Formulation and Process Development: Gate 6 of the Nine Gate Transfer Process for Moving Production

February 12, 2014

On the Blog- Focusing on the critical role of testing and validation with Gate Six of the Nine Gate Transfer Process: Formulation and Process Development.

Image via Andy Dean Photography
The most recent FDA report (FY2010) said the third highest reason a 483, warning letter, or consent decree was issued was because of discrepancies and/or failures in investigations due to inadequate content or timeliness. So what are the reasons the industry continues to be “dinged” by regulatory agencies for poor investigations? Five commonly identified mistakes for investigations are: close-minded investigations, failing to identify and/or execute the appropriate CAPA, incomplete investigations, poorly written investigations, and inadequate Quality Impact Assessment.

It’s never good to begin anything close-minded – Initiation of an investigation when the
investigator(s) is already convinced of the cause is contradictive. The true intent of any investigation is to systematically evaluate an event to determine the problem. Assuming that the cause is already known can, and has, lead investigations to incorrect and biased conclusions which usually results in another common mistake.

Failing to identify and/or execute the appropriate Corrective and Preventative Action (CAPA) – How many times in your organization have personnel mistake been identified as the root cause of an investigation with a CAPA or re-training assigned? How many times do you think it applies? Let’s say that an operator truly made a mistake and does need re-training. Was the initial training adequate? If so, then why did the operator make this mistake? Perhaps a procedure was not clear or labeling was not present or perhaps the task is complex enough that regular training should occur. Investigations need to be in depth enough to identify and assign CAPA to secondary, tertiary, etc. root causes – that’s how the “PA” in CAPA is addressed.

Incomplete Investigation – “Incomplete” refers to the document when it is missing supporting data or references. In other words, the document cannot stand on its own merit. Think about the investigations in your organization. What type of writing or layout do they follow? Whether or not your organization’s investigations are potentially incomplete can most easily be evaluated by looking at the problem statements. For example, which problem statement below most resembles what is documented in your organization?
1. A temperature excursion occurred during execution of the batch record.
2. During batch record review of Bob’s Street Drugs Batch 123 on 27-Jun-2012 identified that the temperature on chart 1 (77°C) exceeded the limit (75°C) during step 20 from 0900 to 1030 on 17-Jun-2012.
If you chose the first problem statement, then you may want to take a closer look at the content of investigations within your system.

Poorly Written Investigations – Incomplete investigations can also lead to poorly written investigations, which is another very common mistake. Poorly written investigations often have a common theme which is assuming that the reader understands or knows your organizations Quality System. For example, if the calibration of a chart recorder is not evaluated because the temperature excursion is also captured /confirmed by an automated alarm system which demonstrates equipment was not the issue, then state that.

Inadequate Quality Impact Assessment – This is a sure sign of an investigation faux pas. These mistakes occur frequently in investigations when the impact is only assessed for immediate intended use or when the investigation assumes no quality impact because the drug is not for human use (developmental use). Both of these impacts have missed the intent of a Quality Impact statement. The intent of a Quality Impact Assessment is to evaluate what happened against the batch/lot, the line/room/equipment used, the system/instructions/batch records, the end use, etc.

The next time you start to write or review an investigation, think about these common mistakes and see if your organization has room to improve.


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