Opportunities, Challenges and Benefits of using HACCP as a Quality Risk Management Tool in the Pharmaceutical Industry

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1 Opportunities, Challenges and Benefits of using HACCP as a Quality Risk Management Tool in the Pharmaceutical Industry Saurabh Dahiya 1,, Roop K. Khar 1 and Aruna Chhikara 2 1 Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, Hamdard Nagar, New Delhi , India 2 Department of Chemistry, Dyal Singh College (University of Delhi), Lodhi Road, New Delhi , India Summary Effective quality risk management can facilitate better and more informed decisions, provide regulators with greater assurance of a company s ability to deal with potential risks and can beneficially affect the extent and level of direct regulatory oversight. The Hazard Analysis and Critical Control Points (HACCP) method is now a recognized and useful tool in the pharmaceutical industry to meet the primary principles of quality risk management. Global perspective, forward-looking view, open communication, integrated management, continuous process, shared product vision and teamwork are the principles, which provide a framework to accomplish effective risk management. The quality risk management process includes risk identification, risk analysis and risk evaluation. Control and reduction of the risk focuses on processes for mitigation or avoidance of quality risk when it exceeds an acceptable level. The quality risk management tools provide documented, transparent and reproducible methods to accomplish the steps of the quality risk management process. The HACCP methodology aims to prevent known hazards and reduce the risk that they will occur at specific points in the pharmaceutical manufacturing processes. It covers both the Good Manufacturing Practices (GMP) and the safety of the personnel engaged in the manufacturing processes. HACCP is the systematic method (comprised of seven principles) for the identification, assessment and control of safety hazards associated with physical, chemical and biological hazards. The problems associated with the implementation of HACCP may be overcome by training and education in the HACCP system for the personnel engaged in pharmaceutical industry. The HACCP system benefits all, the consumers, industry and the government as it focuses on prevention rather than relying mainly on end product testing. This scientific and systematic system is cost-effective and leads to reduced product loss *Correspondence to: Saurabh Dahiya, Research Scholar, Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, Hamdard Nagar, New Delhi , India. saurabhdahiya@gmail.com Copyright r 2009 John Wiley & Sons, Ltd. Qual Assur J 2009; 12,

2 96 S. Dahiya et al. and wastage, and assures the safety of pharmaceutical products. Copyright r 2009 John Wiley & Sons, Ltd. Key Words: Hazard Analysis and Critical Control Points (HACCP); quality risk management; Good Manufacturing Practices; GMP; Critical Control Point (CCP); risk analysis Introduction It is commonly understood that risk is defined as the combination of the probability of occurrence of harm and the severity of that harm. The manufacturing and use of a drug (medicinal) product, including its components, necessarily entail some degree of risk. The risk to its quality is just one component of the overall risk. It is important to understand that product quality should be maintained throughout the product lifecycle such that the attributes that are important to the quality of drug (medicinal) product remain consistent with those used in the specifications in the marketing authorization. Use of quality risk management can improve decision making if a quality problem arises. Effective quality risk management can facilitate better and more informed decisions, can provide regulators with greater assurance of a company s ability to deal with potential risks and can beneficially affect the extent and level of direct regulatory oversight. Principles of Quality Risk Management The primary principles of quality risk management are [1]: The evaluation of the risk to quality should ultimately link back to the protection of the patient. The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk and be based on scientific knowledge. In order to guarantee the consistently high quality of medical products for human use, it is absolutely necessary that flawless hygiene conditions be maintained by the strict observance of hygiene rules. With the growing understanding of the impact of process conditions on the quality of the resulting product, process controls (surveillance) have gained increasing importance to complete the quality profile traditionally defined by post-process product testing. Today, process controls have become an important GMP requirement for the pharmaceutical industry. However, before quality process controls can be introduced, the manufacturing process has to be analyzed, with the focus on its critical quality-influencing steps [2]. The Hazard Analysis and Critical Control Points (HACCP) method is well recognized as a useful tool in the pharmaceutical industry. Although a systematic approach to a quality risk management is generally preferred, it is neither always appropriate nor necessary to use a formal risk management process. The use of informal risk management processes can also be acceptable. Appropriate use of quality risk management can facilitate but does not obviate industry s obligation to comply with regulatory requirements and does not replace appropriate communications between industry and regulators. The seven principles given below in tabular form provide a framework to accomplish effective risk management. These principles are embodied within risk management tools and services like HACCP that address the need to establish a baseline set of risks in a project or programme and the need to create and implement a continuous process by including all parts of the program in the joint management of risks. The seven principles given in Table 1 provide a framework to accomplish effective risk management [3]. Genesis and Growth of Quality Risk Management Process Quality risk management includes systematic processes designed to coordinate, facilitate and

3 Opportunities, Challenges and Benefits of using HACCP 97 Table 1. Seven principles providing the framework to accomplish effective risk management [3] Global Perspective Forwardlooking View Open Communication Integrated Management Continuous Process Shared Product Vision Teamwork Viewing all product and process development work with in the context of the larger systems-level definition, design, and development. Recognizing both the potential value of opportunity and the potential impact of adverse effects. Thinking toward tomorrow, identifying uncertainties, anticipating potential outcomes. Managing project resources and activities while anticipating uncertainties. Encouraging free-flowing information at and between all project levels. Enabling formal, informal, and impromptu communication. Using processes that value the individual voice (bringing unique knowledge and insight to identifying and managing risk). Making risk management an integral and vital part of project management. Adapting risk management methods and tools to a project s infrastructure and culture. Sustaining constant vigilance. Identifying and managing risk routinely through all phases of the project s life cycle. Mutual product vision based on common purpose, shared ownership, and collective communication. Focusing on results. Working cooperatively to achieve common goal. Pooling talents, skills, and knowledge. improve science-based decision making with respect to risk. Possible steps used to initiate and plan a quality risk management process might include the following: Define the problem and/or risk question including pertinent assumptions identifying the potential for risk. Assemble background information and data on the potential hazard, harm or human health impact relevant to the risk assessment. Define how decision makers will use the information, assessment and conclusions. Identify a leader and necessary resources. Specify a timeline and deliverables for the risk management process. The steps include risk identification, risk analysis and risk evaluation. Quality risk assessments begin with a well-defined problem description or risk question. What might go wrong? What is the likelihood (probability) it will go wrong? What are the consequences (severity)? Identification of the risk involves a systematic use of information to identify hazards referring to the risk question or problem description. Information can include historical data, theoretical analysis, informed opinions, and the concerns of stakeholders. Risk identification addresses the What might go wrong? question, including identifying the possible consequences. This provides the basis for further steps in the quality risk management process. The analysis of risk includes the process of estimation of the risk associated with the identified hazards. It is the process that focuses on the second and third question, seeking the likelihood that risks identified in risk identification might occur and the ability to detect them. Finally the evaluation process compares the identified and analyzed risk against given risk criteria. A qualitative or quantitative process might be used to assign the probability and severity of a risk. Risk evaluations consider the strength of evidence for all three of the fundamental questions. Control and reduction of the risk focuses on decision making to reduce and/or accept risks. The purpose of risk control is to reduce the risk to an acceptable level, while risk reduction focuses on processes for mitigation or avoidance of quality risk when it exceeds an acceptable level. Risk reduction might include actions taken to mitigate the severity and probability of harm. Exchange or sharing of information about risk and its management between the decision maker and other involved parties constitutes the risk communication

4 98 S. Dahiya et al. process. The involved parties can communicate at any stage of the risk management process. Also a formal risk communication process may be developed as part of the risk management process. Once a quality risk management process has been initiated, that process should then be continued, reviewed and utilized for events that might impact the original quality of the product and processes. Figure 1 presents the quality risk management process. Risk Management Tools Quality risk management tools support a scientific and practical approach to decision making by providing documented, transparent and reproducible methods to accomplish steps of the quality risk management process. Failure Mode Effects Analysis (FMEA). Failure Mode Effects and Criticality Analysis (FMECA). Fault Tree Analysis (FTA). Hazard Analysis and Critical Control Points (HACCP). Hazard Operability Analysis (HAZOP). Preliminary Hazard Analysis (PHA). Risk ranking and filtering. Supporting statistical tools. Basic Risk Management Facilitation Methods Some of the simple techniques that are commonly used to structure risk management by organizing data and facilitating decisionmaking are: Flowcharts. Check Sheets. Process Mapping. Cause and Effect Diagrams (also called an Ishikawa diagram or fish bone diagram). Figure 1. Presentation of the quality risk management process [1]

5 Opportunities, Challenges and Benefits of using HACCP 99 Hazard Analysis and Critical Control Points (HACCP) HACCP is a systematic, proactive and preventive method for assuring product quality, reliability, and safety [4]. It is a structured approach that applies technical and scientific principles to analyze, evaluate, prevent, and control the risk or the adverse consequence(s) of hazard(s) due to the design, development, production, and use of products. This is a method which in effect seeks to plan out unsafe practices, differing from traditional produce and test quality control methods. Hazard Analysis and Critical Control Point (HACCP) methodology has been considered to be a food safety management system. It aims to prevent known hazards and to reduce the risks that they will occur at specific points in the food chain. The same principles are also increasingly being applied in other industries also. Hazards affecting quality are controlled to a certain extent through the validation of critical operations and processes in the manufacture of finished pharmaceutical products in accordance with Good Manufacturing Practices (GMP). However GMP does not cover the safety of the personnel engaged in manufacture, while safety and quality aspects are covered by HACCP [5 9]. Procedures, including GMP, address optional conditions and provide the basis for HACCP. HACCP is the systematic method for the identification, assessment and control of safety hazards. Such hazards are defined as biological, chemical, or physical agents or operations that are reasonably likely to cause illness or injury if not controlled. In the manufacture of pharmaceuticals [5], these may include the manufacture of certain antibiotics, hormones, cytotoxic substances or other highly active pharmaceuticals, together with operations such as fluid-bed drying and granulation, which are examples of hazard unit operations. The use of inflammable solvents (solutions) and certain laboratory operations may also constitute hazards. Historical Background of HACCP HACCP programs first began as a natural extension of GMPs that food companies had been using as a part of their normal operations. A system was needed that enabled the production of safe, nutritional products for use by the National Aeronautics and Space Administration (NASA) starting in the late 1950s to feed future astronauts. Food products could not be recalled or replaced while in space [10]. Beginning in 1959, the Pillsbury Company embarked on work with NASA to further develop a process stemming from ideas employed in engineering system development know as Failure Mode and Effect Analysis (FMEA). Through the thorough analysis of production processes and identification of microbial hazards that were known to occur in the production establishment, Pillsbury and NASA identified the critical points in the process at which these hazards were likely introduced into product and therefore should be controlled. The establishment of critical limits of specific mechanical or test parameters for control at those points, the validation of these prescribed steps by scientifically verifiable results, and the development of record keeping by which the processing establishment and the regulatory authority could monitor how well process control was working all culminated in what today is known as HACCP. In this way, an expensive or time-consuming testing procedure is not required to guarantee the safety of each piece of food leaving an assembly line, but rather the entire process has been seamlessly integrated as a series of validated steps. In 1971, the HACCP approach was presented at first American National Conference for Food Protection. From 1988 to the present day, HACCP principles have been promoted and incorporated into food safety legislation in many countries around the world. Beginning in 1996, the United States Department of Agriculture (USDA) established a

6 100 S. Dahiya et al. detailed Pathogen Reduction/Hazard Analysis of Critical Control Point (PR/HACCP) program under the Food Safety and Inspection Service (FSIS) to regulate the production of raw meat products by large-scale facilities [10]. Seven Principles for Achieving HACCP Management a) Conduct a hazard analysis and identify preventive measures for each step of the process. b) Determine the critical control points. c) Establish critical limits. d) Establish a system to monitor the critical control points. e) Establish the corrective action to be taken when monitoring indicates that the critical control points are not in a state of control. f) Establish system to verify that the HACCP system is working effectively. g) Establish a record-keeping system. Potential Areas of Use 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 a risk management tool that facilitates monitoring of critical points in the manufacturing process [1]. Figure 2 is representative of the principles of HACCP for the food industry and the same type of program can be adapted for pharmaceutical industries as well [7]. How to Implement the HACCP Program in the Pharmaceutical Industry 1 Assemble a HACCP Team The pharmaceutical manufacturer should assure that product-specific knowledge and expertise are available for the development of an effective HACCP plan. This may be best accomplished by assembling a multidisciplinary team. Team members should therefore represent all the relevant disciplines, such as research and development, production, quality control, quality assurance, microbiology, engineering and distribution or others as applicable [5]. Team members should have specific knowledge and expertise regarding the product and process. Where such expertise is not available on site, expert advice should be obtained from other sources. Team members should be able to: a) Conduct a hazard analysis. b) Identify potential hazards. c) Identify hazards that should be controlled. d) Recommend controls and critical limits. e) Devise procedures for monitoring and verification. f) Recommend appropriate corrective action where deviations occur. g) Verify the HACCP plan. 2 Describe the Product and Process A full description of the product and the process should be drawn up, including relevant quality information such as the composition, physical/chemical properties, structure, ph, temperatures, method of cleaning, bactericidal/ bacteriostatic treatments (e.g. heat-treatment), drying, screening, mixing, blending, packaging, and the storage conditions. The method of distribution and transport should also be described, especially where products are thermolabile. 3 Identify the Intended Use The intended use 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.

7 Opportunities, Challenges and Benefits of using HACCP 101 Analyze Hazards Recognize potential hazards to the food s safety. Identify measures to regulate and control the hazard. Identification of Critical Control Points (CCPs) Establish CCPs throughout the production process of the product. CCP Prevention Measures Establish a prevention measure at all CCPs. For example, monitor minimal cooking time or temperature at a certain point in the product line. Monitoring of CCP Prevention Measures Establish a system to monitor prevention measures at a CCP. For example, use a computer system to monitor and log the temperature. CCP Not Met Establish a precaution when the CCP has not been met. For example, if the temperature is too low, the computer will alarm, flagging the batch to be destroyed. HACCP & CCP Log Maintain a log system of all CCPs. Keep records of CCP control methods and action taken to correct potential problems. Figure 2. Principles of HACCP for the food industry (the same type of program can be adapted for pharmaceutical industries as well) 4 Prepare a Figure The figure should be constructed by the HACCP team and should cover all operations and decisions in a process. When applying HACCP to a given operation, the steps preceding and following that operation should also be considered. The HACCP team should confirm the processing operation against the figure during all stages and hours of operation. Amendments to the figure may be made where appropriate, and should be documented. Implementing the Principles of HACCP Principle 1. Conduct a hazard analysis and identify preventive measures for each step of the process. A thorough hazard analysis is required to ensure an effective control point. A two-stage hazard analysis is recommended. During the first stage, the team should review the material, activities, equipment, storage, distribution and intended use of the product. A list of potential hazards (biological, chemical and physical) which may be introduced, increased or controlled in each step should be drawn up. In the hazard analysis, the following should be included wherever possible: a) The probable occurrence of hazards and the severity of their adverse health effects. b) The qualitative and/or quantitative evaluation of the presence of hazards.

8 102 S. Dahiya et al. c) The survival or multiplication of microorganisms of concern. d) The production or persistence in drugs of toxins, chemicals or physical agents. e) The conditions leading to the above. During the second stage, a hazard evaluation should be conducted, i.e. the severity of the potential hazards and the probability of their occurrence should be estimated. The team should then decide which potential hazards should be addressed in the HACCP plan, and what control measures, if any, exist that can be applied for each hazard. More than one control measure may be required to control a specific hazard(s) and more than one hazard may be controlled by a specified control measure. Potential hazards in relation to at least the following should be considered: materials and ingredients, physical characteristics and composition of the product, processing procedure, microbial limits, and, where applicable, premises, equipment packaging, sanitation and hygiene, personnel, risk of explosions, and mix-ups. Principle 2. Determine the critical control points. 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. A Critical Control Point (CCP) in the HACCP system can be more easily determined by the use of a decision-tree, which facilitates a logical approach. Principle 3. Establish critical limits. The criteria used for establishing the critical limits often include measurements of temperature, time, moisture level, ph, and sensory parameters, such as visual appearance and texture. Critical limits should be scientifically justified. Principle 4. Establish a system to monitor the critical control points. Monitoring is the scheduled measurement or observation of a CCP relative to its critical limits. Monitoring activities should be recorded. The monitoring procedures used must be able to detect loss of control at the CCP, and this information should ideally be available in time to make adjustments to ensure control of process and prevent violations of the critical limits. Most monitoring procedures for CCPs will need to be done rapidly because they relate to on-line processes and there will not be time for lengthy analytical testing. For this reason, physical and chemical measurements are often preferred to microbiological tests because they can be done rapidly and can often indicate the microbiological control of the product. The personnel conducting the monitoring of CCPs and control measures should be engaged in production (e.g. line supervisors, maintenance staff) and, where appropriate, staff from quality control. They should be trained in monitoring procedures. Principle 5. Establish the corrective actions to be taken. Specific corrective actions should be developed for each CCP in the HACCP system in order to deal with deviations when they occur. These actions should ensure that the CCP is brought under control. Corrective actions should include at least the following: a) Determination and correction of the cause of non-compliance. b) Determination of the disposition of the non-compliant product. c) Recording of the corrective actions that have been taken. Principle 6. Establish a system to verify that HACCP is working effectively. Verification and auditing methods, procedures and tests, including random sampling and analysis, can be used to determine whether the HACCP system is working correctly. The frequency of verification should be sufficient to confirm the proper functioning of the HACCP system. Examples of verification activities include the following: a) Review of the HACCP system and its records.

9 Opportunities, Challenges and Benefits of using HACCP 103 b) Review of deviations and product dispositions. c) Confirmation that CCPs are kept under control. Principle 7. Establish a record keeping system. Documentation and record keeping are essential parts of the HACCP system and should be appropriate to the nature and size of the operation. Examples of activities for which documentation is required include hazard analysis, CCP determination, HACCP plan and critical limit determination. Examples of activities for which records are required include CCP monitoring activities, process steps, associated hazards, critical limits, verification procedures and schedule, and modifications to the HACCP system. Problems Associated With the Implementation of HACCP Pharmaceutical companies, small and medium in size may face problems in implementation of HACCP programme because of insufficient trained personnel. The cost of implementation of the HACCP system in small and medium companies is very high and their small purchasing power cannot often bear it and also cannot exert sufficient influence on their suppliers to start using the HACCP system and the power that they can exert over clients is also limited [11]. Training and Education in the HACCP System HACCP is a relatively new concept in the pharmaceutical industry. Training of personnel in industry, government and universities in HACCP principles and applications is essential for its effective implementation. In developing specific training to support a HACCP plan, working instructions and procedures should be drawn up which define the tasks of the operating personnel to be stationed at each critical control point. Specific training should be provided in the tasks of employees monitoring each CCP. Employees must understand what HACCP is, learn the skills necessary to make it function properly, and must be given the materials and equipment necessary to control the CCPs. Advantages of HACCP Implementation in Pharmaceutical Industry The HACCP system identifies probable hazards to ensure drug safety. It is cost-effective and leads to reduced product loss and wastage. It increases the effectiveness of the quality system by focusing on the critical parts of the process. Its focus is on prevention rather than relying mainly on end product testing. It can aid inspection by regulatory authorities and promote international trade by increasing confidence in drug safety and promote the stability of the business. It complements and strengthens other quality management systems [11]. Conclusion HACCP would enable the producers, processors, distributors, and exporters etc. of pharmaceutical products to utilize technical resources efficiently and in a cost-effective manner in assuring safety of pharmaceutical products. Regulatory inspections and audits would be more systematic and therefore hasslefree. It would no doubt involve deployment of some additional finances initially but this would be more than compensated in the long run through consistently better quality and hence better prices and returns. References 1. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. Draft Consensus

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