Implementation of Quality Risk Management for Manufacturing of a Non-Sterile Pharmaceutical Product- Case study

The holder of a manufacturing authorisation must manufacture medicinal products so as to ensure that they are fit for their intended use, comply with the requirements of the Marketing Authorisation and do not place patients at risk due to inadequate safety, quality or efficacy [1]. As Per ICH Q9, Quality Risk Management, “Risk management is the systematic application of quality management policies, procedures, and practices to the tasks of assessing, controlling, communicating and reviewing risk [2].

To protect patients in terms of quality, safety and efficacy of medicines, international medicines regulatory authorities (MRAs) are recommending pharmaceutical manufacturers to adopt a riskbased approach to the life-cycle of a pharmaceutical product [3]. The quality risk management system should ensure that [4]. The evaluation of the risk to quality is based on scientific knowledge, experience with the process and ultimately links to the protection of the patient; the level of effort, formality and documentation of the quality risk management process is commensurate with the level of risk.

The following procedure will be used to perform the risk assessment (the risk addressed is the microbial contamination of a non-sterile product).

1. First step is to develop a process flow chart to fully describe the manufacturing process
2. Second step is to form a project team
3. A Cause & Effect (Fishbone) diagram will be prepared by the team (using the process flow chart) to evaluate the possible causes of microbial contamination.
4. FMEA will be developed by the team (using the prepared Cause & Effect diagram) to evaluate the risk associated with different factors (Raw materials, Packaging materials, Utilities, etc.)
5. Pareto diagram will be used to highlight the most critical factors that may lead to microbial contamination of the product (using the developed FMEA)
6. Finally, a monitoring plan will be developed to insure that all the identified high risk factors are monitored frequently to insure the risk (microbial contamination risk) is controlled

The team should be composed of to reflect all function that could have a decision influence on quality or compliance

1. The Quality Director
2. The Microbiology manager
3. The production manager
4. The engineering manager
5. The validation manager

Figure 1:

1. Conduct a hazard analysis
2. Identify potential hazards
3. Identify hazards which should be controlled
4. Recommend controls and critical limit
5. Devise procedures for monitoring and verification
6. Recommend appropriate corrective action where deviations occur

One of the most common used methods is Fish –bone diagram which summaries all critical influencing variables on the product quality [6,7]; (Figure 2).

Figure 2: Cause & Effect Diagram.

Determining the risk ranking (using Pareto chart)

Vilfredo Pareto was an Italian economist who lived from 1848to 1923. His study of the wealth distribution in the Italian economy yielded a key finding that 80% of the land was owned by 20% of the population. Since then, his discovery what we call the Pareto principle has been found to hold true in many other situations. For problem solvers, the simple Pareto principle provides a powerful root cause analysis (RCA) tool to separate the vital few factors from the trivial many determining risk ranking for Raw materials & Primary Packaging materials using the Pareto Chart.

Risk ranking policy

(Table 1-7)

Table 1: The Product.

Table 2: The following table showing scoring policy.

Table 3: The following table showing Ranking policy.

Table 4: Risk Assessment for Raw Materials & Packaging Material.

Table 5: Risk Assessment of different processes.

Table 6: Risk Assessment of different Utilities, Equipments and machines.

Table 7: Risk Assessment of different premises.

Determining the risk ranking (using Pareto chart)

Figure 3: Determining Risk Ranking for different Processes using the Pareto Chart.

Vilfredo Pareto was an Italian economist who lived from 1848 to 1923. His study of the wealth distribution in the Italian economy yielded a key finding that 80% of the land was owned by 20% of the population. Since then, his discovery what we call the Pareto principle has been found to hold true in many other situations. For problem solvers, the simple Pareto principle provides a powerful root cause analysis (RCA) tool to separate the vital few factors from the trivial many [10]. Determining Risk Ranking for Raw materials & Primary Packaging materials using the Pareto Chart [11,12]; (Figure 3).

Using the QRM the following monitoring plan was developed which can be considered an effective monitoring plan. The developed plan is highly effective as it will monitor the most critical factors that may cause microbial contamination in a non-sterile product and it found to be a cost effective plan as it will eliminate monitoring the factors that will not affect the product quality (Table 8).

Table 8:

1. Eudra Lex (2010) EC guidelines to Good Manufacturing Practice (GMP) for human and veterinary medicinal products chapter 1 pharmaceutical quality system; European Commission.
2. Quality Guideline (2005) Q9: quality risk management; international conference on harmonization.
3. Good manufacturing practices (2014) WHO guidelines on quality risk management. In: WHO expert committee on specifications for pharmaceutical preparations. Forty-seventh report. World Health Organization, Geneva, Switzerland.
4. L Viornery (2010) Quality Risk Management, Implementation of ICH Q9 in the pharmaceutical field an example of methodology from PIC/S, PIC/S.
5. ASQ Flow Chart Template.
6. ASQ Fishbone (Ishikawa) Diagram.
7. ASQ Fishbone diagram template.
8. ASQ Failure Mode Effects Analysis (FMEA).
9. (2003) Guidelines for Failure Modes and Effects Analysis (FMEA) for Medical Devices, Dyadem Press.
10. Bhalla, Aditya (2009) Don’t misuse the pareto principle. ASQ six sigma forum magazine 3: 15-18.
11. ASQ Pareto Chart.
12. ASQ Pareto Chart Template.