Crucial Steps for Preventing Batch Failures and Protecting Your Business
Preventing batch failures and protecting your business is crucial to success within the manufacturing industry. Insights from In-Pharmatechnologist.com (dated 4/25/2012) shed light on revelations from the FDA’s 2011 Warning Letter data. According to the report:
“In fiscal 2011, the US Food and Drug Administration (FDA) sent biopharma manufacturing-related warning letters to 52 facilities. Close to half of these included an observation about failure to investigate batch failure thoroughly.”
The article goes on to state that:
“The finding reiterates the point made by FDA speakers at industry conferences that companies should clearly and thoroughly document their procedures and activities. Other companies were warned last year for lacking written rules for investigating out-of-specification results.”
Considering the observations cited and the FDA speakers’ comments, this would seem a reasonably straightforward issue to resolve. How hard can it be to look at what happened during the execution of a batch (i.e., by reviewing the batch record) and determine what happened? How hard can it be to document procedures and activities for batch execution? Doesn’t everyone know how to investigate anomalous results?
Oh, were things so simple?
The reality of batch failures and batch failure investigation is much more complicated. Some existing documents don’t help. Some investigation approaches are often superficial.
Getting to the actual root cause (no, TRUE root cause) is often neglected because it’s tough. Given that reasonable investigations may not be as simple as having “rules for investigating out-of-specification results,” let’s look at two areas often not considered in batch failure investigation resolution.
Table of Contents
Area 1: Specifications
Specification review and analysis should be at the core of reasonable investigations. The question we often ask is: why did our batch fail to meet specifications? We try to find reasons related to subpar raw materials, poor execution, different processing, etc., that make the bunch react differently.
We never question our specifications since to do so during an investigation when a product is in play is a huge red flag for an FDA Investigator. The FDA immediately assumed that financial considerations drove the thinking, leading to uncomfortable conversations.
Unfortunately, the question that is rarely asked outside of an investigation is: Do our specifications align with our process capability? In other words, do we have specifications disconnected from our process capability? The answer to this question is critical for a company to understand.
More importantly, a company’s failure to understand the linkage between specifications and process capability is something I’ve seen repeatedly as one of the actual root causes of batch failures. Put more: When companies set release specifications that are too tight — essentially using specifications for process management/process control purposes — unless your processes are competent and well controlled — you create the significant risk of failing to meet your specifications when, in fact, you may only be experiencing routine process control variation.
Remember: the FDA doesn’t create your specifications — you do. You make the box that you need to live within. Using specifications for process control leads to many more failures than are necessary.
There are many more NCs. There are many more CAPAs. Specifications should be at the boundary beyond which a company will not release a product.
Everything inside that line should be evaluated and considered through control limits, subject to either monitoring, action, or review and decision. Specifications, though, should be binary. Batches either pass or they don’t. Using well-defined specifications with well-understood control limits tied to robust product and process characterization will prevent batch failures and save time, energy, and MONEY!
Area 2: Batch Records and Criticality
Here’s an opening question: What is the intended purpose of a batch record? Answer: A batch record is intended (by the FDA) to provide a documented history of the steps, activities, and accompanying data (whether from in-process testing, weigh steps, process parameter settings, etc) that constitute the entire manufacturing record of a pharmaceutical batch’s manufacture. See 21 CFR 211.188(b).
In essence, a batch record is a crucial compliance tool to document that a defined process was followed in the production of the batch. I didn’t say that the batch record was a quality tool. Why not? Simply because most batch records don’t provide nearly sufficient information — differentiated information — regarding the one or two critical steps in almost any process that, if done correctly, result in a “good” batch of product, and if done improperly (or something else goes wrong) result in a sub-standard or failed bunch of product.
If you look at a batch record or watch QA people audit and review batch records, each step in the end-to-end process appears equally essential. There is never (well, rarely) any differentiation concerning criticality or importance. There is no explanation of the linkage between poor step outcomes and overall batch quality. Further, the tricks and tips that the super-operators always use to get batches perfect are rarely incorporated into the record.
Why not? Well, that’s a good question. Likely, it’s just how it’s always been- our record formats and structure are often derived from legacy, potentially ancient.
However, that needs to change. Batch quality is almost always defined by the perfect execution of the 20% of steps and activities most critical to the quality outcome.
Everything else- material handling operations, weigh steps, label recording, etc.- is oriented towards potency and mix-up prevention, which are admittedly essential topics. But the factors — the measures — the precise activities that significantly impact characteristics like disintegration, dissolution, bioavailability, etc., are often buried in a much more significant step and usually not well differentiated.
So, back to the original topic: Industry’s failure to properly investigate batch failures. Even considering the two preceding focus areas, it is easy to see that developing except (or even just plain good) batch failure investigations are challenging. There are other factors: Time, number of resources, production pressures, etc. — the list goes on and on.
However, given the focus and apparent enforcement tsunami this topic has created, the industry should seize the opportunity to look past traditional approaches to specifications, batch, and investigation documentation and create new, more rational, differentiated, and easier-to-investigate document sets.
Necessary for this is improved product and process characterization and an improved ability to explain what is happening in batch production — and the occasional failure. Together, this should result in better interactions with the FDA and, very likely, a reduced cost footprint due to a reduction in out-of-spec product and associated investigation costs.
Do you need help preventing batch failures in your organization? Contact us for a consultation.
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