The long awaited new European Union Good Manufacturing Practice (EU GMP) Annex 1 covering the manufacture of sterile medicinal products has now been released, with the majority of its requirements due to become into operation from the 25th August 2023.
This new Annex 1 will replace the existing Annex 1, which was last updated in 2008.
This article is not an overview of what’s changing in the new Annex 1, but just focuses on CAPA and what the new Annex’s requirements are in this area and what an organisation should be considering going forwards in this area.
The origins of CAPA
CAPA, or Corrective Action and Preventive Action, has its origins in the ISO 9001 standard. ISO 9001 being the international standard for Quality Management Systems.
The year 2000 and then year 2008 versions of ISO 9001 both have requirements for Corrective Action and Preventive Action. However, these are not combined into a single “CAPA”, they are treated as two separate entities, i.e. Corrective Action (CA) and also Preventive Action (PA). In ISO 9001 the focus of Corrective Action is to take action to deal with the cause of problems (it is reactive) and Preventive Action has a focus on avoiding potential problems in the future (it is proactive).
Corrective Action (CA) and Preventive Action (PA) used to be treated as two separate entities
At the time, these terms were not mentioned in Good Manufacturing Practice (GMP). However, in September 2006 the United States Food and Drug Administration (FDA) published its Guidance for Industry - Quality Systems Approach to Pharmaceutical CGMP Regulations. This publication was the first to formally include the concept of CAPA into a pharmaceutical publication.
At the start of the document it talks about CAPA (Section III D) as a single entity, but later on, in the same document, it stops talking about CAPA and then talks about CA and PA (Section IV D 4 and 5) as separate things! Then, in 2008, the International Conference on Harmonisation (ICH) published ICH Q10 on Pharmaceutical Quality Systems. This also introduces the idea of CAPA to the pharmaceutical industry, however in this document it only covers CAPA (Corrective Action and Preventive Action (Section 3.2.2)), and does not cover CA and PA separately.
At the time, at around 2008, there were no direct references to CAPA, Corrective Action or Preventive Action in European Union or United States GMP. There is no real mention of CAPA in the current 2008 version of Annex 1. There is one passing reference to Corrective Action in the 2008 version of Annex 1, and this is in relation to what happens when particulate monitoring limits are exceeded in the different Grades of room.
It states that “appropriate alert and action limits should be set for the results of particulate and microbiological monitoring. If these limits are exceeded operating procedures should prescribe corrective action” (Annex 1 – Clause 20 (February 2008 version)). Other than this, there is no other mention of CAPA at all.
There are a number of references to CAPA in the new Annex 1
As the chapters of EU GMP have been updated over time, then we do start to see increasing coverage of CAPA in the main nine chapters of EU GMP. This includes the following in Chapter 1 of EU GMP on the Pharmaceutical Quality System, which was last updated in 2013. It states that “Corrective Actions and/or Preventative Actions (CAPAs) should be identified and taken in response to investigations” (EU GMP 1.4 xiv). So here we start to see CAPA more formally arrive as a specific GMP requirement.
What does the new Annex 1 say?
As you might expect, there are a number of references to CAPA in the new Annex 1. These include requirements in relation to the Contamination Control Strategy (CCS) and in relation to enhanced requirements for root-cause analysis and investigations in response to problems with procedural, process or equipment failures and problems associated with environmental monitoring. Some quote from the new Annex 1 are below:
- “Elements to be considered within a CCS should include … prevention mechanisms - trend analysis, detailed investigation, root cause determination, corrective and preventive actions (CAPA) and the need for comprehensive investigational tools” (New Annex 1 – Clause 2.5xv).
- “Root cause analysis of procedural, process or equipment failure is performed in such a way that the risk to product is correctly identified and understood so that suitable corrective and preventive actions (CAPA) are implemented” (New Annex 1 – Clause 3.1iii).
- “If action limits are exceeded, operating procedures should prescribe a root cause investigation, an assessment of the potential impact to product (including batches produced between the monitoring and reporting) and requirements for corrective and preventive actions” (New Annex 1 – Clause 9.13).
So, we can see that Annex 1, along with its many other new requirements, certainly expects there to be both Corrective Action and Preventive Action not only in response to problems, but to avoid problems in the future as well.
Using CAPA to deal with any potential deficiencies:
What is clear in more recent updates to the Chapter and Annexes of EU GMP over the past 10 years is the need to have more formal requirements to deal with any problems.
Indeed, when EU GMP Chapter 8 was last updated in 2015 whole new sections were added on “Investigation and Decision-making” (clauses 8.10 – 8.15) and “Root Cause Analysis and Corrective and Preventative Actions” (clauses 8.16 – 8.19). So, the ability just do the quick fix following a problem, with no detailed investigation into finding out the cause of the problem and dealing with that, is over!
The new Annex 1 is no exception here and organisations working to the requirements of Annex 1 will need to investigate the cause(s) of any problems, using root-cause analysis methodology and take action to deal with the identified cause(s) of any problems.
This can, of course, be a challenge when the problem is of a microbiological nature. Here the cause of the problem is not always 100% confirmed, hence in EU GMP Chapter 1 it states that “in cases where the true root cause(s) of the issue cannot be determined, consideration should be given to identifying the most likely root cause(s) and to addressing those” (EU GMP 1.4xiv).
So, as far as dealing with any problems, related to sterile manufacturing or not, do ensure that appropriate mechanisms are in place to formally identify and report any problems, investigate them thoroughly, identify the likely cause(s) of the problem and take action to deal with this, or these.
We need to take action to deal with problems, but we also need to be proactively avoiding problems in the future
In addition, there is also now an expectation to check the effectiveness of actions taken to ensure that these do address the real cause of the problem, with evidence provided as needed. It also states in Chapter 1 of EU GMP that “the effectiveness of such actions should be monitored and assessed …” (EU GMP 1.4xiv). This may take time, and time to gather this effectiveness data should be built into any corrective action plan.
Earlier on in this article I also stated that in ISO 9001 Preventive Action has more of an avoidance role. In the case of making sterile products then we do a great deal to avoid problems. This includes the training of our personnel, the maintenance, cleaning and disinfection of our facilities and the amount of testing we do on the work environment and any sterilisation equipment that we use.
These are all Preventive Actions, designed to avoid problems occurring, or to at least alert us to potential problems in the future. So, the new Annex 1 has both a reactive and proactive stance on CAPA. Yes, we need to take action to deal with problems, but we also need to be proactively avoiding problems in the future, and this can be seen in the new Annex 1’s requirements for its Contamination Control Strategy (CCS). This being a “living document” that should include areas for improvement in the future.
It states that “the CCS should be actively reviewed and, where appropriate, updated and should drive continual improvement of the manufacturing and control methods” (New Annex 1 clause 2.3).
So, in summary, if you work to the requirement of Annex 1 do ensure the following:
- Have mechanisms in place to thoroughly investigate any problems, taking action as necessary to deal with the cause of the problem.
- Have mechanisms in place to identify any potential problems in the future, again taking action as necessary.
- Have mechanisms in place for everyone to suggest any improvement opportunities in relation to how you manufacture and test product and the work environment.
All of these above can help us to avoid problems and help enhance the safety and end product quality of the sterile products that we manufacture. It is highly likely that this will be a major focus of regulatory inspections in the years ahead.