Services: Biologics

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Biologics Manufacturing: Design & Build Out

Client Challenge

A European based company engaged in biological drug development was involved in an enormous undertaking when they contacted RCA. They were in the planning stage of a biologics manufacturing build for a new facility intended for their entire biologics production.

 

RCA Approach

RCA supported the design and assisted in the build out of both their microbiology and physical chemistry laboratories to support its up- and down-stream fermentation process.

RCA was contacted to provide the subject matter experts to review the conceptual designs for the following areas and supporting utilities; Facility; HVAC and cleanrooms; Compressed Air; Purified Water System; Extension of existing clean gases (N2, CO2 and O2); Extension of existing Water for Injection System; Environmental Monitoring System; Building Management System; Extension of Clean Media Automation System.

  • RCA completed the design review and documented their findings in the form of a report. Items reviewed were listed as was the compliance status and risks. Noteworthy results of this engagement included:
  • Recommendations for segregation of manufacturing activities, including pre- and post-viral inactivation sections analyzed with regard to air-handling systems, as well as movement of materials and personnel.
  • Recommendations and findings for the GMP Water systems supporting each stage of the biologics facility manufacturing process.
  • Recommendations and findings for the GMP Clean Steam systems supporting each stage of the manufacturing and sanitization processes.
  • Review and recommendations regarding the Site Validation Master Plan.

 

Results

The outcome was a GMP compliant facility ready to undergo an FDA inspection. Jump forward to the present and the facility is now producing engineering batches.

In a subsequent engagement, the client asked RCA to provide interim temporary staff for a 3-month period. The positions RCA assisted the client with in terms of staff augmentation included, an Acting Director of Quality Assurance whose responsibilities were to review and approve the QMS policy and procedures, handle validation and qualification efforts and inspectional readiness.

Next was a Project Manager to report to the Quality Director. Key responsibilities included: development and maintenance of project schedules, tracking and reporting progress, roadblocks, etc.

Additionally, we placed a Quality Control Scientist to report to the Quality Director of the biologics facility. Their role was to develop methods and operational practices for QC labs, training QC staff as required and assist in the design and implementation of qualification studies, including environmental monitoring programs for all technical systems.

 

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. 

 

 

Biologics Investigation

biologicsContract manufacturing organizations that manufacture traditional and biotech pharmaceutical products are responsible for performing investigations and reporting the results to their clients. But how do biologics consultants recognize the differences between performing an investigation of a biologic product versus pharmaceutical products?

 

Biologics Manufacturing

 

The short answer is there is no process difference when performing deviation investigations for traditional pharmaceutical products vs. biologic products. The differences lie in the complexity of the manufacturing processes. Further, these are the variables that should be considered regarding what could impacted the deviation.

 

Biotechnology Process

 

Chemical processes, although sometimes quite complex, often have fewer variables even though many of the categories are the same. For instance, when investigating an unknown impurity in a biological process from an oligopeptide fermentation process, the considerations are many. This often includes understanding the fermentation conditions, such as time, temperature, oxygen uptake and byproduct production.

 

Contamination

 

Moreover, potential contamination of reactants can include master cell banks and fermentation reagents, equipment integrity, and overall performance. Further considerations for the downstream purification process variables and the effect of a final configuration (e.g., folding) also need to be considered.

 

The purpose of a deviation investigation is to determine why the deviation happened and what its impact was on the product quality. To determine the impact of the deviation on biotechnology engineering in general, it is critically important to find the deviation root cause.

 

Root Cause Analysis

 

Conducting a root cause analysis is especially important when considering the COVID-19 pandemic and global impact on biological matrix supply chain. Small cap or start up biologics companies have virtually no room for production errors in this type of environment. For example, patients may be waiting for biologic medications and any production interruption can impact more than just the manufacturer. 

 

The process used in the industry to determine root cause is, of course, the investigation procedure. This procedure, regardless of whether the product is biotech or traditional, should require the investigator to review various production systems. Equally important, the system review during the investigation should help determine whether they were the cause of the deviation under investigation.

 

Engineering Validation

 

Every biologics consultant understands it is important to remember when performing an investigation to keep in mind a few general rules. Naturally, one size does not fit all. Simple errors require simple corrections while serious deviations require broader investigations. Validating the investigation is related not only to the seriousness of the deviation but also to the complexity of the factors that could influence the outcome.

 

Fishbone Diagram

 

The best tool to have during any investigation is inquisitiveness. Continuing to ask questions and avoid assumptions will lead to a better outcome. Using other tools, such and fishbone diagrams and determination of most probable number (MPN), are always encouraged. Undeniably, they do not take the place of a biologics consultant asking questions.

 

Biologic Performance

 

In performing an investigation, it is important for the biologic investigator to widen their performance perspective and look for ways to relate similar issues. The best way to ensure events are not related is to try and relate them, not the other way around. Keep in mind that human error is rarely a true root cause. There is usually something in the process that causes that human error.

 
And finally, always verify the facts of the investigation. It is also important to include a historical review. This review should determine if the deviation occurred with this or other products, with the specific manufacturing line or other manufacturing lines, and/or with the operators.

 

Biopharma Tools

 

The historical review can help to prioritize the resources and detailed system review. In addition, many biopharma companies make use of tools (fishbone diagram, MPN) to help prioritize resources. These tools, if used correctly, can be helpful in determining root cause. However, keep in mind they are just tools and do not take the place of thinking.

 

The detailed investigation should include a review of various systems. The systems most often reviewed are equipment and machinery, the manufacturing process, the raw materials used in manufacturing, the specifications, the environment, and finally, the operators.

 

Finally, this is not to imply that these systems are the only areas you should look at during the investigation. These are simply the most probable areas where you will uncover the root cause of the deviation.

 

CAPA & Corrective Action

 

Each investigation must address the following elements: root cause, impact to the material or product, the immediate correction taken, the corrective action to prevent re-occurrence for specific product/operation, and the preventive action taken to prevent re-occurrence for all products/operations.

 

Once these elements have been investigated, results from the investigation must be documented. The written narrative should clearly explain what happened, when it happened, and who was involved or observed what happened. The narrative documents the solution and rationale for the root cause that was determined through the investigation process.
 

Quality Assurance

 
The key to any successful investigation is not assuming you have the solution prior to completing the investigation. Increase your quality assurance and compliance by asking questions until you can think of no more questions to ask. Be sure to document the answers to your questions.
 
 
If you follow your investigation procedure and thoroughly document your results, you should have an acceptable investigation regardless of whether you are manufacturing a traditional product or a biotech product. 

 

 

BioPharm International
Vol. 28, No. 11
Page: 46–47

 

About RCA’s Biotechnology Services

 

Regulatory Compliance Associates® Inc. 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 services include:

 

Client Solutions

 

Whether you’re in the product planning, development or pharmaceutical lifecycle management stage or need a remediation strategy for a compliance crisis, Regulatory Compliance Associates will guide you through every pharmaceutical consulting step of the regulatory process and create a customized approach depending on your product and your pharma company’s individual needs. Our regulatory compliance clients include:

 

  • Companies new to FDA, Health Canada or EU regulations and regulatory compliance
  • 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 pharmaceutical consulting firm expertise in the remediation of warning letters, consent decrees, 483’s or import bans

 

Regulatory Affairs

 

Regulatory affairs is Regulatory Compliance Associates backbone. We exceed other pharma consulting companies with industry experts experienced in complexities of the pharmaceutical and biopharmaceutical industries. Our pharma consulting 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 regulatory compliance services with insight, hindsight, and the clear advantage of our breadth and depth of knowledge and regulatory compliance consulting. We offer the following pharma consulting regulatory affairs services for pharmaceutical companies.

 

  • New Product Support
  • Product Lifecycle
  • Other Regulatory Services
  • Combination Products

 

Compliance Assurance

 

The regulations process surrounding pharmaceutical companies can be tricky for even the most experienced industry veteran to understand. Just one misstep could mean significant and lasting consequences for your business. At Regulatory Compliance Associates, we offer the pharma consulting experience and pharma consultants necessary to guide you through the quality compliance process.

 

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

 

Quality Assurance

 

Regulatory Compliance Associates Quality consulting includes assessments, strategy, implementations, staff augmentations, and identification of quality metrics to ensure continuous improvement. Our pharma consultants understand the strategic thinking needed to align your business needs and goals. Regulatory Compliance Associates quality assurance services include quality experts with experience spanning major corporations and start-ups. Our pharmaceutical consulting firm knows firsthand how to achieve, maintain, and improve quality, and we excel in transferring pharma consulting knowledge to your organization.

 

  • 21 CFR Part 11
  • Data Integrity
  • Manufacturing Support
  • Facility Support
  • Quality Metrics

 

Remediation Services 

 

Regulatory Compliance Associates has a proven remediation services approach to managing FDA Warning Letters, Consent Decrees, Remediation and other serious regulatory situations. Our pharma consultants know how to partner with executive, legal, and communication teams. Each RCA pharma consulting Expert will develop a response that will be accepted by the regulatory agency and be realistic to execute.

 

Regulatory Compliance Associates pharma regulatory consultants will develop a comprehensive proof book of documented evidence demonstrating the corrective action taken to remediate non-compliant issues. In addition, each Regulatory Compliance Associates pharma consulting Expert understands compliance enforcement. We’ll prepare a comprehensive pharma consulting strategy to assist in your remediation efforts, drive continuous improvement, and maintain regulatory compliance with the regulations.

 

  • Regulatory Action
  • Regulatory Compliance
  • Regulatory Enforcement
  • Warning Letter
  • 483 Observation
  • Oversight Services
  • Risk Management Plan

 

About Regulatory Compliance Associates

 

pharmaceutical consultantsRegulatory Compliance Associates® (RCA) provides pharmaceutical 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 5,800+ customers in over 50 countries, including 40 of the top 50 medical device companies and 9 of the top 10 pharmaceutical companies.

 

Commitment to Quality

 

Our Certificate of Registration demonstrates that our Quality Management System meets the requirements of ISO 9001:2015, an internationally recognized standard of quality.

 

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. 

 

Expert Witness Services

At Regulatory Compliance Associates®, our consulting team of experts can assists Law firms in helping their clients with legal challenges. Our solutions include quality protocols, operation efficiency, getting products to market, federal acquisition regulation by executing due diligence, as well as GMP and GCP remediation enforcement responses.

 

Regulatory Compliance Associates® has been an Expert Witness for clients providing product regulation compliance and quality for pharmaceutical and medical device operations. As an Expert witness, we can ensure that you and your clients have the right expert for each case.

 

Meet Your Expert Witness

 

Steven J. LynnSteven J. Lynn, Executive Principal Consultant for Regulatory Compliance Associates® has over twenty (20) years of quality and regulatory compliance-related experience in the pharmaceutical, biopharmaceutical, medical device, blood, plasma, and tissue industries.

 

Prior to joining Regulatory Compliance Associates®, Steve served in executive leadership roles with global accountability in both the private sector, as well as at the US Food and Drug Administration (FDA). His professional experience includes:

 

  • Food & Drug Administration
    • Center for Drug Evaluation and Research (CDER)
      • Director of Office of Manufacturing and Product Quality (OMPQ)
      • Office of Pharmaceutical Quality (OPQ)
        • Operations Transition Lead 
    • Office of Regulatory Affairs
      • Director for Office of Medical Products and Tobacco Operations (OMPTO)
      • Office of Operations
        • Senior Advisor to the Assistant Commissioner for Operations (ACO)
  • Novartis AG
    • Global Head of Group (Corporate) Compliance and Audit
  • Mylan, Inc.
    • Vice President of Global Quality Compliance

Click now to read Steve Lynn‘s executive bio.

 

Regulatory Compliance Associates® can help your client who either has to remediate a problem that they’ve self-identified or a problem that a Health Authority (ex: FDA) has identified in an inspection. We have the ability to get you the help you need within the tight response window each regulatory body provides.

 

We can also provide assistance with transitioning to new or updated regulations such as the European Medical Device Regulations (EU MDR), In-vitro Diagnostic Regulations (IVDR), and the European Territorial Cooperation (ETC).

 

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. 

 

Biosimilar Drug Development

Client Challenge

A European based company engaged in biosimilar drug development requested RCA to develop a regulatory strategy, whereby they could seek approval for their drug in the US and EU. A major challenge was that the client wanted to utilize the data from a recently completed Phase III clinical trial conducted entirely outside the US and not under an IND.

RCA’s regulatory affairs team confirmed that CDER’s Office of Biotechnology would have jurisdiction. After reviewing all current FDA guidance, RCA proposed that the client request an initial advisory meeting as this would be their first contact with FDA.

 

RCA Approach

The first hurdle to overcome was verification that clinical data met cGCP, cGMP and FDA regulations and guidance documents pertaining to Use of Foreign Clinical Data. Since the client did not originally intend to seek FDA approval, they adhered strictly to the EMA approach which is different.

 

FDA Regulatory

RCA supported the Client as they retrieved copious amounts of records and documents. Slowly, adequate documentation was sorted from that generated, to conform to EMAs similar but different requirements. When reconstructed, this documentation essentially met FDAs requirements for cGCP.

regulatory compliance

 

Biological License Application

The next hurdle was to pull together a briefing package on behalf of the client to support an Initial Advisory Meeting request. As the client was in the process of preparing a Biological License Application in Europe at the time, substantial Safety, Efficacy, Pharmacology and Bioanalytical data were available.

 

Reference Listed Drug

The client had substantial bioanalytical data comparing their biosimilar to the European marketed reference listed drug (RLD). Generation of comparative bioanalytical data that could be used to build a bridge, to the US RLD drug, was still on-going.

 

FDA Submission

RCA submitted an FDA briefing package on behalf of the client. FDA rejected the meeting request based on insufficient bioanalytical comparison data between the clients biosimilar and the US RLD. Over a four- month time period the client was able to generate additional bioanalytical comparison data to the US RLD.

 

FDA Meeting

RCA updated the original briefing package to include additional data and resubmitted another meeting request. This time the meeting request was granted. However, due to the extensiveness of the supporting data presented in the briefing package, FDA offered the option to the client to convert the advisory meeting into a BPD type II meeting request. As a result, the client saved a significant amount of time towards their goal of filing a BLA in the US.

 

Results

The outcome of the meeting request with FDA is being withheld at this time to maintain confidentiality for our client.

 

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. 

 

 

Regulatory Due Diligence

At Regulatory Compliance Associates, our team of experts help investors make better pre-acquisition decisions by executing regulatory due diligence, evaluating revenue expansion, and cost saving opportunities to help determine a target’s transaction value.

 

Due Diligence 

 

Previous clients have recognized Regulatory Compliance Associates® for offering the same investigative exercises that guide a Private Equity firm toward the proper judgment about proceeding with acquisition and how to negotiate the best deal price. We appreciate a refined approach to deal making and can you’re your entire deal team through each stage of the deal flow.

 

Regulatory Compliance Associates can help your team develop an integrated FDA viewpoint that lets Healthcare buyers develop a sensible viewpoint of the true story beyond the balance sheet. The regulatory due diligence benefit to your team is we’ll show you the asset value of what you’re buying, both tangible and intangible.

 

 

Regulatory Due Diligence

 

Environmental, Social, and Governance (ESG)

 

Environmental, social, and governance (ESG) investing is a set of standards used by socially conscious investors to conduct due diligence. Regulatory Compliance Associates has supported clients from around the world with their ESG programs and due diligence requirements. As sustainable investing continues to become more important in modern society, our regulatory consulting Experts can help you understand how to validate your environmental social governance strategy.

 

Further, the compliance process outlined in your environmental social and governance requirements can be accelerated by the due diligence consultant expertise Regulatory Compliance Associates provides. These are examples of ESG consulting services that RCA provides for global life science clients.

 

Social

  • Supplier Quality Assessment
    • Do your suppliers follow the corporate ESG standards set by your company?
  • Compliance Assessment
    • Are workplace conditions for employee health & safety currently compliant with ESG guidelines?

 

Environmental

  • Gap Assessment 
    • Does your company use accurate and transparent compliance processes for an ethical supply chain?
  • Internal Audit
    • Is your company accountable for following the mission & vision communicated to shareholders or investors? 

 

Governance

  • Change Management Assessment
    • How likely are your employees to pursue integrity during the product development or manufacturing process?
  • Transparency Assessment
    • Would your employees truthfully participate in a corrective and protective action (CAPA) program?

 

Since 2000, thousands of companies across the world have trusted Regulatory Compliance Associates® to care for their unique regulatory compliance needs. Our expertise is backed by more than 500 professionals, including FDA veterans and other subject experts who are here to guide you through every step of the regulatory compliance process. Whether you’re a Fortune 100 company or a small enterprise, trust Regulatory Compliance Associates to partner with you to tailor an ideal compliance services solution.

 

 

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. 

Additional Services

Regulatory Compliance Associates has the healthcare consulting experience and insights to guide Biologics through their entire lifecycle. We help companies navigate complex regulations for Combination Products to increase their successful launch and steer Compounding Pharmacies down the complicated path of compliance.