Q. I am a small-scale parenteral manufacturer and have been approached to support a clinical program through Phases II and III. What sterile manufacturing considerations are important for the small-scale production lots?
A. The sterile manufacturing situation always raises some interesting discussions. The statistical assurances for sterility for normal commercial lots are not available because of the usually small lots during clinical production. At the same time, the need to minimize any unanticipated clinical risks remains high. The best advice is to consult the regulations and determine what requirements you must meet to help ensure the clinical material you are manufacturing is safe.
FDA Aseptic Processing Guidance
Clinical trial material batches can range from as few as 200 to as many as 5000 units or more. It may not be feasible for these small-size batches to be produced on a traditional manufacturing line. In fact, some of the batches might be manufactured under a laminar flow hood by manual aseptic processing.
It is important to remember that sterility assurance of the product must be maintained even when the clinical-trial materials are being prepared by hand because of the small lot sizes required.
For these small-scale batches, manufacturers need to adhere to the recommended requirements for control of the environment as defined in FDA’s aseptic processing guidance, the Parenteral Drug Association’s Technical Report #62 on manual aseptic processing, and in EudraLex Volume 4, Annex 1. In other words, the environment must be maintained and monitored with the recommendations specified in the documentation governing aseptic processing.
Aseptic Pharmaceutical Manufacturing
Properly maintaining an aseptic pharmaceutical manufacturing environment suitable for drug products regardless of batch size is not as clear-cut as it seems. Quality personnel responsible for batch release need to take into consideration a number of factors before the lots in question can be released. These factors include assuring appropriate use of disinfectants before, during, and after manufacturing; proper gowning and aseptic technique of the operators; and making sure the environmental and qualification data support the operations.
So, what does this all mean? It means the company must have a robust program in place to support the sterility of the batch regardless of the lot size.
Sterile Pharmaceutical Manufacturing
There needs to be a cleaning program defining the proper use of disinfectants/sporocides before, during, and after processing. Sterile pharmaceutical manufacturing includes a gowning qualification/requalification program for personnel responsible for the product manufacturing. The gowning program should define how operators are initially qualified, how they are monitored for microbiological excursion during gowning, during manufacturing, and upon completion of manufacturing activities.
It should also define how operators will be periodically requalified and how operators will be requalified in the event of an out-of-specification result. Operator aseptic technique should be tested through the conduction of media fills representative of the actual manufacturing runs. At a minimum, media fills should be performed annually.
There also needs to be a facility maintenance program that challenges the appropriateness of the air handling system during sterile production. Establishing a periodic maintenance program for your high-efficiency particulate air (HEPA) air filtering system and performing periodic smoke studies to make sure the airflow is suitable for aseptic operations should provide quality assurance that the airflow system is in control and is functioning appropriately.
In addition to the above recommendations, the company should have a program to control incoming components. Components used in the manufacture of aseptic processing on a small scale need to be rendered pyrogen free before being introduced into the manufacturing area.
Small-scale batches of sterile products will not be taking advantage of continuous processes associated with large-scale lot manufacturing, so consideration must be given to how the materials and components will be introduced manually into the manufacturing area. This will require even greater emphasis on operator technique.
In some instances, the manufacturing equipment used in small-scale batch production is portable, so this program should also encompass the introduction of the necessary manufacturing equipment into the production area.
There needs to be an established environmental monitoring program. The environmental monitoring program for small-scale batch production should provide the information on the quality of the aseptic processing environment including any ancillary areas such as the equipment/component processing area, gowning rooms, laminar flow hoods, floors, ceilings, walls, and equipment surfaces including those that come into contact with the product components as well as the product itself.
Sterile Product Manufacturing
Determining the appropriate monitoring locations should be determined through a comprehensive risk evaluation. Sterile product manufacturing should periodically be reviewed and updated to reflect the most current operating conditions.
Finally, there needs to be consideration to final product testing and the appropriate number of product samples needed to ensure the product is sterile and safe for patients. The samples needed for testing should be taken from the beginning, middle, and end of the manufacturing run and the number taken should be reflective of the batch size.
Successfully manufacturing small-scale parenteral batches suitable for patients requires many of the same procedures and controls needed for large-scale parenteral manufacturing. If you keep in mind-regardless of batch size or manufacturing process-that the ultimate goal is to assure the sterility of the product throughout the manufacturing run and you use the data collected to determine the suitability of your processes, you should be able to produce any size batch in accordance with regulatory expectations.
Vol. 41, No. 2
Pages: 82, 81
About RCA 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, Health Canada, MHRA 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
About Sotera Health
The name Sotera Health was inspired by Soteria, the Greek goddess of safety, and reflects the Company’s unwavering commitment to its mission, Safeguarding Global Health®.
Sotera Health Company, along with its three best-in-class businesses – Sterigenics®, Nordion® and Nelson Labs®, is a leading global provider of mission-critical end-to-end sterilization solutions and lab testing and advisory services for the healthcare industry. With a combined tenure across our businesses of nearly 200 years and our industry-recognized scientific and technological expertise, we help to ensure the safety of over 190 million patients and healthcare practitioners around the world every year.
We are a trusted partner to more than 5,800 customers in over 50 countries, including 40 of the top 50 medical device companies and 8 of the top 10 pharmaceutical companies.
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.