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Susan J. Schniepp is a fellow at Regulatory Compliance Associates, Inc. and a member of BioPharm International's Editorial Advisory Board.
Investigating deviations or failures of combination products needs to accommodate both the drug and device components, says Susan J. Schniepp, executive vice-president of post-approval pharma and distinguished
Q. I work for a contract manufacturer and am responsible for performing investigations and reporting the results to the clients regarding their drug products. We have recently contracted with a client to manufacture a pre-filled syringe. Can you tell me what changes I should make to my investigation procedure when investigating deviations and complaints for this type of combination product?
A. Overall, the actual investigation process for a pre-filled syringe product should be similar to the process already used by you to investigate the drug products. The purpose of performing an investigation into a deviation is to determine why the deviation happened and what impact it has on the product quality. To determine the impact of the deviation on the product quality, it is important to determine the ‘root cause’ of the deviation. The process used in industry to determine the root cause is the investigation procedure. This procedure, regardless of the product you are investigating, should require the investigator to review various quality and manufacturing systems to determine whether they were the cause of the deviation under investigation. 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. The complication with combination products is that the investigation procedure needs to accommodate both the drug and device components of the product.
It is important to consider a few general rules when performing an investigation regardless of the product being investigated. Remember, one size does not fit all. Simple errors require simple corrections while serious deviations require broader investigations. The complexity of the investigation is related not only to the seriousness of the investigation but also to the complexity of the factors that could influence the outcome.
The best trait to have as an investigator is inquisitiveness. Continuing to ask questions and avoiding assumptions leads to better outcomes. Using other tools, such as fishbone diagrams and determination of most probable number (MPN), are to be encouraged, but they do not take the place of asking questions. In performing an investigation, it is important for the investigator to widen their 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. In addition, you should always verify the facts of the investigation.
Once you develop an investigational history with the pre-filled syringe, you will also want to include a historical review in your investigation. 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 one group of operators or multiple sets of operators. The historical review can help you prioritize the resources and aid in your detailed system review.
In the situation you described, you can provide a historical review for the drug component part of the pre-filled syringe, but you will need to outreach to the syringe supplier and your client to start developing the historical review for the device component until you have a body of knowledge for this component. The best way to obtain necessary information for the investigation of the device component is to establish a communication channel between your company and the supplier of the syringe, with your client’s knowledge and approval. It would be wise to codify what information you would like to have access to through quality agreements with both the syringe supplier and your client.
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. This is not to imply that these systems are the only areas you should look at during the investigation but that these are the most probable areas where you will uncover the root cause of the deviation. The raw material or supplier system may need to be updated to accommodate the syringe supplier. Rather than rely on the client’s evaluation and audit of the syringe supplier, it would be beneficial for your company to perform their own audit and assessment and establish a quality agreement. Inform your client that you want to develop your relationship with the syringe supplier to assure their assistance and timely responses for an investigation; make sure you inform your client when you do reach out to the supplier during an investigation. This will help facilitate both your client’s and the syringe supplier’s involvement and open the lines of communication should you require either of their assistance for an investigation.
Once the aforementioned 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. This should also include any action being taken by the syringe supplier should this component be implicated in the investigation.
The key to any successful investigation is not stopping too soon and assuming you have the solution prior to completing the investigation. Ask questions until you can think of no more questions to ask and be sure to document the answers to your questions. If you follow your investigation procedure, make adjustments to accommodate the new component, and thoroughly document your results, you should have an acceptable investigation regardless of whether you are manufacturing a traditional product or a combination product.
Vol. 32, No. 12
When referring to this article, please cite it as S. J. Schniepp, "Investigating Combination Product Failures," BioPharm International 32 (12) 2019.