Deviation investigations are a very common topic to be reviewed during FDA investigations. Ensuring the firm has robust and complete write-ups of these situations is key to a successful audit. Having inadequate investigations could potentially cause some severe issues for the company and may sometimes result in warning letters, consent decrees or recalls.
Proper root cause analysis of the issue is necessary to make sure that the firm is focusing on the real problem and subsequently the proper corrective and preventative actions can begin.
First, we need to understand the definition of a deviation. A deviation is defined as: any variance from approved, written procedures or any anomalous circumstance that may have the potential to affect the identity, strength, quality or purity of a product material. Thorough deviation investigations are mandatory in the eyes of regulatory agencies (eg, FDA). There are some negative consequences of incomplete investigations:
- No FDA approval
- Loss of jobs
- Unmet patient needs
- Impact to shareholders
- Endangering of patients
- Impure or potentially dangerous product
Incomplete deviation investigations are a top FDA finding during most biopharmaceutical audits. There are many occurrences in the lab and manufacturing areas that can be considered deviations. A few examples are listed below:
- GMP (Good Manufacturing Practices) mistakes or errors
- Reprocessing or Rework
- Unapproved changes to a licensed process
- Performing an activity without proper training
- Outside of operating parameters or in-process control limits
- Failure to follow written SOPs or approved batch record instructions
In many firms, the Quality Unit creates categories for deviations. Three common categories are:
- Minor Deviations
- Major Deviations
- Critical Deviations
When the deviation does not affect any quality attribute, a critical process parameter, or an equipment or instrument critical for process or control, it would be categorized as minor and treated as such by the applicable procedure. Some examples are: Balance out of tolerance used to determine gross weight of raw materials upon reception; Pressure differential out of established limits in class D washing area; Inadequately trained personnel to perform warehouse cleaning activities.
When the deviation affects a quality attribute, a critical process parameter, an equipment or instrument critical for process or control, of which the impact to patients (or personnel/environment) is unlikely, the deviation is categorized as Major requiring immediate action, investigation, and documented as such by the appropriate SOP. Some examples are: Use of unapproved reference standard to test an API or drug product; Filter integrity test has been carried out using equipment with no documented installation qualification completed; Gross misbehavior of staff in a critical aseptic process; Pressure differential out of established limits in aseptic fill areas; Operational parameter out of range for a parameter defined as non-critical; Untrained personnel responsible for segregating the approved and rejected raw material in the warehouse.
When the deviation affects a quality attribute, a critical process parameter, an equipment or instrument critical for process or control, of which the impact to patients (or personnel or environment) is highly probable, including life threatening situation, the deviation is categorized as Critical requiring immediate action, investigated, and documented as such by the appropriate SOP. Some examples are: Expired or rejected API component used; Sterilization record of product-contact material used in aseptic filling process not available or unacceptable; Incomplete inactivation stage of fermentation; Temperature out of control limit during detoxification stage; Product Sterility or Potency Failure; Stability Test Failure.
There are some key elements to keep in mind when writing a deviation investigation. First, you need to document the reason for the investigation. Include such things as, what event or finding prompted investigation; how and when identified; consider tracking / trending; evaluation; consider related activities; think global. Next, you need to describe what happened. Include, when, where, and what immediate actions were taken. Identify root cause, where possible. Document the why, document factors considered, ensure data support conclusions, avoid conjecture, often a multi-disciplinary exercise. Root Cause is one of the most scrutinized parts of a deviation investigation.
Root cause is a system of problem solving methods aimed at identifying the root causes of problems or incidents, predicated on the belief that problems are best solved by attempting to correct or eliminate root causes, as opposed to merely addressing the immediately obvious symptoms. By directing corrective measures at root causes, it is hoped that the likelihood of problem recurrence will be minimized.
Two of the most widely used root cause tools are the 5 Why method and the FighBone Diagram. The “5 Whys” refers to a series of sequential questions (i.e. each response given is asked “why”, normally from 3 up to 5 times). This exercise allows a thorough understanding of the underlying or root causes of the deviation, which may be related to a systemic problem. The Fish bone diagram is a cause-effect type of analysis where the product / process is the main spine, the effect is the actual nonconformance, and the secondary spines are the different factors or causes that could have affected or “caused” the deviation (i.e., materials, controls, personnel, equipment, procedures, etc.).
What if I can’t determine a root cause? It is reasonable to assume that often there will be deviations for which the root cause cannot be readily and clearly determined, and that a probable cause will not be determined. Also, in certain cases, the deviation will be attributed to unpredictable circumstances beyond control. In any case, conclusions and rationale should always be well supported and well documented. It is fundamental that investigations on root causes of deviations be carried out in a systematic and professional manner following an approved procedure and conducted by adequately trained personnel. When well-managed, it provides an excellent opportunity to have departments communicate between them and to improve process understanding. Investigations should be based on historical data and accumulated knowledge.
The root cause investigation process is a key step in handling major and critical deviations as it will provide objective evidence to implement corrective and possibly preventive actions as part of the CAPA system. Corrective Actions are taken to eliminate the root causes of deviations and should be based on good quality investigations. Corrective actions should be QA approved before implemented and their efficacy verified in a documented manner, activity that could require a significant period of time. Corrective actions could be transferred to an independent CAPA system to avoid unnecessary delay for deviation closure. This independent CAPA system should include tracking of all actions required by a pre-approved CAPA plan and effectiveness check.
Not all corrective actions will have associated preventive actions. Corrective actions are “reactive” in nature and are triggered in response to detected deviations and could generate preventive actions as well. These preventive actions (linked originally to nonconformities) will act on similar processes, manufacturing lines or different sites, where there has not been yet a deviation.
Lastly, deviations should be assessed for product impact. In order to evaluate product impact, additional testing may be needed under protocol, Justification of Acceptance/ Rejection Criteria, and Justification if Differences in Lot Disposition. Ultimately, does the deviation affect the purity, potency, safety or efficacy of the product. The answer to this question should help guide you to determine if the lot can be released.
In conclusion, put systems in place that will help you move away from assigning human error as the cause and retraining as a preventative measure, unless this is scientifically justified. Move towards using more formalized Root Cause Analysis techniques. Put in place more rigorous and scientific approaches to Brainstorming and Develop a high level of personnel competency in these areas within your site.