PRODUCTS HAVE TO BE STERILE

Certain pharmaceutical products, such as injections, eye preparations, irrigation solutions, and hemodialyzer solutions.

TWO SERIES OF INDIVIDUAL PRODUCTS

• Those that are terminally sterilizable or able to be sterilized in their ultimate container
• Those that need to be prepared aseptically and cannot be terminally sterilized

PURPOSE : To go over some particular concerns about the production of items that are aseptically prepared:

• Production Setting
• Tidy spaces
• Employees
• Solution preparation and filtration
• Bioburden pre-filtration
• Validation and integrity of filters
• Sterilization and equipment/container preparation
• Filling procedure Aseptic procedure validation

EQUIPMENT OF INJECTABLE FACILITY

• Bung Processor cum Steam Sterilizer – It is necessary to sterilize the rubber bung, clothes, vial filling machine parts, and other random materials during aseptic processing. For both porous and nonporous loads, the Bung processor/steam sterilizer method of sterilization is employed. According to cGMP regulations, this method of sterilizing various loads in various patterns needs to be confirmed.
• Vial Washing Machine – The vials are cleaned using a high-speed linear vial washing machine. At several washing stations, vials are cleaned in accordance with a predetermined and verified protocol utilizing sterile filtered (0.2 µ) compressed air, purified water, and water for injection as a final rinse. Every component that comes into touch with the washing zone or jet is made of stainless steel 316. The PLC in charge of the vial washing machine has one or more validated programs for cleaning glass vials of various sizes. A transparent glass pane allows you to see the entire cleaning process as high-pressure spray jets or nozzles are inserted into the vials to ensure the ideal wash.
• Vial sterilization and Depyrogenation – The sterilizing tunnel for the vials is incorporated with the vial machine’s out-feed. Glass vials of different sizes can be sterilized and depyrogenated in a tunnel using a continuous process that uses hot, dry, unidirectional airflow that is filtered with HEPA. The tunnel sterilizer’s sterilizing zone maintains an air temperature between 320°C and 360°C. Glass vials that have been cleaned are sent into the sterilizing tunnel using a conveyor belt made of stainless steel wire mesh that has lateral guides to prevent the vial from sliding down the walls of the tunnel. The tunnel is made of AISI 316 stainless steel. The vial size and configuration can be taken into consideration while adjusting the conveyor speed.
• Sterile Dry Powder Filling & Rubber Stoppering – The rubber stoppering machine and automated vial filling are integrated into the sterilizing tunnel’s outflow. Using a vacuum and pressure system, the machine fills glass vials of different sizes with sterile dry powder.
• Vial Sealing – A tiny mouse hole in a stiff wall between the vial filling and sealing rooms is where the vial filling and bunging machine’s outfeed connects to the vial sealing equipment. The vial sealing chamber is equipped with an ISO 5 (Class 100) laminar airflow unit situated above the vial sealing machine, making it a hygiene zone of grade 7 (Class 10,000). The vial sealing machine can use flip-off or tear-off over seals made of aluminum to seal glass vials of different sizes. The sealing machine’s vibratory bowl receives pre-sanitized aluminum over seals, which are then correctly orientated and directed toward the feeding chute. The caps are removed from the vibrating chute while the vials are being moved from the timing screw to the star wheel.
• Automatic Vail Inspection Machine – An online, automated vial visual inspection machine is linked with the out-feed of the vial sealing machine.

MANUFACTURING ENVIRONMENT:

Four levels of tidied areas:

1. GRADE D (EQUAL TO CLASS 100,000, ISO 8): Sanitized space for performing less crucial steps in the production of aseptically prepared goods, such as cleaning and handling components.
2. GRADE C (EQUIVALENT TO CLASS 10,000, ISO 7): Clean Space for Performing Less Important Steps in The Production of Aseptically Prepared Goods, Like Filtering Solutions.
3. GRADE B (EQUAL TO CLASS 100, ISO 5): Background environment for grade A zone, such as a cleanroom that houses workstations with laminar flow.
4. Grade A, or class 100 in ISO 5 (ISO 14644-1), is a local zone designated for high-risk tasks such as filling products, handling sterile ingredients, transferring partially stopper containers to be lyophilized, and using stopper bowls or open vials.

A workstation with laminar air flow typically provides these conditions.

There are requirements for both live and non-viable particles for each category of cleanroom.

• First, get rid of the contaminating source!
• Second, the chance of contamination can be lowered by using sterile barriers, monitoring the environment, and using an aseptic approach.
• Third, Putting on a gown and gloves.

ASEPTIC PROCESSING

1) ASEPTIC PROCESSING: It involves sterilizing each component separately or combining many components into a single sterilized combination. The most typical method involves making a solution, filtering it through a sterilizing filter, and then pouring it into sterile containers (active ingredients and excipients dissolved in water for injection, for example).

This could entail combining previously sterilized materials aseptically.

2) PARTS THAT ARE PUT INTO STERILE CONTAINERS: Potentially entails inserting already sterilized powder. Dry heat or radiation sterilization is produced by aseptically crystallizing and precipitating a sterile, filtered solution.

3) STERILISATION & EQUIPMENT/CONTAINER PREPARATION:

• Validated cycles should be utilized for the sterilization of all equipment and product containers. Watch out for stoppers—they shouldn’t be crammed in firmly as they could hinder the elimination of air during the sterilization process’ Hoover step. They were wrapped and loaded with equipment to make air removal easier. Pay close attention to the tubing, housings, and filters. Heat tunnels are frequently used to dehydrogenate and sterilize glass vials.
• Typically, high temperatures for brief periods, lasting little more than three minutes at NLT 300 °C. Conveyor speed must be taken into consideration. Depyrogenation Validation (3 logs Endotoxin units). HEPA-filtered air is supplied through a tunnel (CLASS 100).
• It should be simple to construct and disassemble, clean, sanitize, and/or sterilize equipment. WFI-grade rinse water is recommended. After cleaning, equipment should be let dry unless sterilized right away to avoid pyrogen buildup. It is essential to confirm that washing glass containers and rubber stoppers removes endotoxins. The amount of time that needs to pass between sterilization and use needs to be specified and justified.

4) VALIDATION OF PROCESS (MEDIA FILL TEST)

• Microbiological growth medium (media fill) is used to simulate and validate the manufacturing process.

Process simulation involves:

• Using the identical procedures used in the product’s manufacture for formulation (compounding).
• Filling with appropriate media.
• At least twice a year, process simulation for the formulation stage should be carried out.
• Validation of the process (media mill test): Worst-case scenarios should be included in the media fill program, which are variables linked to the longest run that is allowed (e.g., operator tiredness). The quantity, kind, and intricacy of typical interventions, as well as irregular interventions and occurrences (such as maintenance, power outages, human interference, etc.), are representative. Number of employees and their activities, breaks, shift changes, and gown changes. A reasonable quantity of aseptic additions or transfers (such as sterile ingredients, charging containers, closures, etc.)

Connections and disconnections of aseptic equipment collections of aseptic samples. Line arrangement and speed Checks on weight. Systems for closing containers

• Refer to Attachment-I: List of interventions for media fill; Aseptic Manufacturing Intervention Risk Assessment – Decision Tree Method; Refer to Attachment-II: Container closure systems.

VALIDATION OF THE PROCESS (MEDIA FILL TEST) QUANTITY AND FREQUENCY:

Three First, Next, Each Shift. After that, semi-annually for each shift. Every Employee Should Take Part, At Least Once a Year, In Line With Regular Tasks

Changes must be evaluated, and revalidation ought to be done as necessary line speed

Speed varies according to process type.

DURATION: Depending on the kind of operation, the processes require enough time for modifications and interventions. Include the complete filling time for typical processes (sizes 5000–10,000 generally accepted, or batch size if <5000). More significant numbers should be filled in for processes that require human labor. For isolators, lower values can be filled in.

ECOLOGICAL SITUATIONS: Typical of the real production environment in terms of staffing numbers, activity levels, etc., but there are no further safety measures, such as HVAC adjustment. If nitrogen is required for overlaying or purging, air must be substituted.

VALIDATION OF PROCESS (MEDIA FILL TEST) ANALYSIS OF THE FINDINGS:

• Filling fewer than five thousand units:
• No tainted units should be found.
• After an investigation, one (1) contaminated unit is deemed cause for revalidation.
• Filling between 5,000 and 10,000 units
• An inquiry into one (1) contaminated unit should be conducted, and a repeat media fill should be taken into account.
• After an assessment, two (2) contaminated units are judged to be grounds for revalidation.
• When more than 10,000 units are filled.
• An investigation ought to be conducted into one (1) contaminated unit.
• After an assessment, two (2) contaminated units are judged to be grounds for revalidation. VALIDATION OF PROCESS (MEDIA FILL TEST)

ANALYZATION OF THE FINDINGS:

Video may be helpful. QC should monitor media fills, and contaminated units should be reconcilable with the period and activity being mimicked. No contamination is ideal. It is essential to look into any contamination. It is necessary to identify any isolated organisms down to the species level (genotypic identification).

Conclusion: The aseptic processing of pharmaceutical products, particularly those that cannot be terminally sterilized, demands meticulous attention to detail and adherence to stringent protocols to ensure sterility and product safety. Key aspects such as production setting, equipment sterilization, solution preparation, filtration, and validation of processes play critical roles in maintaining the integrity of the final product. A robust aseptic processing framework, supported by meticulous planning, rigorous validation, and continuous monitoring, is indispensable for ensuring the sterility and safety of pharmaceutical products intended for injection, eye preparations, irrigation solutions, and other critical applications.

How ND Global can help – ND Global provides comprehensive support and expertise in implementing and maintaining a robust aseptic processing system for pharmaceutical products. Here’s how ND Global can help:

1. Consultation and Assessment: ND Global conducts a thorough assessment of your current aseptic processing practices, cleanroom facilities, equipment, and personnel training programs. Based on the assessment, tailored consultation services are provided to identify areas for improvement and develop strategies to enhance your aseptic processing capabilities.
2. Process Optimization: ND Global offers guidance on optimizing your aseptic processing procedures, including solution preparation, filtration, sterilization, and filling techniques. By implementing best practices and leveraging the latest technologies, ND Global helps streamline your processes to improve efficiency and ensure product quality and safety.
3. Validation Services: ND Global assists in the validation of your aseptic processing systems and equipment, including conducting media fill tests and ensuring compliance with regulatory requirements. Our team of experts develops customized validation protocols, performs testing, and analyzes results to verify the effectiveness of your aseptic processes.
4. Continuous Support and Monitoring: ND Global offers ongoing support and monitoring services to ensure the long-term success of your aseptic processing operations. Our team conducts regular audits, environmental monitoring, and quality assessments to identify any deviations or potential risks and provide timely recommendations for corrective actions.