Microbial Process Design

Microbial Process Design

Click now to learn from Sue Schniepp, Distinguished Fellow at Regulatory Compliance Associates, as she describes microbial process design and how your team can improve contamination control. 



Human microbes live in every part of a human being, including the skin, gut, and nose. Trillions of microorganisms live inside the human body — often outnumbering human cells by 10 to 1. However, microorganisms only make up roughly 1 to 3 percent of the body’s mass because of their tiny size. Sometimes microbes in food can lead to illness, but it is more common for microbes in human body functions to safely live in their host. Additionally, many types of microbes provide unique qualities that help increase life expectancy and human survival in general.


Annex 1


microbial process designWhen it comes to microbial control and process design, there are unique drivers listed in the EU’s Annex 1 regulatory guidance that can help your organization. This regulatory compliance guidance contains different types of contamination control requirements.


Further, these drivers come in many different shapes and sizes, but all can impact manufacturing production if not carefully considered.


Sterile Preparations


Manufacturing sterile products covers a wide spectrum of decisions to be considered by the Quality team and manufacturing operations, including:


Sterile product types

  • Active substance
  • Sterile excipient
  • Packaging material
  • Finished dosage form

Packaging sizes

  • Single unit
  • Multiple units

Sterile processes

  • Automated systems
  • Manual processes


  • Biotechnology
  • Small molecule manufacturing
  • Closed systems


Additionally, one of the quality assurance goals of sterile product manufacturing is to minimize risk associated with microbial, particulate, and pyrogen contamination.


Process Design


Contamination sources are the focus of process design and are commonly due to microbial and cellular debris, as well as particulate matter. Understanding how your facility, equipment and employees contribute to uncleanness (whether intentional or not) is essential to contamination control. Lastly, process design should consider each contamination source individually and as a whole to achieve regulatory compliance.


Manufacturing Plant


The facility your product is manufactured in is the first gap analysis that should be conducted. For example, a food manufacturing plant will have a different set of needs to be considered than a pharmaceutical manufacturing environment. Each will have unique requirements based on equipment, environment and process. Further, pharmaceutical production follows unique FDA guidance recommendations that are unlike many commercialized products on the market.  




One of the first priorities your team should understand is clean room classifications and differences in a regulated clean room environment. There are many types of cleanroom services that can help with clean room design and preparing for regulatory compliance (e.g. ISO 7 or ISO 8).


For example, cleanliness standards and cleanroom supplies should be maintained and monitored for environmental conditions. Finally, airlocks for both personnel and equipment should include HEPA (High Efficiency Particulate Air) air filtration to increase air cleanliness and controls that reduce contaminants.




Restricted Area Barrier Systems (RABS) and isolators can help assure environmental conditions help minimize microbial contamination. Further, a reliable containment strategy should consider the types of human intervention that can impact the critical zone. This often goes hand-in-hand with the type of grade the zone is.


There are four primary types of critical zones:


  • Grade A: this area includes high risk operations that must consider air filtration, the aseptic processing line, and filling zone. Additionally, the stopper bowl, open ampoules and vials also must be studied based on contaminates & unidirectional air flow. Finally, process design & SOPs should minimize the number of operators who don’t use barrier protection or glove port
  • Grade B: this area is commonly a background cleanroom for Grade A aseptic preparation and filling zone. Most importantly, airflow visualization studies should show that air does not enter from any lower grade cleanrooms to Grade B. Air pressure differentials should be monitored to ensure clean airflow.
  • Grade C and D: These types of cleanroom spaces are used for lower risk manufacturing stages in the manufacturing process. The most often use class for Grade C and D are the preparation and filling of terminally sterilized


Finally, it is critically important when analyzing the grade of a zone when it comes to modular clean room or portable clean room designs. Make sure your cleanroom construction team understands the types of certified cleanroom principles that follow regulatory compliance.


Water Systems


A water treatment plant is one of the most critical elements of microbial process design. The water filter system should minimize both particulates and pyrogens to help reduce the potential for contamination. Further, special attention should be given to the different types of water filter products used & how they are monitored and maintained over time. Nevertheless, water flow should remain forceful & consistent through water filtration pipes to minimize microbial adhesion & the risks associated with biofilm formation.


Sterilizing Agent


When using a pure steam generator as a sterilizing agent, the design should be correctly purified. Additionally, these agents of sterilization should be designed & validated to confirm steam quality meets both chemical levels and endotoxin levels. For the same reason, measure your steam quality for any additional additives that can cause either contamination of your product or manufacturing equipment.


Central Vacuum System


Understanding when gases come into contact with the product or container surfaces is critical during process design. For example, here are process design concepts to validate proper chemical, particulate, and microbial quality:


  • Relevant parameters (e.g. oil and water content) should be specified in the documentation
  • Consider the use cases inside the facility & type of gas being used during the process
  • Respect the gas generation system & if the design complies with the Pharmacopoeia monograph


Gases used in aseptic processes should always be filtered through a sterilizing filter. If your sterilizing filter is used on a batch basis, consider integrity testing the results during batch certification. Finally, any backflow from vacuum systems or pressure systems can produce hazards to the product. Have your quality team consistently review the mechanisms that prevent backflow when the systems are shut down.


Hydraulic Systems


Manufacturing equipment connected by hydraulics or heating & cooling systems, when possible, should be preferably outside the filling room. Equally important, pump hydraulics or fluid hydraulics located in the filling room should include design controls to contain any spillage. Leaks from these types of systems could pose a contamination risk to the product that should be detectable.


Finally, incorporating an indication system can help monitor leakage scenarios where contamination can become an urgent problem. This can include manufacturing technology such as tank gauges, a tank level sensor, and advanced water level monitor functionality. 


About Regulatory Compliance Associates


Regulatory Compliance Associates (RCA) provides life science consultants & consulting services to the following industries for resolution of compliance and regulatory challenges:


Life Science consultants


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. Our life science consultants 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
  • 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 healthSotera 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.


About RCA’s Pharmaceutical Consulting 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. 


Client Solutions


Whether you’re in the product planning, development or pharmaceutical lifecycle management stage or need a remediation strategy for a compliance crisis, RCA® 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


Regulatory affairs is Regulatory Compliance Associates 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


Compliance Assurance


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 Regulatory Compliance Associates, we offer the experience and resources necessary to guide you in quality compliance.


  • Assessments
  • Audits
  • Regulatory Agency Response
  • Preparation and Training
  • Inspection Readiness


Quality Assurance


Regulatory Compliance Associates 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 life science consultants 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 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 Medical Device Consulting Services


The regulatory process surrounding the medical device industry involves a strict adherence to pre/post market compliance throughout a device’s life-cycle. Even a single compliance issue you have can turn into a significant effect on your business. RCA®‘s medical device consultants can help guide you through any stage of this strategic process, with capabilities during product development through the regulatory clearance/approval of your product.


Our team of over 500 life science consultants — including former FDA officials and other leaders in the field of medical device regulation — will work with your company to create a quality assurance and regulatory compliance approach tailored to your products and regulatory needs. RCA works with both international Fortune 100 companies and small local start-ups, as well as law firms requesting remediation for warning letters, 483’s, import bans or consent decrees. We offer expertise in a variety of medical fields, such




For medical device manufacturers, technology can be a double-edged sword. The innovative technologies that elevate the quality of life for patients can also be used to potentially undermine the organization using the device. The consequences can affect the device itself if we do not implement good IoT cybersecurity and FDA cybersecurity protocols. At Regulatory Compliance Associates®, we offer a wide variety of services for medical devices security to help ensure that your product is protected from cyber-attacks.


With a well-planned design, along with full visibility of product development and the supply chain, RCA can help strengthen your device’s cybersecurity posture throughout. We partner with medical device companies for the entire life cycle, including from the development of your product to the regulatory submission to your notified body.


Regulatory Affairs


Regulatory affairs is Regulatory Compliance Associates® ‘s backbone, and we handle more submissions in a month than many manufacturers do in a lifetime. We have experience working with the FDA, global regulatory bodies and / or agencies, and notified bodies worldwide. Therefore, you can count on us for in-depth and up-to-date insights which increase speed-to-market.


As a trusted regulatory affairs consultant, our FDA veterans and industry experts are here to help you navigate the difficulties associated with new product submissions. They have expertise in both the approval process and post-approval support. 


  • New Product Approval
  • Post-Approval Support
  • Outsourced Staffing
  • EU MDR


Compliance Assurance


Increasingly, life science companies are feeling the pressure of greater scrutiny by regulators, and responding by developing sustainable compliance strategies. Whether it’s preparing for an audit, developing a response to an FDA finding, or remediation to an adverse event, Regulatory Compliance Associates® Inc. can help.


Our network of over 500 FDA, Health Canada & MHRA veterans and industry professionals offers a unique blend of expertise that allows us to handle both simple and complex regulatory compliance challenges within the medical device industry.


  • Gap Assessments
  • Internal Audits
  • Employee Training
  • Notified Body Response


Quality Assurance


Regulatory Compliance Associates®‘s Quality Assurance services include quality system assessments, strategy, implementations, and identification of quality metrics to ensure continuous improvement, aligning with your business needs and goals. Our life science 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.


In the medical devices field, quality assurance (QA) is more than merely ensuring the quality of a finished product. You need the tools to monitor and regulate every process from the design of a new product to continued quality compliance as the device is sent to market. At RCA®, we offer you the assistance you need to monitor these processes and ensure quality compliance every step of the way.


With more than 20 years of experience as a trusted medical device quality assurance consultant, our team of over 500 industry Experts are fully equipped to handle your unique QA needs.


  • ISO13485 
  • 21 CFR 210
  • 21 CFR 211
  • Outsourced Staffing
  • Facility Validation
  • Equipment Validation


Remediation Support


Regulatory Compliance Associates® is widely recognized within the life science industry and global regulatory agencies for its ability to help companies successfully resolve complex regulatory challenges, including remediation. With a proven track record of success, we have significant experience with the development of responses to 483 Observations, Warning Letters, Untitled Letters and Consent Decrees.


Our value goes beyond the initial response by helping companies successfully execute their action plans, develop an improved compliance culture tailored to the needs of their business, and ultimately move beyond the regulatory action to emerge as a stronger business. We negotiate difficult demands of remediation with insight and the clear advantage of our unique expertise and experience that makes partnering with RCA® Inc. a competitive differentiator in the remediation space.


  • Quality System
  • Technical File
  • Design History File
  • Data Integrity
  • cGMP 


Strategic Consulting


Whether it’s a strategy, a technical plan, or project, Regulatory Compliance Associates® life science consultants can help ensure a successful mix of people and product so your project is on time, on budget, and you’re never embroiled in a costly mistake.


Our 500 industry Experts are here to provide the unique insight you need before an M&A deal. RCA can assist during a staffing crisis and in every area of your product’s development and life cycle. As the trusted medical device consultant for global clients, we have the expertise to deliver exceptional results for your business.


  • Manufacturing Optimization
  • Product Lifecycle Management
  • Mergers & Acquisitions (M&A)
  • Due Diligence
  • Device Vigilance
  • Product Complaints
  • Medical Information


To begin the Regulatory Compliance Associates scoping process today, please enter your information in the blue form below and click the submit button at the bottom of the webpage. 



Our website uses cookies to give you the best possible experience.

By continuing to use this site, you agree to the use of cookies.
Privacy Policy