The Devil is in the Details – Trouble Shooting for Biopharmaceutical Products

by Karl Heller

Hell is freezing over: a manufacturing process runs smoothly maybe for years, and then all of a sudden, you’re hit by an OOS! And of course, it is your blockbuster product and you (supposedly) haven’t changed anything in your manufacturing! Worst case!

What are the immediate consequences of that?


The affected lots are put on hold => the clock starts to tick on their expiry date


Production halted => your facility is sitting idle although you’re fully booked as you most likely will not be able to reschedule your manufacturing short term


Impact on your internal capacities in all affected departments => from media prep, manufacturing, QC, fill finish and packing up to supply chain and QP: staff is either (best  case) busy closing out the OOS (e.g. investigations), dealing with   the consequences (e.g. rescheduling of work trains) or (worst case) remanufacture the product.


Reputational impact => your inability to deliver to your customers will not make them happy


strong financial impact => this will give you a very nervous senior management, as it not only creates a gap in turnover, but also significant costs for the investigations

All this means that your Investigation needs to be very well planned and efficiently executed.

What areas should you look at in your investigation?

Depending on the nature of the OOS, you really should look at every aspect of your manufacturing, e.g. seed materials, media preparation, upstream processing, downstream processing, analytical methods and fill finish. Gather your investigation team with representatives from each of those departments. Allow sufficient time for your staff, your investigation will be very time consuming, especially at the beginning.

What are the appropriate investigation activities?

For a thorough investigation you will have to review the historic data of the product, the complete batch documentation, operator’s shift plans, raw materials; possibly you must perform additional experiments in R&D and/or QC and you might want to have Quality on the floor at all steps of the process. Consider this already when you prepare a budget for your investigation, it can become quite costly.

What can be the outcome?

The outcomes from the investigation can have a huge variety. The root cause for the OOS can either be found in the production itself or in the analytical test. The most obvious findings can be e.g. a new batch of raw material, a new piece of equipment, a malfunction of an existing device or a power outage during manufacturing/testing.

Definitely less obvious are usually OOS results which are linked to human operators. It can range from making a wrong entry into a batch record through to a practical handling error all the way up to “misinterpretation” of SOPs or batch records. Very often this happens when an experienced operator, who has performed this task for a long period, retires or leaves the team, and due to her/his experience the SOPs or batch records have not been written in a way that “misinterpretation” can be excluded.

Classic examples are for instance dissolution of substances (do I add the liquid on the dry substance or do I add the substance into the liquid?) or adjustment of pH (do I use plain acid / base to adjust the pH or the acid / basic component of the buffer system, respectively?).

How can you optimize the troubleshooting exercise?


Prevention is the key – ensure all your important steps during manufacturing and QC testing are described and captured as detailed as possible, this will make your processes less operator dependent. Don’t give “interpretation” any room

Risk Assessment – make sure you have captured all critical steps in your risk  assessment, it will help you to better understand your processes and to identify the root causes of any OOS occurring


Communication – make sure you keep all departments involved and ensure comprehensive cross-communication throughout the whole investigation


Do not leave ANY stone unturned – even if it appears to be very obvious in the beginning, sometimes the devil is in the details; if you make assumptions, do not just assume them, prove them


Think outside the box and think the unthinkable -Do not only look on the hard facts; although it is very tempting for people in biotech or pharmaceutical companies to look for scientific explanations, in many cases it can go far beyond that line