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.

MHRA 2019 GMP Inspection Data and Documentation observations

Transparency is something that regulatory agencies need to get better at, both in sharing more and doing it in a timely manner. The fact that the 2019 data from the MHRA was released in October of 2020 is pretty poor. As a reference, the FDA releases their data pretty reliably at the end of the calendar year for the given year.

Been evaluating the MHRA’s 2020 data on Chapter 4 Documentation, which is the 2nd largest category of observations in 2019 (and in 2018 before it).

80 different inspections cited comments against the Principles section

Good documentation constitutes an essential part of the quality assurance system and is key to operating in compliance with GMP requirements. The various types of documents and media used should be fully defined in the manufacturer’s Quality Management System.


Documentation may exist in a variety of forms, including paper-based, electronic or photographic media. The main objective of the system of documentation utilized must be to establish, control, monitor and record all activities which directly or indirectly impact on all aspects of the quality of medicinal products. The Quality Management System should include sufficient instructional detail to facilitate a common understanding of the requirements, in addition to providing for sufficient recording of the various processes and evaluation of any observations, so that ongoing application of the requirements may be demonstrated.


There are two primary types of documentation used to manage and record GMP compliance: instructions (directions, requirements) and records/reports. Appropriate good documentation practice should be applied with respect to the type of document.


Suitable controls should be implemented to ensure the accuracy, integrity, availability and legibility of documents. Instruction documents should be free from errors and available in writing. The term ‘written’ means recorded, or documented on media from which data may be rendered in a human readable form.

Principles, Chapter 4 Documentation

The Principles section then goes on to lay out the required document types.

I would love to see more. Is this 80 companies who don’t known what a SMF is? Good documentation practices? Don’t have SOPs and batch records? Have errors in their documents? Don’t approve them? More transparency would be valuable here.

We can learn more by drilling down in the document.

  • There are 87 inspections with 4.1 in section “Generation and Control of Documents”. 1 is critical and 25 are major. Here we see failures in understanding types of documents and controlling them, or maybe just having them in the first place.
  • The 82 against 4.2 (1 critical and 20 major) are more about having the manufacturing and testing process defined (and matching the filing).
  • 103 inspections with observations against 4.3 (23 major) show companies that do not have appropriate approval and release controls
  • 14 for 4.4 (6 major) means there are 14 companies out there who can’t write a good process and procedure. 4.4 has one of my favorite requirements “written in an imperative mandatory style”
  • 60 against 4.5 (13 major) demonstrates a lack of review and keeping documents up-to-date.
  • 12 companies (6 major) have terrible handwriting and cannot stick to ballpoints, yes in fact 4.7 states “Handwritten entries should be made in clear, legible, indelible way.”
  • 103 against 4.8 (1 critical and 28 major) is ALCOA focused on contemporaneous, attributable and accurate.
  • 18 for 4.9 (6 major) is for not correcting data correctly. That’s right 18 companies do not know how to comment correctly.
  • 22 for 4.10 (1 critical and 9 major) is for not clearly laying out the manufacturing records and keeping them for the retention period.
  • 19 for 4.29 (5 major) is a lack of process and procedure for a grab-bag of quality processes from change control to equipment management to cleaning

There are more, but we are in single digit observation territory.

Useful things to be evaluating in your own organization. As a good place to start, here are some questions to ask when contemplating data integrity.

HR and Quality, joined at the hip

The interface between the Quality and Human Resources departments in pharma and medical devices can be poorly understood by many leaders in both departments. Quality tends to focus on product and process, HR on hiring, benefits, stuff like that. As a quality professional who oversees the training and personnel qualification system, I tend to sit between the two.

A quick summary of some regulations are in order. This is by no ways a comprehensive list.

RegulationRequirement
ICH E6 R2, 2.8Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).
US FDA 21CFR 210.25(a) Each person engaged in the manufacture, processing, packing, or holding of a drug product shall have education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions. Training shall be in the particular operations that the employee performs and in current good manufacturing practice (including the current good manufacturing practice regulations in this chapter and written procedures required by these regulations) as they relate to the employee’s functions. Training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them. (b) Each person responsible for supervising the manufacture, processing, packing, or holding of a drug product shall have the education, training, and experience, or any combination thereof, to perform assigned functions in such a manner as to provide assurance that the drug product has the safety, identity, strength, quality, and purity that it purports or is represented to possess. (c) There shall be an adequate number of qualified personnel to perform and supervise the manufacture, processing, packing, or holding of each drug product.
Canada C.02.006Every lot or batch of a drug shall be fabricated, packaged/labelled, tested and stored under the supervision of personnel who, having regard to the duties and responsibilities involved, have had such technical, academic, and other training as the Minister considers satisfactory in the interests of the health of the consumer or purchaser.
EU EMA/INS/GMP/735037/201 2.1All parts of the Pharmaceutical Quality system should be adequately resourced with competent personnel, and suitable and sufficient premises, equipment and facilities.
WHO Annex 3-GMP9.2 The manufacturer should have an adequate number of personnel with the necessary qualifications and practical experience. The responsibilities placed on any one individual should not be so extensive so as to present any risk to quality. 9.3 Responsible staff should have its specific duties recorded in written descriptions and adequate authority to carry out its responsibilities. Its duties may be delegated to designated deputies of a satisfactory qualification level. There should be no gaps or unexplained overlaps in the responsibilities of personnel concerned with the application of GMP. The manufacturer should have an organization chart. (also see section 9.6 and 9.7 on key personnel)
WHO Annex 5-GDP 7.2Key personnel involved in the distribution of pharmaceutical products should have the ability and experience appropriate to their responsibility for ensuring that pharmaceutical products are distributed properly
Guideline on good pharmacovigilance practices (GVP) EMA/541760/2011Achieving the required quality for the conduct of pharmacovigilance processes and their outcomes by an organisation is intrinsically linked with the availability of a sufficient number of competent and appropriately qualified and trained personnel (see I.B.6.).  All personnel involved in the performance of pharmacovigilance activities shall receive initial and continued training [IR Art 10(3), Art 14(2)]. For marketing authorisation holders, this training shall relate to the roles and responsibilities of the personnel [IR Art 10(3)].
21 CFR 58.29(a) Each individual engaged in the conduct of or responsible for the supervision of a nonclinical laboratory study shall have education, training, and experience, or combination thereof, to enable that individual to perform the assigned functions.
(b) Each testing facility shall maintain a current summary of training and experience and job description for each individual engaged in or supervising the conduct of a nonclinical laboratory study.
(c) There shall be a sufficient number of personnel for the timely and proper conduct of the study according to the protocol.
21CFR 820.25(a)Each manufacturer shall have sufficient personnel with the necessary education, background, training, and experience to assure that all activities required by this part are correctly performed.
A few examples of regulations that ouch on personnel

This assortment of regulations provides structure for every aspect of employment from how we hire to how we manage people. We can divide this into the following major areas: Curricula Vitae, Job Description, Hiring Process, Training Records, Org Chart, External Job Identification. All informed by the rest of our quality system, especially Process (SOP) Roles and Responsibilities.

Like most things that concern us we want all of this to be consistent and accurate.

Training and Personnel Qualification within the Quality System

Looking at the 2020 FDA 483 data we can see that these regulations are a concern throughout organizations.

Citation Program AreaReference NumberShort DescriptionLong DescriptionFrequency
Bioresearch Monitoring21 CFR 58.29(a)Personnel: education, training, experienceNot all individuals engaged in the conduct of or responsible for the supervision of a nonclinical laboratory study have education, training, and experience, or combination thereof, to enable that individual to perform assigned functions.  Specifically, ***1
Devices21 CFR 820.25(b)Training – Lack of or inadequate proceduresProcedures for training and identifying training needs have not been [adequately] established. Specifically, *** 30
Devices21 CFR 820.25(b)Training records Personnel training is not documented. Specifically, ***18
Drugs21 CFR 211.25(a)Training–operations, GMPs, written proceduresEmployees are not given training in [the particular operations they perform as part of their function] [current good manufacturing practices] [written procedures required by current good manufacturing practice regulations].  Specifically, ***18
Drugs21 CFR 211.25(a)Training , Education , Experience overallEmployees engaged in the [manufacture] [processing] [packing] [holding] of a drug product lack the [education] [training] [experience] required to perform their assigned functions.  Specifically, ***14
Drugs21 CFR 211.25(a)GMP Training FrequencyGMP training is not conducted [on a continuing basis] [with sufficient frequency] to assure that employees remain familiar with CGMP requirements applicable to them.  Specifically, ***7
Drugs21 CFR 211.25(b)Supervisor Training/Education/ExperienceIndividuals responsible for supervising the [manufacture] [processing] [packing] [holding] of a drug product lack the [education] [training] [experience] to perform their assigned functions in such a manner as to assure the drug product has the safety, identity, strength, quality and purity that it purports or is represented to possess.  Specifically, ***2
2020 483 citations related to Training and Personnel Qualification

Reaching beyond the regulations, we really need to ensure that a fear climate does not exist inside the organization, what is often called psychological safety. Looking to Deming, quality should extend to the performance check processes, and frankly those that introduce ranking of employees or departments are not the best for a culture of excellence.

As we end the year it is a good idea to think about this question in your organization. I’ll be expanding on the practice in the weeks ahead.

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.

Anger and the job in difficult times

On Wednesday the United States set a devastating new record in the coronavirus pandemic: 3,124 people dead in one day. This was the first time the daily number of deaths has exceeded 3,000 but I fear it will not be the last. There are over 260k deaths in the US so far, over 1.5 million deaths worldwide. This is crippling, and it is difficult to go day-by-day with the pain of this suffering.

And yet, we need to work, support our families and communities. Get the job done. Amidst all that it is important to remember that is important to grieve and it is okay to be angry.

People grieve in diverse ways with different emotions, from anger, to depression to hopelessness, to resentment over what has been taken from them. Combined with the isolation of the pandemic, this is a recipe for poor mental health and poor coping mechanisms. And then there is a question of just how much and what sort of coping is good. Two-hundred-and-sixty thousand people are dead and there is a lot of evidence this is an underreport and a lot more people are going to die.

I hope you understand that I am angry. All day long. And it is a struggle not to bring that anger to work, not to let it twist my relationships. Yet that anger always exists.

I linked earlier this week to an article on mental health. It is particularly important to make this part of our organizations. Burnout must have a systematic fix.

What we need to give permission to, give space to, is a recognition that we are not in an okay state. And it may not be okay for a very long while, long after vaccines are widely available, and we return to the office.

It is okay to have taken a step back from obligations. I have not, for example, been writing much on this blog. It just did not work for me. Be kind to yourself and be okay with the things you must do less of. And when you are ready, go back to it.

Anger and Culture

Our organizational cultures are full of anger. What we must do is work to establish mechanisms to assure that anger is directed at issues or situations, not people. This will build psychological safety, enable good decisions and enhance our problem solving culture.

Some things we should do:

  • Acknowledge what is happening: Senior leadership needs to be working from compassion and generosity and taking real steps to address.
  • Treat toxic positivity as a bias: Toxic positivity is the assumption, either by one’s self or others, that despite a person’s emotional pain or difficult situation, they should only have a positive mindset. This is especially important as we have talent discussions, evaluate performance, and perform other managerial tasks.
  • Have systems around burnout
  • Focus on decision making quality
  • Build employee judgement feedback loops

We are not done. This winter will be very hard for many. As leaders we need to be ensuring our organizations can get through this and then leverage what we’ve learned to build a better culture.