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.




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:


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.


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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® biotech consulting global team can help.


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Quality Assurance


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 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.


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Regulatory Compliance Associates® Inc. 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.


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Whether it’s a corporate needs analysis, corporate growth / transformation strategy or due diligence / acquisition, Regulatory Compliance Associates® Inc.’s 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.


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About RCA


Regulatory Compliance Associates® (RCA) provides regulatory compliance 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.


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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.


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