World Health Organization

World Health Organization
2 June, 2018 Basic Principles of GMP Personnel Companies can make investments and buy facilities and equipment. However, the greatest resource that a company has is its personnel. But human resources also need a lot of attention. If a company does not have correctly educated, trained and motivated people working in its factory or laboratory, it is necessary to provide training in order to overcome any inherent weaknesses and to build upon existing strengths. This module will consist of: Presentation - general issues 30 minutes Group session minutes Plenary feedback minutes Presentation - specific issues minutes Plenary feedback minutes Test minutes Exact times will need to be worked out when details of participant numbers and experience are known. The module should be tailored to run between 1/2 and 1 day. 9

Personnel World Health Organization 2 June, 2018 Objectives To review general issues related to personnel To review requirements for key personnel To review the training of personnel To consider some specific issues There are four objectives for this session: 1. We are going to start by looking at the principles and general issues around personnel such as the personnel policies and practices. 2. We will look at the responsibilities of certain key personnel in the organization. 3. We will review continuous training of personnel. 4. We will look at the specific issues that are likely to arise during your inspection visits.

Personnel 2 June, 2018 Principle A satisfactory system of QA, manufacture and control of products and APIs rely on people. Must be sufficient qualified personnel to carry out tasks Individual responsibilities must be clearly defined and understood by individuals concerned Written job descriptions All personnel should be aware of the principles of GMP that affect them The principle that companies should apply to their people has a number of key features. The personnel is the most important asset of a company, and the easiest to neglect. The establishment and maintenance of a satisfactory system of quality assurance and GMP relies upon people who develop the system, the people who use the system and the people who examine the system to see if it has worked. People are involved, no matter how automated the process or how capital intensive the operation. The behaviour of the people is fundamental to any system of GMP. Personnel policies must reflect this. In our first group session we will be looking at those policies that encourage compliance with GMP. Sufficient number of staff must be available to carry out the work for which the manufacturer is responsible. These people must have the level of training and experience that will enable them to do their work. The staff must have written job descriptions to ensure that they understand clearly what it is that they have to do, and what they are responsible for. Finally these staff must have a knowledge and understanding of GMP to enable them to carry out their duties in accordance with GMP. Let us now look at these areas in more detail. 9.1

Personnel 2 June, 2018 General (1) Personnel requirements: Adequate number of persons With necessary qualifications With practical experience An individual’s responsibilities should not be so extensive as to present a risk to quality For successful and good quality pharmaceutical production, it is essential to have people with sufficient knowledge and experience to undertake the work. They must have the authority and the means to do that work, and there must be enough of them available to carry out tasks effectively. It is most important that the people that are recruited are selected from a group that can meet the requirements. It is not recommended to recruit people to work in manufacturing areas if they are unable to read the instructions for their safety and for product quality. A medical examination should be included during the recruitment processes. Operators working with cytotoxic products may need blood tests at the time of recruitment and at six monthly intervals thereafter. Operators who will work on visual inspection processes should also undertake an eye test at the time of recruitment with a regular check on a periodic basis afterwards. A major and most common problem is that of insufficient people available to do the work. It is of little value having just one person well qualified and experienced, with no backup staff. What then happens in the case of sickness or holiday? This can be a very difficult area, and one which is harder for smaller companies than a multinational company or similar. Another issue that often surfaces is the employment of a well qualified, but inexperienced, person to manage, for example, quality. An illustration of this is the recruitment by the owner of a small company of a relative -- niece or nephew for example -- who is newly qualified, but completely inexperienced to run a laboratory or manufacturing area. The duties incumbent upon any one individual should not be so extensive that he/she cannot cope, resulting in a risk to quality of the product. In our second group session we will be looking at the experiences of bad practice and examining strategies to overcome them. 9.2

Personnel 2 June, 2018 General (2) Specific duties in written job descriptions Adequate authority to carry out responsibilities May delegate to designated deputies with qualifications No gaps or unexplained overlaps Authorized organization chart Staff must have a clear job description which tells them and the rest of the company what their role is, what their responsibilities are and what authority they have to carry out their tasks. The company should also have a written organization chart. The combination of organization chart and written job descriptions enables the company to see quickly whether there are any gaps or whether there are any areas of overlap, owing to too many people being involved. The organisation chart should make clear and ensure the independence of QA/QC from production. Personnel involved in QA/QC must have the authority to carry out their responsibilities. This is very easy to say and sometimes not so easy to ensure. Problems can emerge in every size of company, from small private companies to very large multinational enterprises. They arise because of a combination of human interactions, and the pressures placed on people by the business considerations. 9.3

Basic Principles of GMP
World Health Organization Basic Principles of GMP 2 June, 2018 Organization chart This is NOT what it should look like Explain the expectations: E.g. signed and dated List all key positions, titles and names of people Vacant positions Contract personnel Reporting lines Independent reporting (e.g. Quality unit) Levels of authority Should be in line with what is reflected in the job descriptions

Personnel 2 June, 2018 General (3) All personnel should be aware of GMP Must receive training in GMP: initial training continuing training including hygiene standards Motivated to support the establishment maintain high-quality standards All personnel involved with materials and products should receive GMP training. This training should commence upon recruitment and continue throughout employment. The training should be appropriate to their needs and position within the company, and should include training in hygiene standards. Personnel policies should be designed to encourage people to support the development and maintenance of high quality standards in all work performed. 9.4

Personnel 2 June, 2018 General (4) Prevent unauthorized access to: Production areas Storage areas Quality control Stop personnel who do not work in these areas using them as passageways The company should prevent people who have not been properly trained from entering any production, storage or quality control area without strict supervision. For example: it should not be the case that people from accounts are allowed to walk through the factory to get to the warehouse to pick up or deliver invoices. Access to all other areas of the company should be organized so that no entry to production, storage or laboratory areas is necessary (see Premises). 9.5

Basic Principles of GMP
World Health Organization 2 June, 2018 The trainer should explain ways of ensuring access control to areas. Some companies have electronic card systems that allow entry to authorized persons to specific areas, others have a code that has to be entered at the door, etc. Only people authorized to go to areas, should be allowed to enter, wearing appropriate garments. They should have the relevant training before entering the areas. IN some cases, to ensure also better control between different classes of areas, airlocks are used.

Personnel 2 June, 2018 Key Personnel (1) Key personnel (which normally should be full-time) positions and include: Authorized person Head of Production Head of Quality Unit Quality Assurance and Quality Control May delegate functions – not responsibility Heads of Production and Quality Unit should be independent of each other We have dealt with the generalities of an organization so far. We shall now deal with the requirements for certain key people in the organization. Who are these key people? The heads of production, quality unit, sales and distribution and the authorized person who releases product for sale are all key people. Normally they should all be full-time positions. The heads of production and quality unit should not report to one another (although they may both report to a technical director) but may share certain responsibilities. In large organizations, it may be necessary to delegate some of the functions; however, the responsibility cannot be delegated. The quality unit can consist of QA and QC. We will look in a minute at shared responsibilities. Different countries take a different view of reporting relationships. Legislation in each country differs slightly and, of course, local legislation must be followed. The principle is that there must be independence of quality control from production. These key personnel must have the education and experience which is appropriate to their positions. As we mentioned earlier, difficulties can arise when family members who are recruited and who are inexperienced. 9.6

Personnel 2 June, 2018 Key Personnel (2) Should have appropriate qualifications Scientific education such as: chemistry or biochemistry chemical engineering microbiology pharmaceutical sciences and technology pharmacology and toxicology physiology; or other related science subjects relevant to the responsibilities to be undertaken The WHO GMP text part one, section 9.7 refers to some of the acceptable qualifications of key personnel and it goes into a lot of detail. Key personnel should first of all have the educational background specified by local legislation and with the requirements set out in company policy. This will include a combination of chemistry, biochemistry, chemical engineering, microbiology, pharmaceutical sciences and technology, pharmacology and toxicology, physiology or other related science subjects relevant to the responsibilities to be undertaken. In particular, the GMP text talks about gaining experience not in a haphazard way, but under specific guidance of an expert. This is in order to equip personnel with an ability to take difficult decisions in a professional and scientific way, and to resolve the problems encountered in manufacturing and quality control. It is clear, therefore, that we are talking about professionals who have had a practical as well as an academic training. They should also continue to have training in their area of expertise. There are others who play an important role in the operation of the factory, for example, engineers. Engineers are crucial to the maintenance and operation of the facility and equipment, in particular, for the processes of planned preventative maintenance and validation. 9.7

Personnel 2 June, 2018 Key Personnel (3) Should have appropriate experience Practical experience Manufacture and quality assurance Preparatory period under professional guidance sometimes needed Education and experience should enable personnel to take difficult decisions in an independent, professional and scientific way resolve the problems encountered in manufacturing and QC Personnel should also posses appropriate experience including practical experience in the manufacture and quality assurance of pharmaceutical products. It is common and recommended, that there should be a preparatory period under professional guidance for new employees. Education and experience should enable personnel to take difficult decisions in an independent, professional and scientific way, and to resolve the problems encountered in manufacturing and QC. 9.7

Personnel 2 June, 2018 Shared Responsibilities (1) Heads of Production and Quality Unit may share/jointly exercise some responsibilities relating to quality e.g.: authorization of written procedures (SOPs) and other documents monitoring and control of manufacturing environment hygiene process validation and calibration training, including application and principles of QA approval and monitoring of suppliers and contract acceptors The responsibilities shared by the heads of the production and quality control departments are described in the WHO GMP texts. Clear written job descriptions must be available for these positions, showing where the shared responsibilities are. It is sensible that all procedures and documents used in manufacturing are approved by both the production and quality control departments. It is most important that an effective system of change control is implemented. It is essential that as SOPs are changed, all those who use them are given the latest version. Monitoring of the manufacturing environment is a task to be shared between QA/QC and production. These departments should conduct the monitoring and testing as appropriate, with the results made available to all who need to know. Both production and quality control have a role to play in the development and maintenance of an appropriate factory sanitation and hygiene management system. Both have a major contribution to make in the validation of processes and the calibration of equipment. A comprehensive training programme is required for personnel. The production and quality control department have a role to play in the development of the training programme. The heads of these departments, therefore, have a shared responsibility for the implementation of that programme. Approval of all suppliers and contract manufacturers is also an area of shared responsibility, with each contributing his/her own particular expertise 9.8

Personnel 2 June, 2018 Shared Responsibilities (2) Designation and monitoring of storage conditions for materials and products Performing and evaluating in-process controls Retention of records Monitoring compliance with GMP Inspection, investigation, and taking of samples to monitor factors which may affect quality Responsibility for the designation and monitoring of storage conditions is also shared. Since both have responsibility for the generation of records relevant to batches, then the arrangements for the storage of those records may be a shared responsibility. Alternatively a separate department may be available that manages all aspects of documentation and batch records. Monitoring of compliance with GMP is also a shared responsibility. This has to be correct because the achievement of GMP is everyone's responsibility. Some aspects of inspection, investigation and sampling may be conducted by people other than QC to monitor factors that affect quality of the products. Sampling should only be done by persons trained in the methods to be used. 9.8

Personnel 2 June, 2018 Head of Production: Responsibilities (1) Product production and storage according to appropriate documentation Approval and implementation of production instructions, in-process QC and ensure strict implementation Ensures that production records are evaluated and signed by designated person Let us now look at the responsibilities carried by individuals. The production manager will normally have at least the responsibilities listed here. Let us look at them individually: . He or she must ensure that products are produced and stored in accordance with appropriate documentation to meet the required quality standards. In some facilities, the production manager may not be responsible for the warehouse. The person who is responsible for the warehouse must store and handle the products in such a way that their quality is unaffected by storage. The production manager must have in place the systems to ensure that production follows the instructions that have been prepared for it. . The production manager is also responsible for the preparation and maintenance of the production instructions and their implementation. This will include not only the production documentation itself, but also all the other procedures and documentation that are essential for the good operation of production. He/she will prepare many of these documents in partnership with quality control and product development staff. The in-process testing requirement must be specified. . Having ensured that production takes place in accordance with the available documents, the production manager must ensure that these documents have been used correctly to record the progress of manufacture. To do this, he/she must evaluate or designate someone to evaluate every batch record in order to satisfy himself/herself that all has gone as it should. He/she will also need to ensure that the documents have been completed correctly. Continued on the next slide …. 9.9

Personnel 2 June, 2018 Head of Production: Responsibilities (2) Checks maintenance of production department, premises and equipment Ensures process validation and calibration performed, recorded, and reports are made available Ensures initial and continuous training of production personnel Head of Production responsibilities - Continued … . For manufacture to proceed as planned, it is essential that all the plant, facilities and equipment are operating as they should. This means that maintenance must be planned and implemented. This is normally done within a planned preventative maintenance programme. The production manager is responsible for ensuring that all the facilities and equipment under his/her control are properly maintained in accordance with this programme. . It is essential to check regularly that the processes will routinely produce a product that meets the registered specifications. The production manager must therefore ensure that all processes are validated and all equipment is calibrated in accordance with the written procedures. We will be talking specifically about weigh scales in this respect when we get to the module on equipment. It is particularly important that the production manager takes responsibility for the conduct of the in-process testing routines agreed with QA/QC. . The production manager is responsible for ensuring that the people who carry out all this work are well trained and motivated at the commencement of their work, and that they receive regular refresher training. 9.9

Personnel 2 June, 2018 Head of Quality Unit: Responsibilities (1) Approve or reject starting materials, packaging materials, and intermediate, bulk and finished products in relation with their specifications Evaluate batch records Ensure that all necessary testing is carried out Approve sampling instructions, specifications, test methods and other QC procedures Now let us look in more detail at the responsibilities of a Quality Unit manager: . (a) to approve or reject starting materials, packaging materials, and intermediate, bulk and finished products in relation with their specifications; (b) to evaluate batch records; (c) to ensure that all necessary testing is carried out; (d) to approve sampling instructions, specifications, test methods and other QC procedures; 9.10

Personnel 2 June, 2018 Head of Quality Unit: Responsibilities (2) Approve and monitor analyses carried out under contract Maintenance of the department, premises and equipment Validations (including analytical procedures) and calibrations of control equipment are carried out Initial and continuing training of quality unit personnel (e) to approve and monitor analyses carried out under contract; (f) to check the maintenance of the department, premises and equipment; (g) to ensure that the appropriate validations, including those of analytical procedures, and calibrations of control equipment are carried out; (h) to ensure that the required initial and continuing training of quality unit personnel is carried out and adapted according to need. 9.10

Personnel 2 June, 2018 Head of Quality Unit: Responsibilities (3) Establishment, implementation and maintenance of the quality system Supervision of the regular internal audits or self- inspections Participation in external audit (vendor audit) Participation in validation programmes (See also other duties of QC later) (i) establishment, implementation and maintenance of the quality system; (j) supervision of the regular internal audits or self-inspections; (k) participation in external audit (vendor audit); (l) participation in validation programmes. Other duties of QC are summarized in sections 17.3 and 17.4. 9.10

Personnel 2 June, 2018 Authorized person: Responsibilities (1) Compliance with technical and regulatory requirements Approval of the release of finished product for sale Function may be delegated to another person (e.g. QA) In some countries, overall responsibility including The establishment and implementation of quality system Development of quality manual Supervision of self-inspections and quality audits Authorized person: Responsibilities (1) The authorized person is responsible for compliance with technical or regulatory requirements related to the quality of finished products and the approval of the release of the finished product for sale or supply. The function of the approval of the release of a finished batch or a product can be delegated to a designated person with appropriate qualifications and experience who will release the product in accordance with an approved procedure. This is normally done by QA by means of batch review.. 9.11, 9.15

Personnel 2 June, 2018 Authorized person: Responsibilities (2) No batch of product is to be released for sale or supply prior to certification by the authorized person(s). Assessment of finished product include: Review of production conditions Results of in-process testing Manufacturing (including packaging) documentation Compliance with specifications Examination of the finished pack 9.12 Assessment of finished products should embrace all relevant factors, including the production conditions, the results of in-process testing, the manufacturing (including packaging) documentation, compliance with the specification for the finished product, and an examination of the finished pack. 9.13 No batch of product is to be released for sale or supply prior to certification by the authorized person(s). In certain countries, by law, the batch release is a task of the authorized person from production together with the authorized person from QC. 9.12, 9.13

Personnel 2 June, 2018 Person releasing the batch should ensure: (1) Each batch meets manufacturing and marketing authorization requirements Principles and requirements of GMP are met All checks and tests have been performed Production conditions and manufacturing records Planned changes and deviations reported - including where necessary to drug regulatory authority The person responsible for approving a batch for release should always ensure that the following requirements have been met: (a) the marketing authorization and the manufacturing authorization requirements for the product have been met for the batch concerned; (b) the principles and guidelines of GMP, as laid down in the guidelines published by WHO, have been followed; (c) the principal manufacturing and testing processes have been validated, if different; (d) all the necessary checks and tests have been performed and account taken of the production conditions and manufacturing records; (e) any planned changes or deviations in manufacturing or quality control have been notified in accordance with a well defined reporting system before any product is released. Such changes may need notification to, and approval by, the drug regulatory authority; 9.14 a - e

Personnel 2 June, 2018 Person releasing the batch should ensure: (2) Additional sampling, inspection, checks and tests had been done when required All production and control documents are completed and endorsed Audits, inspections and spot-checks were done QC approval has been given All other relevant factors have been considered The person responsible for approving a batch for release should always ensure that the following requirements have been met: (f) any additional sampling, inspection, tests and checks have been carried out or initiated, as appropriate, to cover planned changes and deviations; (g) all necessary production and quality control documentation has been completed and endorsed by supervisors trained in appropriate disciplines; (h) appropriate audits, self-inspections and spot-checks are carried out by experienced and trained staff; (i) approval has been given by the head of quality control; (j) all relevant factors have been considered, including any not specifically associated with the output batch directly under review (e.g. subdivision of output batches from a common input, factors associated with continuous production runs). 9.14 f - j

Personnel 2 June, 2018 Training (1) Training, in accordance with a written, approved programme all personnel whose duties take them into production areas; into control laboratories; and for others whose activities could affect the quality of the product including technical, maintenance and cleaning personnel Induction and continuing training on theory and practice of GMP and their duties training records should be kept practical effectiveness checked training before undertaking any new task Inspectors should check the company procedure, training materials and records on training provided. Training should be given in accordance with a written, approved programme to all personnel whose duties take them into production areas; or into control laboratories; and for others whose activities could affect the quality of the product including technical, maintenance and cleaning personnel) On induction and continuing; 1. Each company should establish a written training programme. New employees understand what is expected of them and the risks to patients and consumers if the products they make do not conform to requirements. This initial training must be given to all employees who have a direct impact on product quality. The training programme may consist of at least two parts. The first will be a general programme that all employees should receive which explains GMP and the importance of GMP to the company. There may well be a second programme, explaining the specific issues about the individual’s department. 2. There should be a written re-training programme for all employees to ensure that their skills are continually brought up to date and that they are introduced to changes in practice as these develop. 3. As employees go through their training, records should be kept of the training received and performance against tests. People have to realise that good performance is required otherwise retraining will be required. 4. All areas of GMP relevant to the individual must be covered. 5. Training records must be kept to ensure that as employees move around the company, they are not required to carry out work for which they have not been trained. 10.1, 10.2

Personnel 2 June, 2018 Training (2) Specific training for staff in special areas, e.g. Where contamination is a hazard Clean areas Areas where highly active, toxic, infectious, sensitizing materials are handled The concept of QA - ensure understanding and its implementation Inspectors should check records on training. Continued ... 6. People who work in special areas should receive additional training in the special nature of their area of work. Those people who work in sterile areas, with highly active or toxic materials or sensitizing agents, should receive specific instruction in the special nature and hazards associated with this activity. 7. During training, every encouragement should be given to employees to discuss fully all aspects of quality and GMP with their trainers and among themselves. Staff should be encouraged to contribute to increased quality and GMP. A few additional words about visitors are necessary. See the next slide. 10.3, 10.4

Personnel 2 June, 2018 Visitors or Untrained Personnel Should not to enter production and control areas. If this is unavoidable then: They must be given information in advance: GMP personal hygiene protective clothing requirements Behaviour (no samples to be taken, touching etc.) Must be accompanied and closely supervised at all times One of the questions that you should raise in all companies is how they handle visitors. The answer should be that their presence should be treated as a potential risk to the product and, therefore, steps should be taken to ensure that they cannot cause any hazard to product quality. Ideally, the company will do this by factory design that ensures that visitors cannot gain access to areas in operation. This is usually difficult and so it is necessary to give visitors a full briefing and to provide them with full protective clothing and give them strict instructions about where they may stand. For visitors there can be no exceptions to the rule of the wearing of appropriate clothing to protect the product. A word at this stage about visits by the owners of the business. This may be a difficult area because owners may feel that if the company is theirs they may do what they want, when they want. Somehow they have to understand that their investment is at risk if they do not behave as necessary. (Use flipchart again to record comments from the audience). 10.5

Personnel 2 June, 2018 Consultants and contract staff Should be qualified for the services provided Training records maintained Records should prove qualifications A manufacturer may use the services of a consultant and contract staff. The company has to ensure that these people are qualified for the services provided. It may be useful for you to review also the training records maintained for contract staff. Some companies use contract workers for some activities including packaging of products. They should have been properly trained in GMP, QA and the relevant procedures and processes that they are responsible for. Records should prove persons' qualifications 10.6

Personnel World Health Organization 2 June, 2018 Group Session What do you think will be the key personnel issues to arise during an inspection? What sort of responses do you think you should give to these issues when they become apparent? Having heard the presentation on personnel, use what you know to develop thoughts on the likely issues regarding the organization of personnel that you will meet during inspections in your countries. More personal issues arising during an inspection are dealt with in the modules on GMP inspections. Once you have drawn up a list, develop the responses that you feel would be appropriate in those circumstances.

Personnel World Health Organization 2 June, 2018 Possible Issues – I Limited number of staff Inadequate qualifications Inadequate experience Owner interferes in quality decisions Lack of means to develop training materials In a company the issues will be around a lack of skills and resources to comply with all the requirements of GMP: Limited staff numbers may mean that people are under pressure to perform. They may be trying to do too much. There may be a lack of deputies during times of illness or holidays. Recruited staff may have inadequate qualifications. Recruited staff may have inadequate experience or experience in an inappropriate area. Sometimes the owner recruits relatives who are inadequately qualified or experienced. The owner may interfere with quality decisions, particularly if orders are required urgently or are very valuable. Senior staff may have difficulty in combating this, since it may cost them their jobs. Smaller companies may have no means to develop training materials to educate their staff in the requirements of GMP. They do not become members of the local manufacturers’ association because of cost. They do not then have access to training programmes that are available through the association.

Personnel World Health Organization 2 June, 2018 Possible Issues – II Company procedures take precedence over local legislation Unclear organization diagram Staff movement Inadequate training records Illness Subsidiaries of multinational companies may claim that company procedures or standards take precedence over local legislation. If this is claimed, it will be most unusual since all multinationals require local companies to conform first to local legislation. It will be worth exploring with the company what benefits are obtained by not conforming to local legislation. Large organizations often move people around through promotion, training, recruitment or relocation. In so doing they can lose sight of the requirements of GMP. Managers can be promoted into positions for which they are not qualified or experienced. Companies may not keep adequate training records even though people are apparently undergoing training. As with small companies, large companies may have personnel policies that penalize people. The problem is that if people are not going to be paid when sick or injured, they may work on under circumstances that create a risk to the product. What happens when they have an open wound, for example?

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