As per ICH Q9 “Quality Risk Management is a systematic process for the assessment, control, communication and review of risks to the quality of the product throughout its life cycle.” There are many methods and tools to perform Quality Risk Management. It is important to understand that none of the tool or set of tools are sufficient to address every situation of Quality Risk Management. Some of the important tools are as follows:

  1. Basic Risk Management Facilitation Methods
  2. Failure Mode and Effects Analysis (FMEA)
  3. Failure Mode, Effects and Criticality Analysis (FMECA)
  4. Fault Tree Analysis (FTA)
  5. Hazard Analysis and Critical Control Points (HACCP)
  6. Hazard Operability Analysis (HAZOP)
  7. Preliminary Hazard Analysis (PHA)
  8. Risk Ranking and Filtering
  9. Supporting Quality and Statistical Tools

In this article we shall be discussing about one of the most important tool i.e. Hazard Analysis and Critical Control Point (HACCP) using a simple yet effective tool of 5W and 1H.

What is Hazard Analysis and Critical Control Point (HACCP)?

HACCP is a process control system that identifies where hazards might occur in the drug manufacturing process, so that stringent actions may be put into place, to prevent the hazards from occurring. By strictly monitoring and controlling each step of the process, there is less chance for hazards to occur.

HACCP is traditionally implied in Food management system. HACCP is a systematic method for the identification, assessment and control of safety hazards. HACCP covers both the hazards associated with the product quality and personnel safety, however, GMP is more concerned with the product quality only. The output of a HACCP process is a list of critical control points for management of risk.

Manufacturing of hormones, cytotoxic drugs, potent drugs, or handling inflammable solvents, heavy equipment like FBD etc. have inherent hazards associated with them and any accident or procedure violation may cause illness or injury if not controlled.

Additionally, HACCP includes analysis of the critical quality attributes (CQAs) as well as the assessment of hazards affecting the safety of workers and environmental pollution hazards directly related to the process concerned.

Process validation for all the critical processes affecting product quality is an important requisite of GMP for pharmaceutical products. HACCP is a scientific and systematic tool that helps to identify the critical control points where the process validation team shall focus during the process development.

 

What are seven principles of HACCP?

  1. Conduct a hazard analysis and identify preventive measures for each step of a process: Conducting a hazard analysis helps to identify hazards associated, their impact and the preventive measures need to be applied to control the hazards.
  2. Determine the critical control points (CCPs): Critical control point is a step at which control can be applied and is essential to prevent or eliminate a pharmaceutical quality hazard or reduce it to an acceptable level. A drug safety hazard may be anything biological, chemical or physical property that renders a drug potentially unsafe or ineffective for human administration.
  3. Establish target levels and critical limit(s): It is of utmost important to establish target levels and critical limits for each CCP. A critical limit may be defined as maximum and minimum level or value to which a CCP must be controlled to prevent or eliminate a pharmaceutical quality hazard or reduce it to an acceptable level. Design of experiments (DOE) is a statistical tool to determine critical process parameters (CPPs). Upon identification of CPPs, process validation is used to determine the optimal process operating limits.
  4. Establish a system to monitor the CCPs: Various monitoring techniques as explained in “7 Basic Quality Control (QC) Tools – Steps to process improvement” and process capability studies are used to monitor the process and to ensure that the process is under at critical control point.
  5. Establish the corrective action to be taken when monitoring indicates that a particular CCP is not under control: In case of any deviation observed in the established limits of critical control points, corrective action shall be taken. HACCP plan shall be able to identify the corrective action.
  6. Establish procedures to verify that the HACCP system is working effectively: Periodic review of HACCP plans, CCP records, various testing records etc. help to verify if the HACCP system is adequate and is working as per intended.
  7. Record Keeping: Establish documentation concerning all procedures and keep records appropriate to these principles and their application. The documents to be maintained includes HACCP plan, CCP monitoring records, verification records etc.

 

Who perform HACCP?

HACCP shall be performed by a team of cross functional experts. This helps to bring the knowledge and experience of the people from different fields regarding product and process. It also helps to remove the individual bias if any. Wherever required, additional support may also be sough from external vendors who are Subject Matter Experts. The cross functional team shall be selected based on the requirements of the project. The team may include personnel from research and development, production, quality control, quality assurance, regulatory, projects, engineering, administration etc.

This is important to note that the team members shall be well trained on designing and implementation of effective HACCP plan. A firm shall draft a well-defined and elaborate guideline or a Standard Operating Procedure for HACCP.

Why to Perform HACCP?

HACCP is a structured approach that applies technical and scientific principles to analyze, evaluate, prevent, and control the risk or adverse consequence(s) of hazard(s) due to the design, development, production, and use of products. HACCP helps to identify Critical Process Parameters (CPPs). It is a tool that focus on prevention of hazard rather than taking corrective action when product fails after testing.

 

Where to perform HACCP?

HACCP might be used to identify and manage risks associated with physical, chemical and biological hazards (including microbiological contamination). HACCP is most useful when product and process understanding is sufficiently comprehensive to support identification of critical control points. The output of a HACCP analysis is risk management information that facilitates monitoring of critical points not only in the manufacturing process but also in other life cycle phases.

Additionally, it helps to identify hazards related to environment and labour safety.

When to perform HACCP?

HACCP is a proactive technique and it shall be performed during the development stage of System/ Process/ Product. It shall also be performed during modification, addition of processes in manufacturing, analysis, transportation etc. Change in vendor, regulatory requirements, continuous improvement, any failure may also require carrying out HACCP. The basic prerequisite for developing and implementing effective HACCP is Good Manufacturing Practices (GMP).

GMP ensures that basic requirements for developing and implementing effective HACCP like facilities, production equipment, personal hygiene, vendor control, specifications, training, cleaning and sanitation, documentation, chemical control, pest control etc. are available and effective. These proves to be a foundation for establishing HACCP.

How to perform HACCP?

  • Guidelines for the application of the HACCP system:
    1. The basic prerequisite for developing and implementing effective HACCP is Good Manufacturing Practices (GMP)
    2. The HACCP is considered effectively implemented, only if the management shows their 100% commitment towards its implementation.
    3. HACCP should be applied to each specific operation separately.
    4. CCPs shall be identified with utmost precision and using thorough knowledge and experience about product and process, mere reliance on reference documents shall be avoided.
    5. The HACCP application should be reviewed and necessary changes shall be made whenever there is any change in vendor, regulatory requirements, continuous improvement, any failure or change in any step.
    6. Nature and size of the operation shall be taken into account when applying HACCP.
    7. Product, Process or operation specific HACCP plan shall be prepared.
  • Application of HACCP:
  1. Identification of team: As explained above in detail, it shall be carried out by a team of cross functional experts. Hence, in-house as well as external experts from various functions shall be identified to perform HACCP. All the team members shall be well trained on designing and implementation of effective HACCP plan. It is expected that the team members shall be able to:
    • conduct a hazard analysis;
    • identify potential hazards;
    • identify controllable hazards
    • recommend target levels and critical limits;
    • establish procedures for monitoring and verification;
    • recommend appropriate corrective action where necessary;
    • verify the HACCP plan.

 

  1. Product and process description: The product and process shall be described in detail. The product and process description may include but not limited to APIs, excipients, their sources, their specifications, dispensing, milling, drying, blending, granulation, compression, coating, packing, in-process testing, finished goods specifications, storage, stability, transportation etc. The transport conditions and further storage becomes more important in case of thermolabile drug products such as vaccines.
  2. Identification of Intended Use: The intended use of the drug product being manufactured should be based on the expected uses of the product by the end user or consumer. In specific cases, vulnerable population groups, e.g. geriatric patients, infants and immunocompromised patients, may have to be considered during HACCP plan.
  3. Process flow diagram: The HACCP team shall construct a descriptive process flow diagram which shall cover all operations and decisions in a process.
  4. On-site confirmation of process flow diagram: The HACCP team shall verify the process flow diagram with the actual process on-site during all stages and hours of operation. Amendments if required shall be made to the flow diagram, and the same shall be well documented.
  5. Conduct a hazard analysis and identify preventive measures for each step of a process (Principle 1): During hazard analysis, the hazard analysis team shall list down all the possible hazards that may occur at each step from production, testing and distribution up to the point of use. Care must be taken to clearly differentiate safety concerns from quality concerns. Identification of hazards is then followed by hazard analysis. HACCP plan is prepared to identify which hazards are of such a nature that their elimination or reduction to acceptable levels is essential. A thorough hazard analysis is required to ensure an effective control point. Hazard analysis is a two step process:
    1. Enlisting potential hazards after review of the materials, activities, equipment, storage, distribution and intended use of the product. In the hazard analysis, the following should be assessed:
      • the probable occurrence of hazards and the severity of their adverse health effects;
      • the qualitative and/or quantitative evaluation of the presence of hazards;
      • the survival or multiplication of microorganisms of concern;
      • the production or persistence in drugs of toxins, chemicals or physical agents;
      • the conditions leading to the above.
    2. Evaluation of hazard i.e. the severity of the potential hazards and the probability of their occurrence should be estimated.
  6. Determine the critical control points (Principle 2): Critical control point is a step at which control can be applied and is essential to prevent or eliminate a pharmaceutical quality hazard or reduce it to an acceptable level. A CCP in the HACCP system can be more easily determined by the use of a decision-tree, which facilitates a logical approach. The team shall be trained and experienced in the use of decision tree. If a hazard has been identified at a step where control is necessary for safety, and no control measure exists at that step, or any other, the product or process should be modified at that step, or at an earlier or later stage, to include such a control measure.
  7. Establish target level and critical limits for each CCP (Principle 3): A critical limit may be defined as maximum and minimum level or value to which a CCP must be controlled to prevent or eliminate a pharmaceutical quality hazard or reduce it to an acceptable level. Critical limits must be specified and verified, if possible, for each critical control point. Critical limits should be scientifically based.
  8. Establish a monitoring system for each CCP (Principle 4): Monitoring is the scheduled measurement or observation of a CCP relative to its critical limits. Various monitoring techniques as explained in “7 Basic Quality Control (QC) Tools – Steps to process improvement” and process capability studies are used to monitor the process and to ensure that the process is under at critical control point. Monitoring should be recorded and properly signed and dated by the person(s) carrying out the monitoring and by a responsible reviewing official(s) of the company.

The monitoring procedures shall be well defined and shall be able to detect any deviation or out of limit results at the earliest, so that necessary adjustments to the process can be made to prevent any violation. Ideally, continuous monitoring of critical control points is preferred, in absence of continuous monitoring, the frequency of monitoring shall be well defined. Where continuous monitoring is possible, a reliable monitoring procedure and frequency should be identified.

  1. Establish the corrective action to be taken when monitoring indicates that a particular CCP is not under control (Principle 5): In case of any deviation observed in the established limits of critical control points, corrective action shall be taken to brought the CCP under control. HACCP plan shall be able to identify the corrective action in advance. It shall include what to be done, who to take action, what is to be recorded etc.

Individuals with thorough understanding of the process, product and HACCP plan shall be assigned the responsibility for the oversight of corrective actions. Actions taken must also include the proper disposition of the affected product. Deviation and product disposition procedures must be documented in the HACCP records.

  1. Establish verification procedures (Principle 6): Verification and auditing methods, procedures and tests, including random sampling and analysis, can be used to determine whether the HACCP system is scientifically sound and is implemented properly. The frequency of verification should be sufficient to confirm the proper functioning of the HACCP system.

In addition, it is advisable to conduct the HACCP system evaluation by an unbiased, independent third party which shall include technical evaluation of the hazard analysis and each element of the HACCP plan as well as an on-site review of all flow diagrams and appropriate records of the operation of the plan. Such a comprehensive verification is independent of other verification procedures and must be performed in order to ensure that the HACCP plan is resulting in the control of the hazards.

If the results of the comprehensive verification identify deficiencies, the HACCP team should modify the HACCP plan as necessary. Individuals doing verification should have appropriate technical expertise to perform this function. Where possible, verification should include actions to confirm the efficacy of all elements of the HACCP plan.

  1. Establish documentation and record keeping (Principle 7): Establish documentation concerning all procedures and keep records appropriate to these principles and their application. The documents to be maintained includes Hazard analysis, HACCP plan, CCP monitoring records, verification records etc.

Reference:

  1. Annex 7 of WHO TRS 908
  2. ICH Q9 Quality Risk Management
  3. Annex 2 of WHO TRS 981