Root Cause Analysis Deficiencies

An appropriate level of root cause analysis should be applied during the investigation of deviations, suspected product defects and other problems. This can be determined using Quality Risk Management principles. 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. Where human error is suspected or identified as the cause, this should be justified having taken care to ensure that process, procedural or system based errors or problems have not been overlooked, if present.

Appropriate corrective actions and/or preventative actions (CAPAs) should be identified and taken in response to investigations. The effectiveness of such actions should be monitored and assessed, in line with Quality Risk Management principles.

EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Chapter 1 Pharmaceutical System C1.4(xiv)

The MHRA cited 210 companies in 2019 on failure to conduct good root cause analysis and develop appropriate CAPAs. 6 of those were critical and a 100 were major.

My guess is if I asked those 210 companies in 2018 how their root cause analysis and CAPAs were doing, 85% would say “great!” We tend to overestimate our capabilities on the fundamentals (which root cause analysis and CAPA are) and not to continuously invest in improvement.

Of course, without good benchmarking, its really easy to say good enough and not be. There can be a tendency to say “Well we’ve never had a problem here, so we’re good.” Where in reality its just the problem has never been seen in an inspection or has never gone critical.

The FDA has fairly similar observations around root cause analysis. As does anyone who shares their metrics in any way. Bad root cause and bad CAPAs are pretty widespread.

This comes up a lot because the quality of CAPAs (and quantity) are considered key indicators of an organization’s health. CAPAs demonstrate that issues are acknowledged, tracked and remediated in an effective manner to eliminate or reduce the risk of a recurrence. The timeliness and robustness of these processes and records indicate whether an organization demonstrates effective planning and has sufficient resources to manage, resolve and correct past issues and prevent future issues.

A good CAPA system covers problem identification (which can be, and usually is a few different processes), root cause analysis, corrective and preventive actions, CAPA effectiveness, metrics, and governance. It is a house of cards, short one and the whole structure will fall down around you, often when you least need it to.

We can’t freeze our systems with superglue. If we are not continually improving then we are going backwards. No steady state when it comes to quality.

Good practices for research and development facilities (WHO draft guideline)

Last month the World Health Organization published a draft guideline on Good practices for research and development facilities.

This arrow pretty much sums it up:

Application of the guide

Seriously, not much surprising here. What this guide definitely does is place early research in the framework of Q10 and point out that there is one quality system to rule them all and that level of rigor is based on risk.

Give it a read.

2020 FDA 483s around change

The yearly database of 483s has been updated by the FDA. Lots will be written on themes as we end the year, so I decided to give a few of my immediate observations.

I find that over time what I focus in on changes, as my jobs evolve and change, and the interests I have shift. However, some things never change, so let us talk change.

Reference NumberShort DescriptionLong Description2020 Frequency2019 Frequency2018 Frequency
21 CFR 211.100(a)Changes to Procedures Not Reviewed, ApprovedChanges to written procedures are  not [drafted, reviewed and approved by the appropriate organizational unit] [reviewed and approved by the quality control unit].  Specifically, ***8139
21 CFR 211.160(a)Lab controls established, including changesThe establishment of [specifications] [standards] [sampling plans] [test procedures] [laboratory control mechanisms] including any changes thereto, are not [drafted by the appropriate organizational unit] [reviewed and approved by the quality control unit].  Specifically, ***41817
21 CFR 212.20(c)Adverse effects of changes madeYou did not demonstrate that any change does not adversely affect the [identity] [strength] [quality] [purity] of your PET drug. Specifically,***111
483s related to changes

I think its fair to say the decreases as a result of the pandemic and the reduced inspections.

Over on the device side of things we see:

Reference NumberShort DescriptionLong DescriptionFrequency
21 CFR 820.30(i)Design changes – Lack of or Inadequate ProceduresProcedures for design change have not been [adequately] established.  Specifically,***26
21 CFR 820.40(b)Document change records, maintained.Records of changes to documents were not [adequately] maintained.  Specifically, ***6
21 CFR 820.70(b)Production and Process Change Procedures, lack of or Inad.Procedures for changes to a [specification] [method] [process] [procedure] have not been [adequately] established.  Specifically, *** 5
21 CFR 820.75(c)Process changes – review, evaluation and revalidationA validated process was not [reviewed and evaluated] [revalidated] when changes or process deviations occurred. Specifically, ***5
21 CFR 820.40(b)Change records, contentRecords of changes did not include [a description of the change] [identification of the affected documents] [the signature of the approving official(s)] [the approval date] [when the change became effective].  Specifically, ***



3
21 CFR 820.50(b)Supplier notification of changesThere is no agreement with [suppliers] [contractors] [consultants] to notify you of changes in the product or service.  Specifically, ***3
21 CFR 820.75(c)Documentation – review in response to changes or deviationsThere is no documentation of the [review and evaluation of a process] [revalidation of a process] performed in response to changes or process deviations.  Specifically, ***1
Device 473s around change

I’m a firm believer that pharma should always pay attention to the medical device side for 483s. A lot of us are combination products now (or will be) and there is always good trends to be aware of.

My key takeaways:

  1. Think change management and not just change control and document control
  2. Computer change controls need to be holistic and system orientated
  3. Have a process that ensures changes are appropriately reviewed and approved
  4. Risk based and evaluate validation
  5. A robust supplier management program is critical, plan for change

Here’s a more detailed checklist to help you evaluate your change system.

Rocky Road to ICH Q12 Implementation

Prior to the adoption of Q12 in Singapore at the end of 2019 there was a lot of rumbling from regulatory agencies on how Q12 would be more aspirational in many ways. In the last few weeks we’ve started to see just what that will mean.

FDA to release a guidance

The FDA’s Mahesh Ramanadham, from the Office of Pharmaceutical Quality in the FDA’s Center for Drug Evaluation and Research, provided an update on the agency’s implementation of ICH Q12 in the US on 25 February at the annual IFPAC meeting in North Bethesda, Md. He started that the FDA will soon be issuing guidance implementing the International Council on Harmonization’s Q12 guideline in the US that will, among other things, translate ICH post-approval change classification categories to FDA supplement categories, and address how to file established conditions (ECs).

This Q12 guidance will replace the agency’s 2015 draft guidance for industry on established conditions and reportable chemistry, manufacturing and controls changes to approved drug and biological products. It is expected to be issued in May 2020. The guidance will also discuss the relationship between FDA comparability protocols and the post-approval change management protocol (PACMP) established by the ICH Q12 guideline.

EU says not so fast in their adoption

However, additional scientific risk-based approaches to defining Established Conditions and
associated reporting categories, as described in Chapter 3.2.3, and the Product Lifecycle
Management (PLCM) Document, as described in Chapter 5, are not considered compatible with the
existing EU legal framework on variations.

It is important to note that the legal framework always takes precedence over technical and
scientific guidelines. More specifically this means that the definition of Established Conditions and
their reporting categories must follow the requirements laid down in the current EU Variations
Regulation and associated EU Variations Guidelines. With respect to the Product Lifecycle
Management (PLCM) document, in case such a document is submitted, it cannot be currently
recognised in the EU due to the fact that it is not referred to in the EU legal framework.

EMA/CHMP/ICH/78332/2020

In an explanatory note accompanying the adoption of ICH Q12 and related annexes, the European Commission and the European Medicines Agency point out that there are “some conceptual differences” between the ICH guideline and the EU legal framework on managing post-approval changes, ie, the variations regulation (Regulation (EC) No 1234/2008).

The EU authorities offer no clarity on when and how ICH Q12 would be fully implemented in the EU. The note merely states that the new “tools and concepts in the ICH Q12 guideline that are not foreseen in the EU legal framework will be considered when this framework will be reviewed.” The EU regulators said they would continue to work on the implementation of the ICH Q12 within the existing EU legal framework. The explanatory note also points out that despite some conceptual differences between ICH Q12 and the EU framework, there is also considerable common ground. In fact, some tools and concepts in ICH Q12 tools can already be applied by industry by following the current EU variations framework.

Next Steps

Companies should be ensuring that their knowledge management and risk management processes and understanding continue to grow. ICH Q12 will be a rocky road and I’m not sure we’ll see some of the potential streamlining of regulatory processes for a long time.

ICH Q12 pathway for established conditions

How can anyone keep up with all that information?

I hear this from colleagues all the time, how do you keep on top of so much news? How have are you always the first person to know this thing?

Keeping on top of trends, of regulatory changes, of new event is critical. This is a big part of content, and from that we bring context. It is part of what makes us Subject Matter Experts.

But let’s be honest, there is a lot out there to stay aware of, and it can eat a lot of unproductive hours up, especially with so much new content on the web being added daily, it can be tough to keep up with what’s happening online. But if you rely on visiting specific websites every day, doing Google searches, or relying on social media to keep them informed you will get overwhelmed and miss important things. The best solution I have found is pretty old-school: The RSS feed.

About every site you need to follow, from a trade publication to a government agency to a professional society to all those blogs publishes an RSS feed (including this one). Often they publish more than one which can compartmentalize the reading and help you narrow down to specific topics that interest you.

You then use a reader to aggregate these feeds into compartments that make sense to you, skim the headlines at your leisure and read those items that seem relevant to you. This gives you a comprehensive, regularly updated look at all the content your favorite sites publish throughout the day. Think of it as the ultimate aggregator; every morsel from every source you care about, fed directly to you.

I use Feedly, but there are several good ones out there, most free to use. A lot of friends tell me I should move to Inoreader.

Do not be afraid of the massive amounts of information out there. Like anything, it’s all about getting the right tool for the job.