Comprehensive Quality Management System for Regulatory Compliances
By: Ajit. K. Shinde, M. A. Potdar
SUMMARY
United States Food and Drug Administration (USFDA) propose Six System Inspection Model for the audit of pharmaceutical organization for minimization of regulatory submission. Author studied this system, then added and modified this to Eight System Inspection Model to make this more useful and user friendly for the pharmaceutical organization which wants to go for USFDA or other international audits. While doing this author added two additional systems (Management/Regulatory) and four additional points (Validation, HVAC System Validation, Water and Steam System Validation and Vendor Certification). The author feels that, this will help the Food and Drug Administration (FDA) as well as pharmaceutical organization more appropriately.
Key Words: CQMS; USFDA; CGMP; Six System Inspection Model; Eight System Inspection Model
INTRODUCTION
United States Food and Drug Administration (USFDA) in September 2004 announced pharmaceutical Current Good Manufacturing Practices (CGMP) for 21st century [1]. Their intention was to integrate quality system and risk management with existing CGMP guidelines to encourage adopting modern and innovative manufacturing technology. Also to harmonies the USFDA CGMP regulatory requirement with other international CGMP regulatory requirement [2, 3] and other quality management systems like International Standard Organization (ISO-9000) etc. The concept of Comprehensive Quality Management System (CQMS) is emerging from the USFDAs pharmaceutical CGMP for 21st century. The material in this paper is interpreted by the author from the Draft guidance for Industry Quality Systems Approach to Pharmaceutical CGMP Regulations [1].
Here, USFDA propose Six System Inspection Model for Food and Drug Administration (FDA) personnels for conducting inspection. By referring this model we developed Eight System Inspection Model which is a part of CQMS from the auditor and audittee or pharmaceutical organization 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 USFDA but also the other important aspects of CGMP i.e. 21 Code of Federal Regulations (CFR) Parts 210 & 211.
The CQMS is designed to help manufacturer of pharmaceuticals to meet the requirements of the FDAs CGMP regulations and to reduce the frequent regulatory submissions for minor changes. The principal objective of CQMS is to ensure consistent production of a quality product (identity, strength, safety, purity & efficacy) and those activities are sustainable. The robust CQMS will promote process consistency by integrating effective knowledge building mechanism into daily operational decisions.
Basis of C.Q.M.S.:-
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 is supported by one incident which was happen with Boehringer Knoll Laboratories Ltd. There was 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 effect are reported. This incident gives an idea that there are lots of such parameters which could not ensure the quality of product only by the final testing. That means the quality should be built through out the material and process flow and not only by the final testing of the product.
FDAs 20 Points
1. Provide leadership
In developing robust quality management system, the higher authority or senior management has to define organizations mission and strategies. They have to take active participation in system design, implementation, monitoring and review, Committing necessary resources visibly support the quality system. They have to develop internal communication in the area of research development, regulatory affairs, manufacturing, quality unit, personnel and other related issues.
2. Structure the organization
When designing a CQMS, the management has the responsibility to define organizational 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 product.
3. Build your quality system to meet requirement
The CQMS provide system help to ensure compliance within the regulations related to identity, strength, safety, purity and efficacy, to control the outsourcing. It also defines standards of quality (specifications) and implementation of quality policies. The developing, implementing, monitoring and revising quality procedures is one of the major aspects of CQMS
4. Establish policies, objectives and plans
In developing CQMS, the senior management articulates their vision of quality through implementing the policies, objectives and plans. They provide strong commitment to quality into the organizational mission. They are responsible for developing quality manual, quality policies and to communicate policy at all levels of the organization, to make all employees and all other relevant people to understand it in letter and spirit also to revise these policies as and when needed.
The Quality objectives are created at the top level of the organization (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.
5. Review of the system
System review is required to continuing suitability, adequacy and effectiveness of the robust quality system. Such review 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, actions to prevent a potential problem or a recurrence, follow up action from previous management reviews.
The review outcomes typically include improvements to the quality system and related quality processes, improvement to manufacturing processes and products, realignment resources. The review result must be recorded, planned actions should be implemented using corrective and preventive action and change control procedures.
6. General arrangements of resources
The following resources should be provided in adequacy,
ü Building and facilities
ü Equipment
ü Materials
ü Defined manufacturing and packaging process
ü Facilities for laboratory analysis and related resources
7. 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, also gives the training to personnel in CGMP and specific job.
The training programmers should include at least following points,
ü Identification of training needs
ü Provision for training to satisfy there needs.
ü Evaluation of effectiveness of training
ü Documentation of training and retraining
ü Use of skills learned in training, in day to day activities.
8. Facilities and equipment
FDA officers 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 both process as well as testing equipments i.e. manufacturing, utilities and testing instruments or equipments etc.
9. 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 communications mechanisms. Contract giver should satisfy him self about the adequacy and ability of the contract acceptors in terms of his quality systems and its implementation.
10. Design and development of product and processes
In CQMS the product characteristics are defined from design to delivery and exercise change control, and also the manufacturing, quality process and procedures are defined. It also establishes responsibilities for designing or changing products, documenting processes will ensure that critical variables are identified. This document should include resources and facilities needed, procedures to carry out processes, identification & control of critical variables, validation activities including operating ranges and acceptance criteria etc.
11. Monitor packaging and labeling processes
The CQMS recommend planning and documentation of all packaging and labeling procedures. These Procedures should outline Quality Control (QC) activities and responsible position, specifications and controls for packaging and labeling materials should also be determined 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.
12. Examine inputs
In CQMS models, the term “input” refers to any materials 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 such as components (e.g. ingredients, process water etc).container and closures etc. Quality system should address receipt, production, storage and use of all products.
All input 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.)
13. Perform and monitor operations
In the CQMS, areas of process weaknesses should be identified and factors that are influential on critical quality attributes should receive 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 and facilities. Product release record must be in place.
The critical Process parameters monitored during production are as follows
1. Process step should be verified by using validated computer system or a second person; these records must be maintained simultaneously.
2. Procedures should be in place to prevent objectionable microorganisms in finished product that is not required to be sterile and to prevent microbial contamination of finished product purported to be sterile, sterilization process should be validated.
3. The procedure should be developed to monitor, measure and analyses the operations
4. Procedure should be in place to ensure the accuracy of test result.
5. The system should address how to deal with “Out of Specifications” results.
6. The CQMS should address product distributions issues.
14. Address non conformities
A key component in any CQMS is handling of non conformities / or deviations. It includes,
ü Defining and classifying non conformities (e.g. Critical, Major & Minor)
ü Developing document system for identifications, investigation and corrective action to be taken against non conformities.
ü Planed action for remedial purpose to avoid the recurrence in future and segregation of product currently facing non conformities.
15. 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.
16. 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 the year in staggered or planned manner. The managers who are responsible for the areas audited to take timely actions to resolve audit findings and ensure that follow up actions are completed, verified and recorded.
17. Risk assessment
The management should assign priorities to activities or actions based on the consequence 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 anticipated, manage and control change.
18. Corrective action
The corrective action is a reactive tool for a 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, possible actions are determined, selected action is taken within the defined time frame and effectiveness of the action taken is evaluated. It is essential to maintain records of corrective action taken. The management can gather information from following sources for taking corrective action,
a. Nonconformance report and rejection
b. Complaints
c. Internal and External audit
d. Data and risk analyses related to operation and quality system processes
e. Management review decisions
19. Preventive action
The preventive action is an essential tool in quality system management.
The Preventive action may involve areas like, succession planning, training, capturing institutional knowledge, planning for personnel, 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
20. Promote improvement
The effectiveness of the quality system can be improved through the quality activities described as above in CQMS. It is critical that senior management be involved in the evaluation of this improvement process.
Authors Points
1. 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 [3].
Pharmaceutical validation is the major activity under the quality assurance. Validation assures the desired performance of,
ü Buildings
ü Equipment
ü Materials
ü Processes etc
Hence, without validation we can not think of assuring desired quality attributes in any product.
2. Heating, Ventilation and Air conditioning (HVAC) system validation
Air is one of the major constituent in the creating the desired environment including storage and processing. This environment includes requirements related to temperature, relative humidity, class of air, differential pressure; number of air changes etc. and this entire thing is taken care by a suitably designed, operated, monitored and maintained HVAC system.
3. Water and steam system validation
All the regulatory requirements including pharmacopoeia monographs give lot of importance to quality of pharmaceutical water. Particularly USP, not only describes different monographs on pharmaceutical water, but also describes in detail validation system for pharmaceutical water. Pharmaceutical water is to be considered as one of the major raw materials particularly in case of most of the liquid formulations either sterile or non sterile. Hence, generation, storage, distribution, use and disposal of pharmaceutical water are considered as one of the major activity of assuring the quality of the pharmaceutical product and hence it is very important from point of view of regulatory compliance.
4. Vendor certification
USFDA and other drug regulatory authorities world over insist on consistency of quality of all the inputs into manufacturing of pharmaceutical product or hence, certification of vendors becomes a very important activity in assurance of quality of pharmaceutical product. One can depend on certified vendors for consistency of quality, commitment of deliveries and other technical & commercial aspects related to purchase of inputs. Vendor certification is a team activity, consisting of representative from purchase, quality assurance, production, Research and Development (R&D) and engineering etc. Hence, this activity must be considered as one of the major activity under quality assurance.
CONCLUSION
While thorough study of this Six System Inspection Model the author found that the 20 points proposed by USFDA are not get appropriately fitted into the Six System Inspection Model. For this reason the author modified the 6/20 concept to 8/24 that means Eight System Inspection Model which not only covers all 20 points proposed by USFDA but also other 4 points which are very important and other regulations are also emphasized on this 4 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 Audittee i.e. pharmaceutical organizations. The pharmaceutical organizations which are going to be implementing the CQMS are found to prepare for the any type of audit that means either USFDA or any regional audit. One more and most important advantage of this CQMS is that, if in first inspection of USFDA, if FDA inspectors convinced that the CQMS is implemented and followed by the organization then in next inspection of USFDA they should remark that any small changes in facility, equipment or process etc are not required a regulatory submission after any small changes.
For Auditor, this system is useful by means of reduction of time required for the inspection of pharmaceutical organization which can decrease the work load on the inspector and which is ultimately beneficial for the customer getting a quality product for distribution.
REFERENCES
1. Draft Guidance for Industry Quality System Approach to Pharmaceutical Current Good Manufacturing Practice Regulations, September 2004.
2. 21 Code of Federal Regulations Parts 210 and 211.
3. South Africa Guide to GMP, January 2004 v1 doc.
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