1. World Health Organization
19 April, 2017
Basic Principles of GMP
Quality Management
In this section of the programme we are going to address all the issues relating to the quality management of pharmaceutical manufacturing.
Note for the Trainer: these times are very approximate. As part of the preparation phase, the trainer will need to get an understanding of the audience and any special issues involved such as language ability. The times for the different sections may then have to be altered accordingly.
The programme is approximately as follows:
Presentation minutes
Group session I minutes with 20 minutes for feedback
Group session II minutes with 30 minutes feed back
Test paper minutes
The timing for the test paper allows 25 minutes for the test itself and the remaining time for a review of the answers.
The timing is flexible since this is a very important area. We want to ensure that the participants really understand this subject.
Section 1 and 2

2. World Health Organization
Quality Management
World Health Organization
19 April, 2017
Objectives
To understand key issues in quality assurance/good manufacturing practices/quality control.
To understand specific requirements on quality management and quality assurance including:
Organization
Procedures, processes and resources.
To develop actions to resolve your current problems.
In this session we want you to achieve the following:
1. To understand the key issues in relation to quality assurance and quality control.
2. To understand the special needs in terms of organization, procedures, processes and resources, including staffing.
3. In your group session, to look at the special situations and problems that you face in these areas in your country, and to develop practical solutions.
This area of work is potentially difficult because of the need to understand clearly the difference between quality management, quality assurance (QA) and quality control (QC).
We will be looking at the issues that can arise in implementation, and at your own experiences.
We will consider questions such as what to do about the owner of a factory who insists on appointing his/her son or daughter, who is not qualified, into a position of responsibility, and what to do about a factory that insists that it can manufacture penicillin products without cross-contamination risk, in the same equipment and premises used for manufacture of other types of product.

3. World Health Organization
Quality Management
19 April, 2017
Quality relationships
Quality Management
Quality Assurance
GMP
Production and Quality Control
It is worthwhile repeating the relationships between the different levels of quality management.
We have a cascade arrangement:
Quality management, defining the overall policy of the organization towards quality, is over everything else.
Next comes quality assurance, which is the concept that ensures the policy is achieved.
GMP is part of quality assurance. It deals with the risks that cannot be tested. It builds quality into the product.
Quality control is a part of GMP. It is that part of GMP that is focused on testing of the environment and facilities, as well as the testing of the materials, components and product in accordance with the standard.
Section 1 and 2

4. World Health Organization
Quality Management
World Health Organization
19 April, 2017
Philosophy and essential elements
What is Quality Management?
The aspect of management function that determines and implements the “quality policy”
The overall intention and direction regarding quality, as formally expressed and authorized by top management
Quality management is defined as the aspect of management function that determines and implements the quality policy. (There is a handout available if thought useful.)
The quality policy is a statement by the top management of the company of its overall intentions and direction relating to quality, formally expressed as a corporate policy. The top management of a company usually includes the board of directors or general manager of the company, the plant or factory managers together with the senior managers.

5. World Health Organization
Quality Management
World Health Organization
19 April, 2017
Quality Management
The basic elements are:
An appropriate infrastructure or “quality system” encompassing the organization structure, procedures, processes and resources
The systematic actions necessary to ensure adequate confidence that a product (or service) will satisfy given requirements for “Quality”
The totality of these actions is termed “Quality Assurance”
There are two basic elements of this aspect of the management function of a pharmaceutical company:
A working infrastructure = quality system. This includes:
Organizational structure
Procedures
Processes
Resources
A company needs to have a plan to develop all these items and a statement of its intent to carry out that plan. It is only when all the elements of the plan have been carried out that there is a system of quality management in place. Any company or organization making pharmaceuticals should show that there is a structure – an organization dedicated to making the products correctly. This structure must have the backing of the most senior management of the company to be sure that it will succeed.
Systematic actions to bring the quality policy to life. The totality of these actions is termed quality assurance (QA).
Inside an organization, QA is a management tool. In contractual situations, it provides confidence in the supplier. An important part of the systematic actions is the availability of a complete system of standard operating procedures. These are normally known as SOPs. They describe all the actions that need to be taken in a standardized way. This means that everyone involved in pharmaceutical manufacturing has a book of procedures that guides them in the way that they should do their job. It provides a standardized way of working.

6. World Health Organization
Quality Management
World Health Organization
19 April, 2017
Quality Management
Quality assurance is a management tool
In contractual situations, it also serves to generate confidence in a supplier
QA, GMP and Quality Control are interrelated aspects of Quality Management
They are described on the following slides in order to emphasize their relationship and their fundamental importance to the production and control of pharmaceutical products
Terminology may differ.
“Quality System” is increasingly being used in drug manufacturing and is on the increase because of the influence of ISO 9000, a model for a Quality System
The concepts of QA, GMP and Quality Control are interrelated aspects of Quality Management.
They are described on the following slides in order to emphasize their relationship and their fundamental importance to the production and control of pharmaceutical products.
This is an important relationship and 4 of the multiple choice questions will investigate your understanding of the relationships!

7. World Health Organization
Quality Management
19 April, 2017
Principles of Quality Assurance (QA)
Wide-ranging concept
covers all matters that individually or collectively influence the quality of a product
Totality of the arrangements
to ensure that the drug is of the right quality for the intended use
Quality Assurance incorporates GMP
and also product design and development which is outside the scope of this module
QA is a wide-ranging concept that covers all matters that individually or collectively influence the quality of a product.
Therefore QA is not the duty of one organizational unit in the company alone, but is the responsibility of all staff members who in any way can influence product quality.
1.1

8. World Health Organization
Quality Management
19 April, 2017
QA System should ensure:
Products are designed and developed correctly
Complying with, e.g. GMP, GCP, GLP
Production and control operations are defined
Managerial responsibilities are defined
In job descriptions
The manufacture, supply and use of correct starting and packaging materials
A lot more detail on each of these topics will follow during the course of this training programme. However, this list may serve as a basis to determine whether each element of GMP has been addressed.
A comprehensive QA system has to be developed and implemented which fulfils a number of requirements:
1. It must ensure that products are formulated and developed in accordance with quality assurance principles. Product quality begins with the development process. All of the development work should be undertaken with a commitment to quality assurance. This will enable easier adherence to quality assurance principles in the other areas of manufacturing.
2. It must ensure that all production and control operations are defined
3. It must identify all management responsibilities, with written job descriptions and organization diagrams. This will assist in ensuring that there are sufficient qualified and experienced people available who have the correct training to carry out their responsibilities.
It must ensure the manufacture, supply and use of correct starting and packaging materials
1.1 a- d

9. World Health Organization
Quality Management
19 April, 2017
QA System should ensure (2):
Controls are performed, including intermediates, bulk, calibration and validation
Correct processing and checking of the finished product
Products are sold/supplied only after review by the authorized person
Complying with marketing authorization, production and QC requirements
Proper storage, distribution and handling
Controls are performed, including intermediates, bulk, calibration and validation
Correct processing and checking of the finished product
Products are sold/supplied only after review by authorized person
Complying with marketing authorization, production and QC requirements
Proper storage, distribution and handling
1.1 e - h

10. World Health Organization
Quality Management
19 April, 2017
QA System should ensure (3):
Procedures for self-inspection and/or quality audits
Reporting, investigation and recording of deviations
System for change control/approval
Regular evaluation of product quality to verify consistency and continued improvement
9. A QA system must ensure that there is a self-inspection process available and implemented, leading to a programme of critical self-evaluation and continuous improvement. A very important part of the management of the manufacturing operation is the means of auditing the operation for its compliance with all the GMP requirements. The auditing is done at several levels within the company. There should be an internal audit function within departments (self-inspection). This is backed up by quality audit, an independent internal organization, charged with looking at all departments and assessing the application of the quality system within a company.
The ultimate auditing organization is the external auditing organization. This is normally the drug regulatory authority inspection or audit. See section 9.
Duties and responsibilities for the individual tasks need to be clearly defined and assigned to departments and individuals. This should be done in writing. Again, this is all part of the SOP process. Every department involved in quality assurance should have SOPs that describe its activities and who is responsible for carrying out those activities.
Reporting, investigation and recording of deviations
System for change control/approval
Regular evaluation of product quality to verify consistency and continued improvement
1.1 i - l

11. World Health Organization
Quality Management
19 April, 2017
Quality Assurance
Manufacturer is responsible for the quality of the product
Fit for intended use
Comply with marketing authorization
Safety, efficacy and quality
Senior management and commitment of all staff
The manufacturer is responsible for the quality of the product and has to ensure that it is fit for the intended use, complies with marketing authorization and the requirements for safety, efficacy and quality
It requires involvement of senior management and commitment of all staff
1.3

12. World Health Organization
Quality Management
19 April, 2017
Quality Assurance
Requires a comprehensively designed and well implemented QA system
Fully documented, and effectiveness monitored
Competent personnel, sufficient premises, equipment and facilities
To ensure quality, a comprehensively designed and well implemented QA system is required. It should be fully documented, and effectiveness monitored
Competent personnel, sufficient premises, equipment and facilities are integral parts of a quality assurance system
1.3

13. World Health Organization
Quality Management
19 April, 2017
Good Manufacturing Practices (GMP)
That part of QA that ensures that products are consistently produced and controlled
Quality standards
Marketing authorization
Aim: Diminishing risks that cannot be controlled by testing of product
Contamination and cross-contamination
Mix-ups (confusion)
Good Manufacturing Practice (GMP) is the part of quality assurance that ensures that products are produced and controlled consistently and reliably. This consistency of production and control is essential. It can only come about by having clear descriptions of the way in which the work will be done.
GMP specifically addresses risks that cannot be fully controlled by testing of the final product:
Cross-contamination
Mix-ups
These risks can best be controlled by having a properly managed system of working that takes them into account. This means that there must be good design, sound operation, and planned maintenance of facilities. It also means that the quality checking system must be designed with these risks in mind and set out to find whether any errors have occurred. Let us look at this problem in another way. If we do not know what sort of cross contamination we have, then the work of the analyst is very difficult. The analyst should ideally know what to test for before commencing testing. In other words, if we do not know what the likely cross-contaminant is then we cannot analyse for it.
There are a number of basic requirements for GMP, which we shall look at next.
2.1

14. World Health Organization
Quality Management
19 April, 2017
Basic Requirements for GMP – I
Clearly defined and systematically reviewed processes
Qualification and validation is performed
Appropriate resources are provided:
Qualified and trained personnel
Premises, space, equipment and services
Materials, containers, labels
Procedures, storage, transport
Laboratories and in-process control
Basic requirements for GMP are as follows:
1. Clearly defined and systematically reviewed manufacturing processes. This means that all batch documentation, all quality specifications and all relevant SOPs must be prepared in harmony with one another. It also means that all departments involved must be aware of the work of the other departments in order to eliminate discrepancies. Finally, the quality control staff acting as the overall coordinator of all these activities should be involved in all decisions related to the quality of the production. It is their responsibility to ensure that the activities are aimed at producing products that meet the required specifications. The specifications are approved by the drug regulatory authority.
2. Critical steps of production processes are validated. Since there is variability in the quality of materials and in the performance of the equipment, we need to check whether the process works with all the variability that can arise. This process of checking and documenting variability is known as validation. It means that the company must have sufficient knowledge of its materials, equipment and processes that it knows what variables are likely to arise. It can then carry out controlled experiments to ensure that whatever variables do occur, they can still produce products meeting specifications. Validation is also required if there is a change in any part of the process, materials or equipment used in the manufacturing.
3. Appropriate resources: personnel, buildings, equipment and materials are available to produce a quality product. This means that the company has evaluated all of the elements it needs to produce a product and has sufficient resources of the right quality for its production.
4. Manufacturing is based on clearly written procedures. The procedures referred to here include the batch manufacturing and testing instructions and the SOPs needed for every department. Preparing these procedures and documents is a very important task that needs careful thought. The module on documentation goes into this in more detail.
5. Operators are trained. A company can have "all the documentation in the world" but if its operators are not properly trained to carry out the tasks that they are supposed to perform then the company will not be successful. We will talk more about this in the session on personnel. Operators not only need initial training but also follow-up training.
2.1 a - c

15. World Health Organization
Quality Management
19 April, 2017
Basic Requirements for GMP – I
Clear, written instructions and procedures
Trained operators
Records of actions, deviations and investigations
Records for manufacture and distribution
Proper storage and distribution
Systems for complaints and recalls
Basic requirements for GMP are as follows:
1. Clearly defined and systematically reviewed manufacturing processes. This means that all batch documentation, all quality specifications and all relevant SOPs must be prepared in harmony with one another. It also means that all departments involved must be aware of the work of the other departments in order to eliminate discrepancies. Finally, the quality control staff acting as the overall coordinator of all these activities should be involved in all decisions related to the quality of the production. It is their responsibility to ensure that the activities are aimed at producing products that meet the required specifications. The specifications are approved by the drug regulatory authority.
2. Critical steps of production processes are validated. Since there is variability in the quality of materials and in the performance of the equipment, we need to check whether the process works with all the variability that can arise. This process of checking and documenting variability is known as validation. It means that the company must have sufficient knowledge of its materials, equipment and processes that it knows what variables are likely to arise. It can then carry out controlled experiments to ensure that whatever variables do occur, they can still produce products meeting specifications. Validation is also required if there is a change in any part of the process, materials or equipment used in the manufacturing.
3. Appropriate resources: personnel, buildings, equipment and materials are available to produce a quality product. This means that the company has evaluated all of the elements it needs to produce a product and has sufficient resources of the right quality for its production.
4. Manufacturing is based on clearly written procedures. The procedures referred to here include the batch manufacturing and testing instructions and the SOPs needed for every department. Preparing these procedures and documents is a very important task that needs careful thought. The module on documentation goes into this in more detail.
5. Operators are trained. A company can have "all the documentation in the world" but if its operators are not properly trained to carry out the tasks that they are supposed to perform then the company will not be successful. We will talk more about this in the session on personnel. Operators not only need initial training but also follow-up training.
2.1 d - j

16. World Health Organization
Quality Management
World Health Organization
19 April, 2017
Group session – I
How many GMP deficiencies can you find in the photographs in the handout?
This brings us to our topic for this group session.
We want you to identify the influences that the following situations may have on a company’s management system. We would like to know what action you would propose to counter any negative effects.
Please use a brainstorming technique to bring out all the possible problems quickly and then start to focus on the most important using your own practical experiences.
Your team here will move around the groups, so please use them to help on any difficult issues.
Your allocated groups are now up on the board, together with the room allocated. Please get there quickly to make maximum use of the time.
We will meet here again at _____________.

17. World Health Organization
Quality Management
World Health Organization
19 April, 2017
Group session II
Imagine you are inspecting a pharmaceutical company for compliance with GMP
Consider the situations in the next slides which may have impact on a company’s quality management programme
Describe the action to be taken in each case
This brings us to our topic for this group session.
We want you to identify the influences that the following situations may have on a company’s management system. We would like to know what action you would propose to counter any negative effects.
Please use a brainstorming technique to bring out all the possible problems quickly and then start to focus on the most important using your own practical experiences.
Your team here will move around the groups, so please use them to help on any difficult issues.
Your allocated groups are now up on the board together with the room allocated. Please get there quickly to make maximum use of the time.
We will meet here again at _____________.

18. World Health Organization
Quality Management
World Health Organization
19 April, 2017
Issues – I
Quality Management manual not established in writing
Limited human resources
Lack of qualified people
Processes not properly validated
Poor SOPs or standard batch documentation
More consideration to cost than quality
Family members in key positions of authority
Issues to discuss
Imagine that within a company you are inspecting:
Quality Management Manual – Senior management will not allow a quality management manual to be created.
Limited human Resources – Owners will not recruit sufficient people to undertake the work. Existing staff are harassed and overworked. They are kept under pressure to perform and there are no spare staff with the skills and experience needed. When staff are ill or go on holiday then there are no replacement staff available.
Lack of qualified people - Unqualified or inexperienced people are employed in key positions.
Processes – Senior staff do not subscribe to the value of validated processes.
SOPs – There are few or no SOPs in operation. Those SOPs that do exist are not adhered to.
Standard batch documentation – Batch documentation is poor. Different batch sizes are made in inappropriate equipment.
Cost is emphasized over quality. The owners of the company do not subscribe to GMP other than the meaning "Get More Product". They see that GMP mean additional costs with no return. They do not subscribe to any moral code in respect of patient health. Any audit is seen as interference with their ability to manage the company the way that they want.
Family members play a major part in the company. Inexperienced or unqualified family members are promoted into positions of responsibility for which they are not qualified.
Imagine in a company you are inspecting :

19. World Health Organization
Quality Management
World Health Organization
19 April, 2017
Issues – II
Substandard materials deliberately purchased
Technical staff not involved in purchasing
Inability to re-export substandard materials
Owner insists on selling rejects
Corruption
No commitment to training
Imagine in a company you are inspecting :
Substandard materials are purchased because they are cheap.
The technical staff are not involved in the purchasing decisions so inappropriate materials are bought. If material is imported at great cost and then rejected, it can be very difficult to re-export that material for replacement or exchange owing to currency regulations.
The owner of the company insists on taking inappropriate decisions about the quality of products that are to be sold.
Is there corruption concerning product quality? What do you do if you are offered an inducement not to report GMP deficiencies?
Because training costs money, the owner is not prepared to make a commitment to training that is needed.