Shedding Light on Quality Investigations in Chemical Manufacturing


Despite all the controls, protocols, processes and practices to ensure quality control in drug substance manufacturing, deviations or excursions can arise that could compromise the integrity of the drugs being developed.

CMOs that proactively address any issues that could compromise quality protocols or jeopardize their current Good Manufacturing Practice (cGMP) compliance, however, often ward off such issues by getting to the root cause of the problem, addressing it and learning from it.

Here at PCI Synthesis, quality investigations are performed in response to any deviation from an established process or product specification.  These investigations systematically review the circumstances or conditions in which the deviation occurred, and evaluate the resulting impact of the deviation on a product, a process, a system or the safety of staff.

Even in a tightly controlled cGMP manufacturing environment, process deviations and quality excursions can occur, so all team members must be committed to quickly identifying the cause of root incidents, fully investigating and analyzing them, and documenting them to ensure they enable continuous improvement.

At PCI Synthesis, a specially assigned Quality Assurance Group launches a quality investigation immediately upon notification of an excursion, and tailors the investigation response to the individual event.  All actions, meetings and pertinent facts from the investigation are included to provide a comprehensive narrative and to ultimately assign a root cause.  A thorough trend analysis and impact assessment also is performed to identify all corrective and preventative actions.

Quality Investigations are Key to cGMP Compliance

In addition to raw materials testing, in-process monitoring, release and stability testing and process validation, adequate investigations of any deviation, or Out-of-Specification (OOS) result, is required by the FDA to ensure cGMP compliance.

FDA regulations state that an investigation should be conducted to determine the cause of any OOS issue and the source of the aberration – either in the measurement process or in manufacturing. Even if a drug batch is rejected based on an OOS result, a quality investigation is necessary to determine if the result is associated with other batches of the same drug product or other products.

According to FDA guidelines, to be meaningful the investigation should be thorough, timely, unbiased, well-documented, and scientifically sound. The first phase of a quality investigation should include an initial assessment of the accuracy of the laboratory’s data. If this initial assessment indicates that no meaningful errors were made in the analytical method used to arrive at the data, a full-scale OOS investigation should be conducted.

Below are three key steps that will ensure an effective and proactive quality investigation:

  1. Gather the facts. When first initiating an investigation, make sure all aspects of the event are understood, including what happened, where it happened, who was involved and what materials were involved. You also should review the Standard Operating Procedures (SOPs) that were used in the process, and what was done to immediately address the problem, such as isolating any products that were involved.
  2. Conduct interviews with all team members.  Even though you may have a completed event summary at the outset of the investigation, conducting thorough interviews will all personnel involved with the incident can provide valuable information.  In discussions with lab technicians, supervisors and managers inquire about SOPs, as well as how the system may be improved, so you’re not just getting to the root cause of the problem, but learning how it can be improved in the future.
  3. Understand and improve the SOP.  It’s important to understand the SOPs and protocols each department implements to see where there was an excursion from that protocol, as well as to determine if there are any deficiencies in the SOP. Often problems arise not from human error, but from inefficient processes. It’s essential to understand the SOPs to not only see what happened, but also to see what should have happened.

Does your CMO have the right quality auditing assets?

While it’s clear that quality audits are necessary to ensure cGMP compliance, what questions should you ask to ensure your CMO is putting the right focus on them? Below are five key questions to ask:

  1. Does it have internal quality auditing professionals? Every project should have a professional who works closely with your regulatory representatives.
  2. Does it conduct continuous monitoring of all critical raw suppliers? This is crucial to ensure bad raw materials don’t come into the facility to begin with.
  3. How many times have you been audited this year and what were the findings? Ask how many times they have been audited by customers, federal regulatory agencies and quality professionals.
  4. Does it meet ICH guidelines and USP specifications? This will ensure they have the right protocols in place to meet all key recommendations.
  5. Does it have on-site cGMP laboratories? These labs should be fully staffed and equipped for raw material testing, in process testing, final release testing, method development and full stability testing.

There’s no doubt that deviations and excursions can occur when it comes to manufacturing chemical entities.  Yet in regulated environments, CMOs must implement aggressive measures to minimize the severity and frequency of these issues.  A commitment to sound and effective quality audits is the only way to counter these challenges, by finding the root cause of these events and learning valuable lessons to ensure future projects don’t confront the same challenges.