡️The well-defined cleaning process in place to assure contamination level is not go beyond the approved specification limit and subsequent not cross contaminated to next product.➡️Cleaning process should be validated by using worst case molecules and routine monitoring to be done whenever changeover between two products to get assurance that validated cleaning procedure are in well placed.
2.2 Line clearance procedures
➡️A well-established line clearance procedure should be placed which ensured that the area and equipment are required during manufacturing and filling activities of drug products are free from any potential cross contamination/mix-ups.➡️There are well elaborated checkpoint are available in line clearance of critical stages of process.
➡️Personnel involved for line clearance should be trained on SOP.
2.3 Manufacturing Practices
➡️The manufacturing process i.e. all interventions and aseptic connections must be monitored and controlled. Proper aseptic technique and personnel behaviours must be utilized to prevent cross contamination of product during manufacturing.2.4 Decontamination
➡️Decontamination practices for aseptic processing must be documented in SOPs. This could include chemically sanitizing equipment to take into the clean rooms, wiping items down with disinfectants, or using decontamination devices such as vaporized hydrogen peroxide (VHP) generators or autoclaves.2.5 Sterilization and Depyrogenation
➡️The use and sterilization of equipment, components, or other materials for aseptic processing must be governed in SOPs. This could include purchasing items that are ready to use or preparing the items for use in-house.2.6 Validation
➡️Media fills (Aseptic process simulation) help to demonstrate that the manufacturing process can produce a sterile final product. The manufacturing process should include inherent interventions & corrective interventions and aseptic connections.➡️Media fill study will show contamination control effectiveness throughout the manufacturing process.
➡️Process validation proves that process is capable of consistently delivering sterile quality product.
3. Material
3.1 Product and Material Movement
➡️It must be procedures and practices for product and material flow to prevent cross contamination.➡️The routes should include levels or methods of sanitization of products, materials, and/or waste as they enter or exit the clean room areas. These routes must also be established in standard operating procedures and understood by personnel.
3.2 Supplier Qualifications
➡️Qualifying suppliers is an important approach to control items that are purchased sterile and ready to use. It is important that vendors are trusted to provide quality supplies to maintain sterility assurance of the final product that is being manufactured. Supplier qualifications must be governed by SOPs.3.3 Material Control
➡️Products and materials must also be controlled to prevent contamination and increase sterility assurance. Raw materials, components, active pharmaceutical ingredients, container closures, and product contact surfaces should all be monitored and controlled.➡️Sterility must be assured for cleaning solutions, tools and equipment, raw materials, container closures, and any other materials that will be introduced into the clean room area.
3.4 Storage Conditions
➡️When considering storage conditions, it is important for warehouse cleanliness, order, and quarantine areas when all raw material, container closure material are stored. Temperature and humidity should be monitored and controlled when required.➡️Conditions should be maintained to ensure the sterility of the final product. In addition, container closure integrity should be established to ensure the product remains sterile in its packaging.
4. Machine/Equipment
➡️The use and preparation of equipment for aseptic processing must be documented in SOPs and respective batch records.➡️It must be designed appropriately for the intended use and housed in a manner to prevent cross contamination. Equipment used in the generation, measurement, or assessment of data and equipment used for facility environmental control must be of the specified design and capacity to function according to GMPs.
➡️The equipment must be suitably located for operation, inspection, cleaning, and maintenance. It must be inspected, cleaned, and maintained. Equipment used for the generation, measurement, or assessment of data must be tested, calibrated, standardized, and/or sterilized.
➡️The design of equipment used in aseptic processing should limit the number and complexity of aseptic interventions by personnel.
➡️Equipment should be appropriately designed to facilitate ease of sterilization. It is also important to ensure ease of installation to facilitate aseptic setup.
➡️Horizontal surfaces or ledges of equipment that accumulate particles should be avoided. Equipment design should not obstruct unidirectional airflow in critical areas.
4.1 Equipment Qualifications
➡️Equipment designed such as for it intended use will be demonstrated by successful qualification.➡️Equipment should also be qualified for use in the clean rooms. There should be cleaning validations that include clean and dirty hold times of equipment.
4.2 Maintenance
➡️Annual maintenance planner of all equipment to be prepared and maintenance must be performed within predefined duration.5. Facility Management
5.1 Design
➡️The design of the facility should be documented on approved layouts and flow diagrams to help personnel in their daily tasks.➡️The facility must be constructed to prevent microbial contamination. This could include items like differential pressure cascades, the use of classified areas, and temperature monitoring.
➡️Separate areas should be available for the storage and quarantine of materials. The warehouse must be neat, clean, and temperature/humidity controls where appropriate. Cardboard or other items containing cellulose fiber should not be allowed in clean areas as they could be a source of mold contamination.
➡️Laboratory practices must also be implemented to prevent microbial contamination from outside of clean rooms. This could include changing uniforms and shoes and using proper aseptic gowning practices wherever applicable.
5.2 Supporting Clean areas
➡️The effects from supporting areas should also be considered. If an adjoining room has microbial contamination, that contamination could migrate into the inner core of the clean rooms. Transition areas should be monitored and controlled.➡️This areas should be designed such as to minimize the level of particle contamination in final product and control the microbiological content (bio burden) of articles and components that are subsequently sterilized.
5.3 Decontamination, Cleaning, and Disinfection Programs
➡️Decontamination, cleaning, and disinfection programs must be established. The programs must be governed by SOPs and should describe what gets cleaned, how the cleaning is performed, how often the cleaning is performed, what cleaning agents are utilized, and the validation of the cleaning, decontamination, or disinfection process.➡️Room cleanings should include items like the walls, floors, ceilings, and equipment. Also, there should be established clean and dirty hold times for equipment and the clean rooms.
➡️When utilizing disinfectants, consider items like disinfectant efficacy date, wet contact times, and the method of application of the disinfectants. Cleaning, disinfection, and/or decontamination concepts should be considered for both product contact and non-product contact surfaces.
6. Measurements
6.1 Laboratory Testing & control
➡️Laboratory testing are sterility testing, endotoxin testing, bioburden testing, raw material testing, in-process testing, finished product testing, and container closure integrity testing.➡️A sterile product is to undergo analysis for microbial endotoxins and sterility testing to assure the absence of contamination.
➡️Laboratory practices must also be implemented to prevent microbial contamination from outside of clean rooms. This could include changing uniforms and shoes and using proper aseptic gowning practices wherever applicable.
7. Environmental Monitoring Program
➡️Temperature, %RH and differential air pressure should be maintained through qualified installed AHU system.➡️Environmental monitoring assesses the microbial contamination level in the cleanrooms and adjacent areas. This data may highlight areas that need extra cleaning, monitoring, and/or maintenance.
➡️Air (i.e. Viable and Non-viable airborne particulates) and surfaces are routinely monitored within the clean rooms to make sure the environment continuously meets specifications.
➡️Environmental monitoring should promptly identify potential routes of contamination, allowing for implementation of corrections before product contamination occurs.
➡️The monitoring program should cover all production shifts and include air, floors, walls, and equipment surfaces, including the critical surfaces that come in contact with the product, container, and closures.
➡️It is especially important to monitor the microbiological quality of the critical area to determine whether or not aseptic conditions are maintained during filling and closing activities. Air and surface samples should be taken at the locations where significant activity or product exposure occurs during production.
➡️Clean areas must be validated and maintained. This should include environmental monitoring qualification programs (EMPQ) and clean room qualifications.
➡️High efficiency particulate air (HEPA) and heating, ventilation, and air conditioning (HVAC) systems should be used with differential pressure cascades, temperature controls, and humidity controls to prevent microbial contamination.
➡️If the temperature is too hot or humid, people could sweat, compromising their clean room gowning. In addition, when pressure cascades are not controlled properly, microbes could enter the clean rooms. Excessively humid environments can increase the potential for fungal contamination.
Reference:
➡️FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice. US Department of Health and Human Services. 2004.➡️EMA Annex 1 – Manufacture of Sterile Products.
➡️United States Pharmacopeia (USP) <1211> Sterilization and sterility assurance of compendial articles.
➡️United States Pharmacopoeia Chapter <71> Sterility tests.
About the Author:
Dhansukh Viradiya is a highly accomplished expert in the pharmaceutical and biopharmaceutical industries. With over 10 years of experience in the field, he has gained comprehensive knowledge and expertise in various areas, including Process Validation, Cleaning Validation, Quality Management System, In-process quality assurance, Qualification etc.
Mr. Dhansukh holds a Master's degree in Pharmacy from a renowned University, where he specialized in Quality Assurance.
As a thought leader, Mr. Dhansukh has published numerous articles and white papers on various topics related to pharmaceutical and biopharmaceutical industries. His research work focuses on emerging trends, current regulatory expectations, advancements in technology, personalized medicine, and the intersection of healthcare and technology.
With his passion for improving patient care and dedication to advancing the field, Dhansukh Viradiya continues to make significant contributions to the pharmaceutical and biopharmaceutical industries. His insights and expertise make him a valuable resource in understanding the dynamic landscape of these sectors and their impact on global healthcare.
Disclaimer: The author's biography is provided for informational purposes only and does not imply any endorsement or affiliation with the article or its content.
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