FDA Publishes Updated Biologics Guidance

FDA Publishes Updated Biologics Guidance

The US Food and Drug Administration (FDA) recently issued final guidance for Biologics industry executives to help define modifications to existing products and update submission procedures.  The primary focus of the guidance is to help biologics industry employees responsible for reporting understand which type of risk category is appropriate for updated variations in chemistry, manufacturing, and controls (CMC).


The guidance is applicable to CMC products with an existing biologics license application (BLA) currently approved by the FDA. It’s a critical update since any Biologics company or regulatory partners must notify the FDA about every change to an approved BLA under the Code of Federal Regulations (21 CFR 601.12).

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FDA submission data


FDA Guidance

The final FDA guidance goes into detail about each post-approval change in the product, including production process, quality controls, equipment and facilities, responsible employees, and established labeling. Expanded submission data will potentially provide greater detail about the the risk profile related to the changes, and how revised changes impact the intended safety or efficacy of the product.


Assessing and implementing manufacturing changes is laid out in great detail in the FDA guidance. Comparability data will be used to show variations of the product pre- and post- changes. The comparability analysis is necessary to help gauge possible effects of the product changes. Data from the analysis will be represented through a variety of sources, including a combination of testing, validation studies, and non-clinical or clinical studies.


FDA submission procedure


More importantly, the guidance provides a greater amount of detail about the updated FDA submission procedure. A significant focus of the guidance acknowledges the opportunity for adverse effects and how to measure and minimize based on data about the revised formulation. The biologic submission must show reference information that considers the new identity, strength of the product, quality of the product, and purity or potency of the product.


The three unique types of Biologics reporting includes Prior Approval Supplement, Changes Being Effected in 30 Days/Changes Being Effected (CBE30/CBE) and an Annual Report:


Prior Approval Support (PAS)

  • This includes changes that have significant potential for an adverse effect on product quality. The PAS must be approved by the FDA before a Biologics company can distribute any updated BLA approved product to the market involving the changes.


Guidance Changes Being Effected in 30 Days/Changes Being Effected (CBE30/CBE)

  • This includes changes that have a moderate potential to have an adverse effect on product quality. The CBE30/CBE requires an applicant to report the change to the FDA in a supplement at least 30 days before distribution of the product to the market.


Annual Report (AR)

  • This includes changes that have a minimal potential to have an adverse effect on product quality.


FDA process validation


Assessing the impact of the change on product quality is critically important in the reporting submission.  Reporting data should include prior knowledge and findings from product development activity. Documentation surrounding process validation activities and manufacturing expertise of the approved BLA product are also requested.


Quality risk management activities or pre-commercial studies that provide expanded awareness of the effects of the changes can also be very valuable for FDA decision makers. Finally, a cumulative impact assessment of multiple changes on the updated BLA product can help ensure post-market surveillance activities are aligned between the FDA and Biologics company.


Quality Management System


References to a robust quality culture appear throughout the guidance, including developing of robust manufacturing processes and process controls. Innovative process validation techniques and analytical testing are listed as critical drivers Biologics companies should practice to help mitigate risks associated with manufacturing changes.


Having an effective quality risk management system allows Biologics industry executives to make knowledgeable choices regarding manufacturing variations. The quality system data increases the confidence of product quality and process consistency for both executives and the FDA. Formal and informal risk assessments to support of post-approval manufacturing changes increases the accuracy of a more effective assessment of the change, which can increase the speed of the FDA’s decision.


About RCA’s Biologics & Biotech Consulting Services

Regulatory Compliance Associates® can assist you in ensuring the quality of your biologics or biosimilar product during its entire lifecycle. From pre-market to post-market reviews, inspection, and compliance, our Biotech consulting experts can shepherd your biologics through design, labeling, promotion, production, and testing. Our Biologics consultants & consulting services include:


Regulatory Affairs


Regulatory affairs is Regulatory Compliance Associates®  backbone and we fully understand the complexities of the biologics industry. Our biotech consulting expertise spans all facets and levels of Regulatory Affairs, from early phase & bioanalytical sciences through late phase and post approval.


  • Preclinical & CMC Consulting
    • FDA Meetings & Briefing Package Assistance
    • Clinical Trial Applications
    • Marketing Applications
    • Medical Writing
  • Lifecycle Management
  • Submission Planning & Strategic Support
    • eCTD Publishing & Submissions
  • Strategic Consulting & Intelligence
  • US Agent
  • Project Management Support
  • Clinical Development Support
    • Clinical Research Organization (CRO) Sourcing
  • Analytical Development Support
    • Bioassay Design & Validation
    • Immunoassay Support
    • Statistical Analysis & Specification Setting


Compliance Assurance


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


  • Assessments
    • Current Good Manufacturing Practice (cGMP)
    • Corrective & Preventive Action (CAPA), Investigations & Deviations
    • Facility & Maintenance 
    • Data Integrity
    • Quality System Gap Assessment
  • Audits
    • Supplier Audits
    • CRO Audits
    • cGMP Compliance Audits: Manufacturing, Pilot Plant, Laboratory
    • cGLP Audits
    • Good Clinical Practices
  • Preparation, Training & Inspection Readiness
    • cGMP Fundamentals (Annual Training Required by Regulations)
    • Quality System Regulation
    • Risk Management
    • Investigations, Deviations & CAPA & Root Cause Analysis
    • Validation & Technology Transfer
    • Purchasing Controls & Supplier Management
    • Document Management & Change Control
    • Audit Readiness
    • Quality Culture & Management Responsibility
    • Data Integrity & Good Documentation Practices (GDP) Centered on How the Data is Recorded, How to Correct an Error, and How to Document the Reason(s) for the Error


Quality Assurance


Regulatory Compliance Associates® Quality consulting services include assessments, strategy, implementations, staff augmentations, and identification of quality metrics. Our biologics consultants goal is to ensure continuous improvement, aligning with your business needs and goals. Our biotech consulting subject matter experts have 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.


  • Quality Management System Implementation
  • SOP Development
  • Document Control Systems
  • Change Control
  • Laboratory Operations & Control


Remediation Services


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


  • Regulatory Action
    • 483 Response & Remediation
    • Warning Letter Response & Remediation
    • Consent Decree Response & Remediation
    • Oversight Services
  • Consulting
    • Comprehensive Audits
    • Remediation Plan Development & Implementation
  • Manufacturing Support
    • Re-validation of Existing Equipment & Processes
    • Remediation of System Deficiencies Related to, Manufacturing Process, Equipment, or Facility 
    • Facility Improvements (Aging Facilities) 


Strategic Consulting


Whether it’s a corporate needs analysis, corporate growth / transformation strategy or due diligence / acquisition, Regulatory Compliance Associates®  worldwide biotech consulting experience can help ensure a successful mix of top-notch advice and people so your engagement is on time, on budget, and you’re never embroiled in a costly mistake.


  • Portfolio Management
  • Mergers & Acquisitions / Due Diligence
  • Staffing Support


About RCA


fda guidanceRegulatory Compliance Associates® (RCA) provides biologics consulting & biotech consulting to the following industries for resolution of life science 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.


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