By: Steve Langille

1. Data Integrity.

• ALCOA must be attributable, legible, contemporaneous, original, and accurate. ALCOA + also refers to it being complete, consistent, enduring, and available.
• Make sure that the documents are reviewed and signed by appropriate personnel and that the dates and signatures are unambiguous.
• Ensure appropriate controls over computer systems. Consider computer system access, such as how long you can be logged in for, can you use other monitors, can you leave your workstation. Etc.
• Provide robust training on the importance of data integrity and how to ensure and computer system validation and maintenance are key to ensuring data integrity.

2. Deviations and Failure Investigations.

This is always one of the FDA’s leading observations. Root cause analysis and CAPAs will be evaluated to determine if they truly address the issue and whether the corrective action was effective and how that was determined.

How does the manufacturer know that the corrective actions were implemented and effective? Verification of implementation, verification of training and verification of effectiveness are all important for CAPA proper implementation.

OOS results, the consequent investigations, and the effect on marketed products are also very important. Retesting or the appearance of retesting and testing into compliance are pain points that are heavily scrutinized by the FDA and a robust OOS protocol that covers the investigation process and appropriate re-testing protocols will aid the process.

3. Laboratory controls and scientifically sound specifications.

Representative sampling, demonstration of conformance to written procedures, recording and justification of any deviations are common issues there.

Conformance to compendial procedures is also important. Sometimes people think the compendial method is being used but they’ve actually inherited the method or there have been changes to either the laboratory method or the compendial method that could cause issues.

Keeping up with what regulatory authorities expect as far as compendial tests are concerned is another issue. For example, as a microbiologist, I often deal with Burkholderia cepacia complex in non-sterile drug products and knowing when testing for that organism is appropriate and when it’s not needed is very important.

I also believe internal audits of your laboratory system are very important to make sure that all your methods are up to date, they’re being executed correctly, and they support specifications that are appropriate for your product.

4. Stability testing.

Your sample sizes, storage conditions, containers, and test methods to ensure product quality throughout the shelf life are all very important. ICH Q1a is the go to standard for stability testing, especially for new drug and biologic products and drug substances but the FDA also has a specific guidance for generic drug products and drug substances as well.

5. The responsibilities of the quality unit are not adequately documented.

The FDA uses this as sort of a catch all for improper establishment or documentation of laboratory procedures, internal and external audits, training regimen, quality risk management, recall management, complaint oversight, failure investigations, change control, and other quality oversight issues.

For this, I would suggest an outside audit of your Quality System to make sure there aren’t any gaps and that it has the proper structure and documentation. The FDA’s 2006 guidance on a Quality Systems Approach to Pharmaceutical CGMP regulations is a good place to start if you’re wondering if you may have issues there.