EMA Publishes 2021 GCP Compliance Report

The EMA has published the Annual Report of the Good Clinical Practice (GCP) Inspectors Working Group (IWG) 2021.

Beyond wishing for an 11 month cycle of writing and approval on my annual reports, there is some valuable information there.

In 2021, three CHMP GCP inspections were conducted entirely remotely, and three inspections were conducted in a hybrid setting. A total of 286 deficiencies, comprising 24 critical, 152 major and 110 minor findings were recorded for the 27 CHMP requested inspections conducted in 2021. This represents an average of 10-11 findings per site inspected. The three top categories were: “General”, “Trial Management” and “Computer System”. An increase in findings related to computer systems (e. g. Audit Trail and Authorized Access, Computer Validation, Physical Security System and Backup) is noted compared to the last reports.

More information is available at EMA´s Good Clinical Practice Inspectors Working Group website.

Under organisation and personel we see “Delegation of tasks to inappropriate team members.” This reinforces the needs for strong cv and job descriptions, and linking to both hiring and personnel qualification.

The computer systems observations are the greatest hits of data integrity, and should be a wakeup call to any company that treats GCP and GMP computer systems differently.

Let the 2022 annual GCP training development begin. And make sure you get that training done on time!

Level of Training

I want to talk about levels of training. I am not going to go into an Instructional Design model/framework, but more stay focused on the purpose of training in the quality system. I am also going to try to discuss training in terms that will make sense to folks who mostly dwell in a verification/validation mindset. So, all my professional learning developer friends please be gentle.

Categories of Training

There are three levels of training (lots of subdivides) that can be viewed as a risk based approach

Awareness Training

This can be barely considered training. Awareness training conveys the subject matter to an audience with the goal of making the audience aware of the content of the communication. It is either informational or actionable. At best, just a ”tell” activity.

Read-and-understand fits in this bucket.

Facilitated Training

Facilitated training strives to improve the workplace proficiency and is hopefully based on some real adult learning principles. There are a lot of delivery modalities that are usually broken into two big buckets of eLearning and classroom delivery. It always has an assessment component to ensure the training had the desired impact. Usually a “tell, show” model with limited “do”.

Employee Qualification

On the job, hands on training that confirms the individual can do the work by independently performing the tasks while being monitored and assessed by the trainer. Usually follows a “tell, show, do, follow-up” model.

The Level of Training is Risk Based

The level of training should be driven by the criticality of the process/procedure/task. I recommend several questions driving this:

The complexity knowledge or skills needed to execute the changed process?
How complicated/complex is the process/procedure/task?
Criticality of Process and risk of performance error? What is the difficulty in detecting errors?
What is the identified audience (e.g., location, size, department, single site vs. multiple sites)?
Is the goal to change workers conditioned behavior?

The Personnel Qualification Model

Qualification means fitness for some purpose, shown by meeting necessary conditions or qualifying criteria. This applies as much to our people as it does to our equipment, and we can break this own with the three phases of IQ/OQ/PQ:

Personnel IQ is provides objective evidence that the trainee has the requisite education and experience for the process/procedure/task.
Personnel OQ is proves that the trainee can function in the training situation (event) in an appropriate fashion and performance is within the control limits set by the process/procedure/task. It proves that the trainee can perform the task correctly and independently.
Personnel PQ demonstrates the acceptable performance during representative operational conditions. The trainee’s performance consistently produces results that meet the standards set by the process/procedure/task.

Once the process of employee qualification I successfully completed, the employee is qualified and stays so unless and until they become disqualified or the process/procedure/task changes significantly enough to require requalification.

Disqualification and requalification

There should be a process for disqualification, whether from extended absences, job changes or a detrimental trend in performance such as serious or repeated deviations.

CVs and JDs and Training Plans

In the post “HR and Quality, joined at the hip” I covered some of the regulations that set the expectations in the pharmaceutical and medical device industries that employees have the appropriate education, experience and training to do their jobs. What is often called the personnel qualification triangle.

A job description is a written document that outlines the duties, responsibilities, contributions, behaviors, outcomes and required qualifications for a specific job in an organization. A good job description is a specification that results from a detailed job analysis. It is used in hiring and performance evaluation. It is also the starting point for determining a good GxP training plan.

In order to providing the specific knowledge, skills, abilities and behaviors that need to be addressed for each employee, the job description needs to specifically call out the roles in the processes an employee will play. Instead of providing broad statements like “participate in CAPAs” or “Manufacture product” it should be more specific such as “create and project manage CAPAs” or “Perform visual inspection.”

I challenge everyone to think broadly about the job description as a tool to drive excellence. Utilized throughout the life of employment, a job description is a powerful tool that can aid managers. Managers have a road map that can help them with their duties of planning, leading, organizing, controlling and staffing. With a road map, the complexities of the organization become easier.

The curricula vitae provides evidence that the employee is fit-for-purpose to the job description. The curricula vitae shows education and experience that demonstrates the possession of knowledge, skills, abilities and behaviors.

The training plan then lays out what the employee needs to bit fit-for-use, to be able to do all the roles in the job description. It includes all the process and role specific training, as well as filling in any gaps that might exist on the curricula vitae.

The Personnel Qualification Triangle of Education, Experience and Training

It is important to note that this may not be a fine equilateral triangle. Experience, for example, can often, but not always make up for education.

Failure Points in the Personnel Qualification Triangle

Position and experience descriptions on CVs do not match the corresponding job description. This red flag stems from a lack of coordination between the curricula vitae and job description, which can be particularly concerning when an employee has a job description that requires very specific technical knowledge or oversees other seemingly unrelated areas that their experience would indicate.
Employee positions current position is not included in curricula vitae. The curricula vitae should always include the current position. While not a deal breaker, this is perhaps the easiest way to see large gaps in the cv, especially if the employee moves around or up in the same organization.
Curricula vitae do not reflect the level of experience expected given the employee’s job title.
The roles and responsibilities documented in in the job descriptions do not correspond with those included in SOPs. A reviewer should be able to go from a process to anyone engaged in the process and be able to see the work the individual does reflected.
Job titles match. Curricula vitae, job descriptions and what an individual is listed as on an organizational chart need to all match. I usually go as far to check someone’s business card before they go into meet with an inspector or external auditor.

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.

Regulation	Requirement
ICH E6 R2, 2.8	Each 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 211.25	(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.02.006	Every 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 2.1	All parts of the Pharmaceutical Quality system should be adequately resourced with competent personnel, and suitable and sufficient premises, equipment and facilities.
WHO Annex 3-GMP	9.2 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 7.2	Key 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/541760/2011	Achieving 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 touch 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 Area	Reference Number	Short Description	Long Description	Frequency
Bioresearch Monitoring	21 CFR 58.29(a)	Personnel: education, training, experience	Not 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
Devices	21 CFR 820.25(b)	Training – Lack of or inadequate procedures	Procedures for training and identifying training needs have not been [adequately] established. Specifically, ***	30
Devices	21 CFR 820.25(b)	Training records	Personnel training is not documented. Specifically, ***	18
Drugs	21 CFR 211.25(a)	Training–operations, GMPs, written procedures	Employees 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
Drugs	21 CFR 211.25(a)	Training , Education , Experience overall	Employees engaged in the [manufacture] [processing] [packing] [holding] of a drug product lack the [education] [training] [experience] required to perform their assigned functions. Specifically, ***	14
Drugs	21 CFR 211.25(a)	GMP Training Frequency	GMP 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
Drugs	21 CFR 211.25(b)	Supervisor Training/Education/Experience	Individuals 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.

There are many transactional differences in the roles, but if quality is not at the table for key decisions on hiring and culture the organization has missed opportunities.