Elements of a Thorough Investigation

Nonconformances are an inevitable part of any process. Whether it is in a manufacturing, production or laboratory environment, at some point, you will encounter an observation or result that is contrary to its pre-determined requirements or specifications. In such instances, some type of an investigation will be required. The subject of this week’s blog is to outline some of the elements of a thorough investigation that supports compliance to the regulations and provide some brief examples.

A comprehensive quality system or GMP investigation must be substantiated by documented evidence. Documentation provides the necessary objective evidence to support any claims or findings of the investigation. Documentation is what provides an investigator or auditor, the assurance that the claims that you are making in support of the root cause(s), or corrective action(s) are valid.

Documentation also serves as proof of what element or process or idea that has been eliminated as potential root causes. And in the eyes of an investigator, “if it is not documented, it’s a rumor”. Your investigation packet can contain all of the elements to show how the product was manufactured, packaged, or tested in a laboratory setting; but unless you can show via documented evidence the actions taken and relate those actions back to your investigation, then you do not have the necessary evidence required to support your claim.

What does documentation consist of and what sorts of actions require documentation? Well, Documentation consists of written records that guide activities and prove what has occurred. Documentation in support of an investigation must clearly demonstrate the actions that were taken, when they taken, who executed such actions, as well as the qualifications of such individual. If you recall, personnel qualifications is mandated by both the GMP and QS regulations. 21 CFR 211.25 states the following in regards to personnel qualification:

(a) "Each person engaged in the manufacture, processing, packing, or holding of a drug product shall have education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions. Training shall be in the particular operations that the employee performs and in current good manufacturing practice (including the current good manufacturing practice regulations in this chapter and written procedures required by these regulations) as they relate to the employee's functions. Training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them."

Next, the documentation to support your investigation must clearly show the sequence of events and conclude whether they confirm or eliminate a root cause. This can be easily accomplish by a heading or a brief footer that describes what this data support. It should not be left to the auditor to “guess” at what the data support. They may arrive at a different conclusion than you intended. Be upfront and clear at all times.

Finally, documentation of your corrective actions must not only comply with the points above but must also support your root cause. That is, the documentation that you are including as part of your investigation packet to support the validity of your corrective actions must clearly tie back to your root cause(s). If it does not, the investigation leaves the door open to potential causes that remain unexamined and the possibility that the given nonconformance may reoccur.

Is it really a Training Issue?

When it comes to identifying the root cause of a nonconformance, invariably, training will always be evaluated as a potential cause of the event. While I completely agree that training must always be evaluated as a potential root cause, I must caution the investigator to go further. Going further means not to accept at face value that training is the culprit in every nonconformance event. It means challenging the notion that “training” or “training effectiveness” played a role in the identified nonconformance. It also means having an established guideline / process for measuring training effectiveness within your organization.

Identifying the root cause of a nonconformance as a “training” issue happens very often in the investigation world with little to no supporting evidence to justify this position. I believe that many organizations sign off on these investigations for several reasons:

(1) It is an easy way out—many companies incorporate a 20-working day due date for the investigation which includes: identifying the problem, determining the root cause, evaluating trends, implementing corrective and preventive actions and monitoring for effectiveness of the actions. This extremely limited time period often forces well-meaning investigators and approvers to simply accept “training issue” as a rationale for the root cause of the event.

(2) Organizations do not have a pre-established guideline and/or process for measuring training effectiveness. The question of how does an organization measure training effectiveness is one that many shy away from. Is training effectiveness measured by simply reading the SOP? Is an instructor-lead training the best vehicle to execute training? Is an acknowledgement of “read and understood” for a given procedure equivalent in comprehension to an instructor-lead training?

Before you signoff on your investigation and accept the root cause of the nonconformance as being attributed to “training” or “training effectiveness”, be sure to:

*Evaluate all other potential root cause
*Perform a trend analysis to determine whether there is a trend that may require

further evaluation
*Evaluate your current training program to determine how training is disseminated
and the mechanism for evaluating effectivenessChallenge, challenge, challenge!

Verifying or Validating CAPA

The topic of verifying or validating CAPA is a very important step in the investigation process and one that is often overlooked. Many investigations will adequately investigate the nonconformance, determine the root cause, may identify actions needed to correct and prevent the recurrence of the nonconformance, but will often fall short of the mark when it comes to the verifying or validating the corrective and preventive actions to ensure that the actions taken are effective.

Verification or validation of a corrective and preventive action is mandated by the quality system regulations as defined in 21CFR820.100 (a) (1) (4):

Verifying or validating the corrective and preventive action to ensure that
such action is effective and does not adversely affect the finished device;

What this means is that once you have clearly identified the actions that you need to take in order to correct and prevent this problem, you must take it one step further and verify or validate that the action(s) will in fact work to fix the issue at hand. Why is this an important step in the investigation process?

Well, first of all, investigations are to have what I like to call a “defined lifecycle”. By that I mean:
(1) Identify the nonconformance.
(2) Contain the nonconformance. That is, immediately identify how you are going to contain this nonconformance to ensure that nonconforming product does not enter the marketplace.
(3) Next, you will investigate the nonconformance to identify the root cause
(4) Identify and implement certain actions to correct the nonconformance
(5) Finally, you must validate or verify that those actions will work and will not adversely affect the product

This “defined lifecycle” is supposed to be part and parcel of a clearly defined process that will not only investigate the issue at hand, but also to ensure that when investigated correctly, you should not have a recurrence of this same issue. Hence, the importance of verification or validation of the actions identified in the investigation. Where there is no verification or validation that the actions will work, then the likelihood of a recurrence of this same issue is not only probable, but inevitable.

An investigation is supposed to be a finite event that leads you not only to identify the root cause, but whatever actions are taken should prevent a recurrence of the nonconformance. If it does not, then you can rest assured that there has been a break in the “defined lifecycle” and the nonconformance is likely to repeat itself.