In September 2004, the United States Food and Drug Administration (US FDA) announced pharmaceutical current good manufacturing practices (cGMP) for the 21st century. Their intention was to integrate quality system and risk management with existing good manufacturing practice (GMP) guidelines to encourage adopting modern and innovative manufacturing technology. Also, they intended to harmonize the US FDA cGMP regulatory requirement with other international cGMP regulatory requirements and other quality management systems like international standard organisation (ISO-9000). The concept of comprehensive quality management system (CQMS) is emerging from the US FDA's pharmaceutical cGMP for the 21st century.
Here, US FDA has proposed a six system inspection model for FDA personnel for conducting inspection. By referring this, an eight system inspection model has been developed, which is part of CQMS from the auditor and auditee or pharmaceutical organisation's point of view. It consists of two more systems, i.e., regulatory / management and engineering. Here, we consider quality system as separate section, which comprises the quality assurance and other quality related aspects. This system covers not only the 20 points referred by US FDA but also the other important aspects of cGMP, i.e., 21 code of federal regulations (CFR) parts 210 and 211.
The CQMS is designed to help pharmaceutical manufacturers to meet the requirements of the FDA's cGMP regulations and reduce the frequent regulatory submissions for minor changes. The principal objective of CQMS is to ensure consistent production of quality products, i.e., meeting the identity, strength, safety, purity and efficacy and to make manufacturing activities sustainable. The robust CQMS will promote process consistency by integrating effective knowledge building mechanism into daily operational decisions.
Basis of CQMS
It is based on the philosophy that, 'quality should be built into the product, and testing alone cannot be relied on to ensure product quality'.
This statement can be supported by one incident which happened to a well known pharmaceutical organisation. This particular company was into the production of an antibacterial drug containing active ingredient as antibacterial agent along with other excipients. But due to failure in dispensing practice, the dispensing officer dispensed Glibenclamide as one of the excipients along with antibacterial agent. In final quality control testing all test parameters were acceptable. But the incident of wrong addition of Glibenclamide came in focus, only after the complaints related to hypoglycemic effects were reported. This incident gives an idea that there are lots of such parameters, which may fail to ensure the quality of product only by the final testing. Hence, it is important that the quality should be built throughout the material.
FDA's 20 points
US FDA has suggested 20 points as part of its cGMP for 21st century, which is also the basis of CQMS. They include:
Provide leadership: In developing robust quality management system, the higher authority or senior management has to define organisation's mission and strategies. They have to take active participation in system design, implementation, monitoring and review. Committing necessary resources will visibly support the quality system. They have to develop internal communication in the area of research and development, regulatory affairs, manufacturing, engineering, validation, quality management, personnel and other related issues.
Structure the organisation: When designing a CQMS, the management has the responsibility to define organisational structure and document it and also to determine the jobs (employee roles), responsibilities and authorities within the system to empower employee to detect and resolve the problems affecting quality of products.
Build your quality system to meet requirement: The CQMS provides system help to ensure compliance within the regulations related to identity, strength, safety, purity and efficacy of the product to control the outsourcing. It also defines standards of quality (specifications) and implementation of quality policies. Developing, implementing, monitoring and revising quality procedures are major aspects of CQMS.
Establish policies, objectives and plans: In developing CQMS, the senior management should articulate their vision of quality through implementing the policies, objectives and plans. They should provide strong commitment to quality and set the organisational mission. They are responsible for developing quality manual, quality policies and conveying policy at all levels of the organisation to make all employees and other relevant people to understand it in letter and spirit. They also revise these policies as and when needed.
The quality objectives are created at the top level of the organisation (and other level as needed) through a formal quality planning process. Use quality planning process to identify resources and define methods to achieve the quality objectives.
Review of the system: System review is required for continuing suitability, adequacy and effectiveness of the robust quality system. Such reviews should typically include both an assessment of the product as well as customer needs. The quality system review should cover the points like, quality policy and objectives, result of audit and other assessment, customer feed back, including complaints, trend analysis and actions to prevent a potential problem or a recurrence and follow up action from previous management reviews.
The review outcome typically includes improvements to the quality system and related quality processes, improvement to manufacturing processes and products and realignment of resources. The review results must be recorded and planned actions should be implemented using corrective and preventive action and change control procedures.
General arrangements of resources: The resources such as trained manpower, building and facilities, equipment, materials, defined manufacturing and packaging process and facilities for laboratory analysis and related resources should be provided in adequacy.
Develop personnel: The CQMS recommends qualified and trained personnel to do an assigned work properly, without overruling the cGMP regulations. The senior management defines qualification for each position and gives the training to personnel in cGMP and specific job.
The training programmers should follow points like:
■ Identification of training needs
■ Provision for training to satisfy their needs
■ Evaluation of effectiveness of training
■ Documentation of training and retraining
■ Use of knowledge, skills and attitude learned in training, in day to day activities
Facilities & equipment: FDA officer's expertise can be used to identify and select the proper facilities and equipment (pre inspection approval may be sought). These facilities and equipment must be qualified, calibrated, cleaned and maintained to prevent contamination and mix-ups. Equipment should include process and testing equipments, i.e., manufacturing, utilities and testing instruments or equipments etc.
Control outsourced operations: While outsourcing for operational processes to a second party, the quality agreement should clearly describe materials and services, quality specifications, responsibilities and communication mechanisms. Contract giver should satisfy himself about the adequacy and ability of the contract acceptors in terms of his quality systems and implementation.
Design & development of product and processes: In CQMS the product characteristics are defined from design to delivery and exercise change control. It also defines manufacturing, quality process and procedures and establishes responsibilities for designing or changing products and documenting processes, ensuring that critical variables are identified. This document should include resources and facilities needed, procedures to carry out processes, identification and control of critical variables and validation activities, including operating ranges and acceptance criteria.
Monitor packaging & labelling processes: The CQMS recommends planning and documentation of all packaging and labelling procedures. These procedures should outline quality control (QC) activities and responsible persons, specifications and controls for packaging and labelling materials before commercial production.
In CQMS, a design plan should include authorities and responsibilities, design and development stages and appropriate review, verification and validation. Change control should be maintained through out the design process.
Examine inputs: In CQMS models, the term 'input' refers to any material that goes into a final product, no matter, whether it is traceable or not in the finished product and also whether the materials is purchased by the manufacturer or produced by the manufacturers for the purpose of processing. Materials can include items like components (e.g., ingredients, process water etc), container and closures etc. Quality system should address receipt, production, storage and use of all inputs.
All inputs must be tested or use of certificate of analysis of manufacturers may be accepted under suitable conditions. But even in the case of use of certificate of analysis, identification of the materials is needed. Materials produced in house should also go under the same acceptance criteria and testing procedures as other purchased materials (e.g., purified water, N2 gas etc.).
Perform & monitor operations: In the CQMS, areas of process weaknesses should be identified and factors that influence critical quality attributes should be given increased scrutiny. The process should be validated and sufficient testing data should be provided. A system for continuous improvement of operations should be developed and implemented. The entire life cycle should be addressed by the establishment for continuous improvement mechanism in the CQMS.
The procedure of review and evaluation should be in place to anticipate change control and monitor it. The deviations control procedures should also be in place. This deviation control should cover personnel, materials, equipment, facilities and systems. Product release record must be in place.
The critical process parameters monitored during production are:
■ Process step should be verified by using validated computer system or a second person. The records must be maintained simultaneously
■ Procedures should be in place to prevent objectionable microorganisms in finished product that are not required to be sterile and to prevent microbial contamination of finished product purported to be sterile. Sterilisation process should be validated
■ The procedure should be developed to monitor, measure and analyse the operations
■ Procedure should be in place to ensure the accuracy of test result
■ The system should address how to deal with 'out of specifications' results
■ The CQMS should address product distributions issues
Address non conformities: A key component in any CQMS is handling of non conformities / or deviations. It includes,
■ Defining and classifying non conformities (e.g. critical, major and minor)
■ Developing document system for identifications, investigation and corrective action to be taken against non conformities
■ Planned action for remedial purpose to avoid the recurrence in future and segregation of product currently facing non conformities
Analyze data for trends: It involves collecting data from monitoring, measurement, complaint handling and other activities. This information is useful for detection and prevention of problems as early as possible.
Conduct internal audits: CQMS approach call for audits to be conducted at planned intervals to evaluate effective implementation and maintenance of the quality system and to determine if processes and products meet established parameters and specification.
The entire system should at least be audited once in a year in staggered or planned manner. The managers, who are responsible for the areas audited, should take timely actions to resolve audit findings and ensure that follow up actions are completed, verified and recorded.
Risk assessment: The management should assign priorities to activities or actions based on the consequences of actions or inaction otherwise known as risk assessment. The risk assessment is used as a tool in the development of product specifications and critical process parameters used in conjunction with process understanding, risk assessment helps anticipate, manage and control the changes.
Corrective action: The corrective action is a reactive tool for system improvement to ensure that significant problems do not occur. The procedure is to be developed and documented to ensure that the need for action is evaluated relevant to the possible consequences, the root cause of the problem is investigated and possible actions are determined and selected action is taken within the defined time frame. The effectiveness of the action taken should be evaluated and it is essential to maintain records of corrective action taken.
The management can gather information for taking corrective action from sources such as:
■ Nonconformance report and rejection
■ Complaints
■ Internal and external audit
■ Data and risk analyses related to operation and quality system processes
■ Management review decisions
Preventive action: The preventive action is an essential tool in quality system management. The Preventive actions may involve areas like, succession planning, training, capturing institutional knowledge, planning for personnel and policy and process changes. The selected preventive action should be evaluated and recorded and the system should be monitored for the effectiveness of the actions.
Promote improvement: The effectiveness of the quality system can be improved through the quality activities described as above in CQMS. The involvement of the senior management in the evaluation of this improvement process is critical.
In addition to the US FDA's 20 points, we have added four more points in the system. They include validation, heating, ventilation and air conditioning (HVAC) system validation, water and steam system validation and vendor certification.
Validation
Initially pharmaceutical industry was heavily depended on controlling the quality, over a period of time this concept has changed to assuring the quality of product.
Pharmaceutical validation is a major activity under the quality assurance. Validation assures the desired performance of:
■ Buildings
■ Equipment
■ Materials
■ Processes etc
Hence, without validation we can not think of assuring desired quality attributes in any product.
Heating, ventilation and air conditioning (HVAC) system validation
Air is one of the major constituents in creating the desired environment, including storage and processing. This environment includes requirements related to temperature, relative humidity, class of air, differential pressure and number of air changes etc. This entire thing is taken care of by a suitably designed, operated, monitored and maintained HVAC system.
Water and steam system validation
All the regulatory requirements, including pharmacopoeia monographs give a lot of importance to quality of pharmaceutical water. Particularly United States Pharmacopeia (USP), not only describes different monographs on pharmaceutical water, but also details validation system for pharmaceutical water. Pharmaceutical water is to be considered as one of the major raw materials, particularly in the case of most of the liquid formulations either sterile or non sterile. Hence, generation, storage, distribution, use and disposal of pharmaceutical water is considered as one of the major activities of assuring the quality of the pharmaceutical product and hence it is very important from the point of view of regulatory compliance.
Vendor certification
The US FDA and other drug regulatory authorities world over insist on consistency of quality of all the inputs into manufacturing of pharmaceutical product. Hence, certification of vendors becomes a very important activity in assuring quality of pharmaceutical product. One can depend on certified vendors for consistency of quality, commitment of deliveries and other technical and commercial aspects related to purchase of inputs. Vendor certification is a team activity, consisting of representative from purchase, quality assurance, production, research and development and engineering etc. Hence, this activity must be considered as one of the major activities under quality assurance.
In this six system inspection model we found that the 20 points proposed by US FDA do not get appropriately fitted into the six system inspection model. For this reason, we modified the 6/20 concept to 8/24 that means eight system inspection model not only covers all 20 points proposed by US FDA, but also other four points which are very important. Besides, other regulations are also emphasised on these four points.
In this eight system inspection model, these 24 points fitted in such a way that it is found to be very useful for both auditor and the pharmaceutical organisations. The pharmaceutical organisations, which are going to implement the CQMS should prepare for any type of audit - either US FDA or any regional audit. The most important advantage of this CQMS is that, if in first inspection of US FDA, if FDA inspectors are convinced that the CQMS is implemented and followed by the organisation, then in the next inspection of US FDA they make a remark that any small changes in facility, equipment or process etc do not require a regulatory submission.
For auditor, this system is useful because it reduces the time required for the inspection of pharmaceutical organisation which can decrease the work load on the inspector. u
(Ajit Shinde is QA executive, Matrix Pharma & Dr Manohar A Potdar is Professor Emeritus, Deptt. Of QA Techniques, Poona College of Pharmacy, Bharati Vidyapeeth University, Pune.)