E-Lesson 1
Starting Off Right: The Problem Statement

Let’s face it: no one likes writing investigations.

You’re always doing them in a rush, because you’re busy with your ‘real’ work, and you may not be sure how to write a good one—right?

Why then, considering the pressures and time constraints you are under, should you take the time and make the effort to do these e-lessons?

It’s simple.

Doing these “e-lessons” as the first phase of our training program will help you write investigations more effectively and easily.

Better Means Fewer, and Fewer Is Better

Obviously, writing better investigations means fewer investigations to write. Better investigations solve problems so that they don’t happen again. That means improving processes and procedures and having fewer deviations. And you’ll like having fewer investigations to write (and best of all, it will save you a lot of time).

So we hope you’ll stick with us through these five short e-lessons brought to you by Working Words before we meet all of you in person. You can read them at your own pace and then answer the questions provided at the end of each one. This will help all of us “get on the same page” before the group training.

In the training, you’ll be introduced to a new investigation template provided by Working Words. Knowing how to write the sections of the template correctly and thoroughly will help speed you on to better investigations (and less time spent on them).

The examples presented in the e-learning text and in the homework are general and represent types of materials, equipment and processes found throughout the pharmaceutical industry in companies with similar product lines as yours. They are intended to illustrate the key points of the lessons, so don’t worry if they don’t exactly reflect your company’s products, equipment or processes. In the examples, we’ve changed the product name to “Ducarase Solution for Injection, 5 mg/mL” and “Ducarase Concentrate for Infusion,” imaginary sterile injectable products, so you won’t be distracted by too-familiar details. However, as you will see, we have included your own investigations in the face-to-face training and in Lesson 2.

This puts you in the position of “the educated, but less informed reader.” Your typical audience for an investigation is also in that position: the person outside your department—including the FDA—who may not know the details of your procedures and processes.

What the E-Lessons Will Cover

In this lesson and the four that follow, we’ll help you better understand:

• how to write an effective problem description
• how to think through the analysis required in an investigation
• how to get to root cause
• how to consider other material that may be affected by the problem
• how to determine effective corrective and preventive actions.

The Making of a Good Problem Statement

The problem statement is the first thing the reader sees. If you write a complete, concise, and clear problem statement, you let the reader know that—although something occurred that was out of specification—you are in control of the details of what happened.

So what is a good problem statement?

Let’s start with the definition of a problem (deviation) requiring an investigation:

Any out-of-specification (OOS) analytical result or any deviation from established procedures during manufacturing, processing, testing, or holding that may affect quality, purity, identity, safety, or efficacy.  For an OOS analytical result, there must first be a lab investigation, followed by a manufacturing investigation if no laboratory-assignable cause is found.

In order to write a good problem statement, you should:

Write exactly what you knew at the time of the event:

  • What test result was out of specification, or
  • What happened that did not conform to standard operating procedures.

But not what you think:

  • might have caused it, or
  • what you learned after the event.

In addition, explain how the deviation was discovered.

For example, if you review a batch record and a jacketed mixing tank temperature chart shows:

  • A temperature of 61.8°C…
  • For a period of 45 minutes…
  • Although the temperature range established for the process is 47±5°C

The deviation is:

The temperature (61.8°C) exceeded the process range (42-52°C) for 45 minutes (see chart Y).

The elements required in the problem description are:

The product identity (name, lot and batch number);
The date it happened (and the date it was discovered, if different);
What was out of specification (and what the specification was or what should have happened);
Where in the process it happened (if known); and
How it was discovered.

So a complete problem statement for the previous example would be:

Batch record review of Ducarase Solution for Injection, 5 mg/mL Lot 123456 on March 6, 2017 discovered the temperature on chart Y (61.8°C) exceeded the maximum (52°C) for 45 minutes from 0857 to 0942 on February 15, 2017 during the mixing step.

After you have clearly described the problem, it’s also important to let readers know what you did in response to discovering that problem. In most report forms, this information is captured in a separate section of the form. In the Working Words template that will be presented in the two-day training, we call this section the “Immediate Actions Taken.” A description of the Immediate Actions Taken must show:

The steps you took –

  • To isolate any possibly affected product and/or
  • To stop the event.

For example:

Ducarase Solution for Injection, 5 mg/mL Lot 123456 was quarantined and an investigation was initiated.

Applying the Criteria

Let’s look at three common flaws in problem statements:

(1) not enough information to describe the incident or test result completely and clearly;
(2) too much information so the reader gets lost;
(3) a description contaminated by assumptions about the cause of the problem.

The Not-Enough Problem Statement

Remember that not everyone who might read your report knows as much as you do.
Write down enough information so no one has any questions later.

What about the following problem statement?

One replicate was within specification and one was out of specification.  Results were 98.6% and 97.9%.

Which one is out of specification? Without knowing the specification, it is impossible to tell! If the specification is ³95.2% and ≤98.5%, then 98.6% is the out of specification result. But if the specification is ³98.0% and ≤100%, then 97.9% is out of specification. The product identity, name of the test, and test date also should be included, even if the information appears in the header of the report.

Does this description meet the criteria?

Balance failed calibration.

What balance? And what calibration? A scheduled calibration? Last calibration? What product and balance location and use? Well, it almost meets the criteria: if you already knew what had happened, you could probably fill in the missing blanks. But if you weren’t there, you don’t really know what happened, do you? What the writer probably meant to say was:

On October 14, 2017 during scheduled monthly calibration check, Balance S789 used to reweigh Ducarase HCl drug substance drums was out of calibration.  The last calibration was September 17, 2017.

The Too-Much Problem Statement

Saying too much is no better than saying too little. Don’t describe the process in the problem statement: you can supply background information in the investigation section if your reader needs it.

Just describe what happened this time, without adding details that aren’t directly related to the event itself or speculating about how it happened.

The goal of writing a problem statement is to define the problem so it is clear, but confined to the single, observable event that caused an investigation to have to be written.

Consider the following problem statement:

Upon entering the manufacturing room at 0700 on November 9, 2017, the operator noticed that the mixer on the Mixing Vessel # MV3 was turned on and that the vessel was empty except for some condensation on the sides of the vessel.  The mixer spindle and bearing could be damaged if run while the vessel is empty.  Although the vessel was empty at 0700, the mixer had been submerged in liquid during initial sanitization, allowing adequate lubrication of the bearing and spindle as described in Manufacturing SOP MFG-49-563 entitled “Operation and Maintenance of Mixing Vessels in Manufacturing Areas.”  The mixer speed was approximately 30-40 rpm.  Ducarase Solution for Injection, 5 mg/mL  Lot 987987 was being manufactured in Room 3.  It was the second batch in a three-batch campaign to re-supply Phase 1 material.  This was a deviation from Manufacturing SOP MFG-49-563 entitled “Operation and Maintenance of Mixing Vessels in Manufacturing Areas,”  Section 7.3.4 which contains a note stating that the mixer should not be operated in a dry condition.

What is the initial observable problem or deviation? The problem appears at the beginning, with the specification at the end. Is the explanation in the middle appropriate here? With all the additional information, it’s hard work to retrieve the pertinent thoughts. Also, the long SOP references get in the way of the narrative flow. Do we need to know the SOP title and section yet? Instead, these could be referenced in the methods section of the investigation. And, we certainly don’t need to see the SOP number and title twice!

A more concise version:

Around 0700 on November 9, 2017, the operator noticed that the mixer was running in the empty Mixing Vessel #MV3 in manufacturing Room 3.  Manufacturing SOP MFG-49-563 contains a note stating that the mixer should not be operated in a dry condition.  The vessel was being prepared to manufacture Ducarase Solution for Injection, 5 mg/mL Lot 987987.

The Contaminated-with-Conjecture Problem Statement

Until you actually investigate, you do not know what caused the problem, even if you think you know what must have caused it. Don’t guess why it happened, but give a complete statement of everything you knew or observed when it happened, including how it was discovered.

What’s wrong with this problem statement?

It’s missing the product identification and date, but that’s easily fixed.

The words “because” and “again” are, however, the bigger problem.

“Because” tells the reader you’ve reached a conclusion before you’ve investigated.
“Again” says that you have a recurring problem that you have not fixed.

Be aware of what your words imply, as well as what they say. Read your statement carefully to see whether what you meant to say is what the reader will think you said.

Speculation or conjecture about the cause does not belong in the description of the problem.  Don’t “contaminate” your problem statement with assumptions about root cause.

Here’s an “uncontaminated” rewrite:

Because While John Smith was setting up the next step, he again ran the mixing process for Ducarase Solution for Injection, 5 mg/mL (Lot 987777, April 17, 2017) for 26 minutes instead of 20 minutes as specified in the batch production record. The batch record says run for 20 minutes.

This rewritten description “contains” the problem.

It is the investigation section of the report that will reveal answers (e.g., that John Smith has done this before). At the beginning, though, you want to craft a clear, complete, uncontaminated problem description, so you will avoid confusion in starting down the road to root cause.

Suppose you’re a reviewer. . .

Based on the criteria we’ve given you, how would you rate the following problem statements? Which problem statements have too little information, which have too much, which ones speculate about the cause (are “contaminated”), and which ones are ok? (Please note that some may fall into more than one category.) Underline your ratings and tell us why.

Your Information:

The calculated batch yield was 62.4% which is below the alert and action limits of 85% and 75%, respectively, according to SOP MFG-23-010 “Reconciliation Limits.”
2. The 12-hydroxyducadone impurity result for finished product Lot 987123 was 12 ppm versus a specification of ≤10 ppm. The 12-hydroxyducadone impurity level in the Active Pharmaceutical Ingredient (API) batch used to manufacture the product was also tested and was higher than normal but within the validation parameters. The batch will be rejected.
USP Purified Water use points #2 and #4 located on the first floor and second floor, respectively, of Building E were sampled on February 4, 2018. Later that day, QC obtained a Total Organic Carbon result of 608 ppb for use point #4 which was greater than the specification of less than 500 ppb. The result for use point #2 met the specification. Facilities locked both use points out of service.
Each lot meets current specifications. However, the R&D group pulled a sample from the downstream process for development work. The material did not perform as expected. Subsequent analysis of the three commercial lots 213798, 412798 and 512798 indicated that the pH of each lot was ≥ 10, 10 and 7, respectively.
Work Order WO 2017-10-XYZ was generated to install set screws on glass washer nozzles that are position specific. After consulting with the vendor, the engineer determined that the set screws were not needed because the vendor had developed a new nozzle design. The new nozzles were purchased and installed on the referenced washers. The work order was not rerouted to approve the modified scope of work as required by the current procedure MFG-13-423. The Responsible Engineer left the company before the work was completed.

Now use the information given below to write a problem statement that meets the criteria we’ve discussed and that doesn’t say too little or too much, and is not contaminated by conjecture about why the problem occurred.


How did you do?  In the answers file that you will download after you complete and upload this lesson, we will show you how we think the problem statement should have been rewritten, as well as point out some of the pitfalls you might have encountered.