Susan J. Schniepp, Distinguished Fellow at Regulatory Compliance Associates, answers some commonly asked questions about aseptic processing and environmental controls.
Q. What is aseptic processing?
A. Aseptic processing is a manufacturing method that can produce product that is absent of bacteria without subjecting the product to terminal sterilization processes.
Many products degrade and become ineffective when subjected to the harsh conditions of terminal sterilization. Aseptic manufacturing allows these products to be produced in a sterile environment, allowing them to maintain their effectiveness while being safe to inject into patients.
Q. What is the difference between aseptic processing and terminal sterilization?
A. The major difference between aseptic processing and terminal sterilization is when the sterilization step occurs in the process. In terminal sterilization, the sterilization is performed after the API, excipients, containers, and stoppers have been assembled.
The final assembled product is then subjected to high heat and/or radiation that renders the product sterile. Terminal sterilization processes are harsh and can have negative effects on product efficacy.
For products that can’t withstand terminal sterilization, drug manufacturers employ aseptic manufacturing. The aseptic manufacturing process requires the drug product and any excipients, the container, and the stoppers to be individually sterilized.
Aseptic Clean Room
All must be done before being introduced into the cleanroom or sterile manufacturing core where the final product is manufactured. Additionally, this highly controlled environment is constantly monitored for air quality and potential microbial ingress.
Q. Why must manufacturers establish environmental controls for aseptic processes?
Proper Aseptic Technique
This requirement is addressed in global current good manufacturing practices (cGMPs). The purpose of these controls is to prevent product contamination due to insanitary conditions.
The environmental controls to be monitored include, but are not necessarily limited to, air quality including particulate matter, ventilation, temperature, humidity, air pressure, and microbial contamination.
The environment controls have, as expected, stricter limits for aseptic processing manufacturers due to the nature of their business.
Q. What does PUPSIT stand for, and why is it required?
A. PUPSIT is a term used in aseptic processing operations, and it stands for pre-use post-sterilization integrity testing. This testing is performed on the sterilizing filter after it is installed before product manufacturing. Follow up testing occurs again after the product manufacturing is completed.
The purpose of the pre-test is to ensure that the sterilization and installation process has not damaged your filter prior to the filtration of your product. The purpose of the post-test is to demonstrate that the filter remained intact and undamaged during actual product filtration.
An article published by the Parenteral Drug Association (PDA) states:
“Since 1998, the EU Guidelines to Good Manufacturing Practice: Medicinal Products for Human and Veterinary Use, Annex 1 (Manufacture of Sterile Medicinal Products) or ‘Annex 1’ has contained the requirement for verifying the integrity of a sterilizing grade filter before use and after its sterilization.
The requirement remained in the 2008 revision and in the 2017 draft revision to Annex 1. While not a requirement by the U.S. FDA, EMA inspectors and some PIC/S inspectors have been increasingly expressing expectations for companies to employ this testing procedure”.
The article goes on to explain the concerns that led to the PUPSIT requirement:
“Concerns have been raised that a sterilizing filter could develop certain flaws that would allow microbiological contamination to pass during filtration. The key is that flaws may be blocked or clogged by fluid contaminants or components during the filtration process and remain undiscovered during post-use integrity test. This phenomenon is sometimes referred to as ‘filter flaw masking’”.
Additionally, the article explores the rationale for not employing PUPSIT because of:
“the contamination/product deterioration risk associated with performing PUPSIT may greatly outweigh the risk of product contamination as a result of the masking effect.”
To test a filter during sterile filtration, the sterile filtrate side must be under atmospheric pressure. This requires a fluid pathway to remove any wetting agent.
“The exposure of the downstream portions of the sterile product transport line poses a risk to maintaining the sterility of the filtered product. This, along with other risks, is greater than the remote likelihood of microbiological contamination from a flaw which can be masked during use of the filter that is not detected afterwards.”
Further, the PUPSIT concept is still actively being debated. The best way to address the use/non-use of PUPSIT in your organization is to make sure you have an appropriate risk assessment in place defending your position.
Q. What makes aseptic drug manufacturing so challenging?
A. Aseptic manufacturing requires highly trained and experienced people to carry out the operations. Even when not in use, special equipment and cleaning procedures must be part of the constant environmental monitoring. Finally, the risk to the product and patients is significant when the aseptic process is compromised.
Volume 45, Number 10
Pages: 58, 57
About RCA’s Pharmaceutical Services
Regulatory Compliance Associates (RCA)® has helped thousands of pharmaceutical companies meet regulatory, compliance, quality assurance, and remediation challenges. With more than 20 years of experience with FDA, Health Canada, EU and global regulatory agencies worldwide, RCA offers leading pharmaceutical consultants that can help you navigate through the challenges associated with evolving industry regulations.
Our team of over 500 seasoned FDA, Health Canada and EU compliance consultants and regulatory affairs experts can understand the complexities surrounding the pharmaceutical industry and the unique inner workings of the regulatory process.
Whether you’re in the product planning, development or pharmaceutical lifecycle management stage or need a remediation strategy for a compliance crisis, RCA® Inc. will guide you through every step of the regulatory process and create a customized approach depending on your product and your pharma company’s individual needs. Our clients include:
- Companies new to FDA, Health Canada or EU regulations and the pharmaceutical industry
- Start-up organizations with novel submissions to 510(k) submissions from multi-national corporations
- Investment firms seeking private equity due diligence for pre-acquisition and post-deal research
- Law firms seeking expertise in the remediation of warning letters, consent decrees, 483’s or import bans
Regulatory affairs is Regulatory Compliance Associates® Inc.’s backbone and we fully understand the complexities of the pharmaceutical and biopharmaceutical industries. Our expertise spans all facets and levels of Regulatory Affairs, from Regulatory Support for New Products to Life Cycle Management, to other services like Outsourced Regulatory Affairs, Submissions, Training, and more.
As your partner, we can negotiate the potential assessment minefield of pharmaceuticals with insight, hindsight, and the clear advantage of our breadth and depth of knowledge and experience. We offer the following four regulatory affairs services for pharmaceutical companies.
- New Product Support
- Product Lifecycle
- Other Regulatory Services
The regulations process surrounding pharmaceutical companies can be tricky for even the most experienced industry veteran to understand, and just one misstep could mean significant and lasting consequences for your business. At RCA® Inc., we offer the experience and resources necessary to guide you in quality compliance.
- Regulatory Agency Response
- Preparation and Training
- Inspection Readiness
Regulatory Compliance Associates® Inc.’s Quality Assurance services include assessments, strategy, implementations, staff augmentations, and identification of quality metrics to ensure continuous improvement, aligning with your business needs and goals. Our consultants are quality experts with experience spanning major corporations and start-ups. We know firsthand how to achieve, maintain, and improve quality, and we excel in transferring this knowledge to your organization.
- 21 CFR Part 11
- Data Integrity
- Manufacturing Support
- Facility Support
Regulatory Compliance Associates® Inc. has significant experience and a proven approach to managing FDA Warning Letters, Consent Decrees, Remediation and other serious regulatory situations. We know how to partner with executive, legal, and communication teams, and will assist management with a response that will be accepted by the regulatory agency and be realistic to execute.
We can develop a comprehensive proof book of documented objective evidence demonstrating the corrective actions taken to remediate non-compliant issues. In addition, RCA can help prepare a comprehensive strategy to assist in your remediation efforts, drive continuous improvement, and maintain compliance with the regulations.
- Regulatory Action
- Warning Letter
- 483 Observation
- Oversight Services
Regulatory Compliance Associates® (RCA) provides healthcare consulting services to the following industries for resolution of compliance and regulatory challenges:
We understand the complexities of running a life science business and possess areas of expertise that include every facet of R&D, operations, regulatory affairs, quality, and manufacturing. We are used to working on the front lines and thriving in the scrutiny of FDA and globally-regulated companies.
As your partners, we can negotiate the potential minefield of regulatory compliance and regulatory due diligence with insight, hindsight, and the clear advantage of our unique expertise and experience.
- Founded in 2000
- Headquartered in Wisconsin (USA)
- Expertise backed by over 500 industry subject matter experts
- Acquired by Sotera Health in 2021
To begin the RCA® scoping process today, please enter your information in the blue form below and click the submit button at the bottom of the webpage.