1. Good Manufacturing Practices in the manufacture of medicines
The World Health Organization (WHO) GMP rules are the subject of the course

2. I am afraid, the industrial drug manufacture is a bit more complicated than this…

3. starting already outside, in the yard

4. active substance manufacture

5. dosage-form manufacture

6. computer-aided manufacture

7. control lab

8. GMP certificate
issued by the
national GMP compliance monitoring authority

9. GMP
Basic Principles
Specific rules

10. GMP: „soft” and „hard” law
„The manufacturer should possess adequate…
number of personnel...
with adequate qualification...
manufacturing area…”
Impossible to specify the values in a law!
The inspector will decide on the spot whether the requirement is met!

11. Basic Principles of GMP
Introduction
to the Training Course
Welcome
Good morning and welcome to all delegates to this training course offered by the World Health Organization to develop the practical implementation of the WHO GMP text of Good Manufacturing Practice for Pharmaceutical Products.
Thanks
Our thanks to ______________________ for the arrangements that have been made to accommodate us all for the duration of the programme.
Housekeeping
(cover fire or emergency procedures, and domestic arrangements including location of toilet facilities, tea or coffee breaks, meal breaks)

12. Basic Principles of GMP
Programme Overview – I
Basic Principles of GMP
1. Quality Management
2. Sanitation and hygiene
3. Validation
4. Complaints and recalls
We shall start by reviewing the programme and introduce our interactive way of working together. We will explain the way the group discussions will work.
Modules 1-14 cover the basic principles of GMP.
There will be a half-day module on Quality Management and the requirements for a quality assurance unit. You will need to have a clear understanding of the organizational structures that must be in place if a pharmaceutical company is to have the product quality that is required by the National Health Regulator.
We shall look at complaint handling procedures and product recall procedures that you should expect pharmaceutical companies to have. This ensures that complaints are properly handled and that patients are protected from dangerous or substandard medicines that have been placed on the market by a proper recall system.
This will be followed by a half-day session on Sanitation and Hygiene.
Next we will spend a half-day looking at Validation.
We then have a half-day module on Contract Production and Analysis. This is becoming much more important all over the world as companies decide not to manufacture all their own products in their own factories or manufacturing sites. This means that companies are putting more and more work out to contractors. Companies are also contracting out analytical work as methods become more complex or use expensive equipment. All of this contract work requires careful your inspection.

13. Basic Principles of GMP
Programme overview II
Basic Principles of GMP
5. Contract production and analysis
6. Self Inspection
7. Personnel
8. Premises
9. Equipment
Next we will have a short session on Self-inspection.
We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject.
This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module.
We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions.
This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

14. Programme overview - III
Basic Principles of GMP
10. Materials
11. Documentation
12. Sterile production
13. Active pharmaceutical ingredients
Documentation: This short module covers the design and use of documentation -- often poorly done, especially in less developed countries. Correct recording of activities as they occur is vital for the production and testing of products to meet GMP standards.
The full-day module on Sterile Production will look at the very demanding activities required to achieve the highest standards. There are special demands that these very important products make upon a company’s resources and systems. Companies are often tempted to take shortcuts because of the expense involved and you will have to know where to look to see if the companies are strictly following Good Manufacturing Practices.
A half-day module on Active Pharmaceutical Ingredients is covered next. This is an area where regulatory authorities should be increasing their inspection activities. It is a vital area for proper drug efficacy. If poor quality actives are used then the drug attributes sometimes cannot be tested for later on when the material is compounded into product. A problem at a later stage is also more expensive to detect and correct.
Personal objectives: On completion of the GMP Basic Training Modules, we shall distribute a Personal Action Plan form in order to check your understanding of the materials, and to give you the opportunity to develop your personal action plans.

15. Programme overview - IV
GMP Inspection Process
14. Introduction
15. The role of the inspector
16. Preparation for the inspection
17.Types of GMP inspection
18. The inspection
Modules cover the G MP Inspection Process. Modules consist of short sessions on:
. an introduction to the topic
. the role of the inspector
. preparation for the inspection
. types of GMP inspection
. the inspection
and will take approximately one-and-a-half days to complete.
Module 20 provide trainer’s notes.

16. Basic principles of GMP in more detail

17. 1. 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 30 minutes
Group session I 20 minutes with 20 minutes for feedback
Group session II 30 minutes with 30 minutes feed back
Test paper 45 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.

18. European Union Directive
„The manufacturer shall establish and implement an effective pharmaceutical QA system, involving the active participation of the management and personnel of the different services involved”

19. The Quality Management
The first, introductory chapter of the WHO GMP
Having defined some concepts and terms, it summerises what is also detailed in other chapters (do not be surprised if its parts are also reproduced elsewhere)

20. Quality Management Objectives
To understand/identify key issues in quality assurance/quality control
To understand/identify specific requirements on 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.

21. Quality Management Determines and implements the “quality policy”
The basic elements are:
an appropriate infrastructure or “quality system” encompassing the 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”
We shall be looking in detail at the quality management issues mentioned during the Introduction to this training programme. As we indicated then, quality management is defined in the WHO GMP texts.
The definition given there is in conformance with the definition contained in the international standard ISO 9000, standard established by the International Standards Organization, aimed at ensuring that an organization has a quality management system and that it complies with all aspects of that system.
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.
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.

22. Quality Management Terminology may differ (e.g. from ISO)
“Quality System” is said to be rarely used in drug manufacturing
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
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!

23. Principles of Quality Assurance
Quality Management
Principles of Quality Assurance
Wide-ranging concept
covers all matters that individually or collectively influence the quality of a product = responsibility of everyone
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.

24. Requirements for QA Systems
Think over what should be done properly during drug manufacture!

25. Requirements for QA Systems – I
Quality Management
Requirements for QA Systems – I
1. Ensure products are developed correctly
2. Identify managerial responsibilities
3. Provide SOPs for production and control Standard Operating Procedures
4. Organize supply and use of correct starting materials
5. Define controls for all stages of manufacture and packaging
Basically, QA covers at least the 9 points in 1.2
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 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.
3. It must provide SOPs for all manufacturing and testing methods. Written procedures are essential for all aspects of manufacturing and supply. They should state what should be done and how.
4. It must ensure that there are up-to-date written procedures for the supply and use of all starting and packaging materials. These will include all the procedures relating to purchasing, reception, sampling and testing of materials.
5. It must ensure that there are up-to-date, written procedures to control all starting materials, intermediate and bulk products. Proper management of all the handling and storage of materials is essential. This must apply to all materials whether incoming, intermediate or finished goods for sale.

26. Requirements for QA Systems – II
Quality Management
Requirements for QA Systems – II
6. Ensure finished product correctly processed and checked before release
7. Ensure products are released after review by authorized person
8. Provide storage and distribution
9. Organize self-inspection
6. A QA system must also ensure that there are written, up-to-date SOPs describing how the product is to be processed and checked.
7. It must ensure that no product is released for distribution before it has been checked by the authorized person. These checks are that the product has been produced and controlled in accordance with the established SOPs and the requirements of the marketing authorization. The registered product details will state what the standards are that the product must meet.
8. It must ensure that appropriate conditions are provided for all storage and distribution. During product development, stability testing will have been done. This will indicate the conditions under which the product must be stored. Normally, there is a specification for temperature and humidity. Sometimes there is also a specification for exposure to light and other parameters. Arrangements should be in place throughout the storage and distribution chain to ensure that the product will not be exposed to conditions that could adversely affect it.
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.

27. Quality Management GMP
Ensure that products are consistently produced and controlled
Diminishes risks that cannot be controlled by testing of product
Cross-contamination
Mix-ups
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.
the most life-threatening mistakes!

28. Basic Requirements for GMP – I
Quality Management
Basic Requirements for GMP – I
1. Clearly defined and systematically reviewed processes
2. Critical steps validated
3. Appropriate resources: personnel, buildings, equipment, materials
4. Clearly written procedures
5. Trained operators
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.

29. „Clearly defined and systematically reviewed manufacturing processes”
= all relevant quality specifications, SOPs and batch documentation must be prepared in harmony with each other
It also means that the Departments involved know each other’s task to eliminate discrepancies
Also: QC/QA staff is acting as coordinator and is involved in all decisions

30. „Critical steps validated”
There is a variability in the quality of incoming materials and in the performance of the equipment, we need to check whether the process works with all varibaility that can arise
The process of checking and documenting variability = validation
if validation, we have sufficient knowledge of materials, equipment and process = what variables arelikely to arise.
Then we carry out controlled experiments to ensure that whatever variables cab occur, the product still meets the specification
Validation is also needed when there is any change in materials, process or equipment

31. „Appropriate resources: personnel, buildings, equipment and materials”
These all should be available to produce a quality product.
Thus, the company should evaluate all of the elements it needs to produce a drug to see that it has sufficient resources

32. „Manufacture is based on clearly written procedures”
batch manufacturing instructions
testing instructions
SOPs needed for all departmants
Preparing these documents is very important task (see Documentation)

33. „Trained operators”
Documentation, instructions, etc. are not enough if the operators can not work with them properly
Training includes also follow-up training

34. Basic Requirements for GMP – II
Quality Management
Basic Requirements for GMP – II
6. Complete records, failure investigations
7. Proper storage and distribution
8. Recall system
9. Complaint handling
Basic requirements for GMP are as follows:
6. Complete records document the manufacturing process. Failure investigations are carried out if quality problems come up. In the same way that the company has documentation specifying how it is to make and test the products, it must also have records that show what is actually done each time it makes and tests those products. These records are very important because in the future they show what was done, by whom and whether the work conformed to the standards. If there is cause to check back, then the records will enable the company and the inspector to look at what happened at the time. If failures are reported, such as product complaints, then a review of the records will enable effective action to be taken to prevent the problem from re-occurring. We will look at the great learning opportunity that failure investigations offer us later.
7. Proper storage and distribution of the products. When a product is developed, stability testing is undertaken in order to determine the storage conditions and its shelf-life. Proper storage and distribution of the product minimize risks to their quality.
8. A recall system providing a final safety net, in case quality problems are detected after release of the product. If a product in the market is found to be defective, there needs to be a means of getting that product off the market. This is a recall. Recalls can be done in different ways and with different degrees of severity, depending upon the reason for the recall. Usually the recall procedure will need to be agreed with the drug regulatory authority of each country where the product is sold.
9. Complaint handling procedures are established to react to feedback from the market. For those products that develop quality problems while marketed a complaint handling procedure is required. If the customer's complaint is related to some aspect of manufacturing, then it is worth investigating and, where necessary, taking some action to improve the process to prevent re-occurrence.

35. „Complete records, failure investigations”
(We have just seen there are manufacturing, packaging, QC, etc. instructions how to perform the work)
Also records are needed to show what and how was actually done each time, by whom, etc.
If there is a reason later to come back to check what happened with a given batch, the only possibility is to check the records
E.g. when failures are found later

36. „Proper storage and distribution”
When a new drug is developed, stability studies determine the storage conditions and its shelf-life
However, the storage conditions should be met!
Also during distribution!

37. „Recall system”
If quality problems detected when the product is already on the market, there should be a system to recall them (from wholesalers or from pharmacy level)
System, for there can be different ways anddegress of severity, depending upon the reasons for the recall
Simple circular information by letter<by fax<TV and press warning if life threatening, etc.
Involvement of national regulatory authorities – according to local law

38. Complaint handling
If the complaint of a purchaser or consumer is possibly related to manufacturing defects, it is worth of investigation
This way its re-occurrence can be prevented

39. Quality Management Cascade
Quality relationships
Quality Management (overall policy)
Quality Assurance (concept ensuring that the policy is achieved)
GMP (how to do it)
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.
including

40. Quality Control (QC) Department
Quality Management
Quality Control (QC) Department
Each holder of a manufacturing authorization should have a QC Department
Independence from production and other departments is considered to be fundamental
Under the authority of an appropriately qualified and experienced person with one or several control laboratories at his or her disposal.
Each holder of a manufacturing authorization should have a quality control department (except for a holder performing only a fraction of the manufacturing process under a contract).
The independence of quality control from production is considered fundamental. The quality control department should be independent fromother departments and under the authority of a person with appropriate qualifications and experience, who has one or several control laboratories at his disposal.

41. Basic Requirements for Quality Control
Quality Management
Basic Requirements for Quality Control
Resources
Adequate facilities
Trained personnel
Approved procedures
The quality control department must have adequate resources.
This means:
Adequate laboratory facilities or access to them e.g. government or contract laboratories
Appropriately qualified, trained and experienced personnel
Approved written procedures.

42. Basic Requirements for Quality Control
Quality Management
Basic Requirements for Quality Control
Tasks
Sampling
Inspecting
Testing
Monitoring (materials, environmental conditions)
Releasing/rejecting
The operational tasks of the quality control department are:
Sampling
Inspecting
Analytical testing
Monitoring of all materials and environmental conditions in the factory
Releasing or rejecting materials for production use and finished products

43. Basic Requirement for Quality Control - I
Objects
Starting materials
Packaging materials
Intermediates
Bulk products
Finished products
Environmental conditions
The objects of these activities are:
Starting materials
Packaging materials
Intermediates
Bulk products
Finished products
Environmental conditions

44. Basic Requirements for QC - II
1. Sampling approved by QC department not necessarily done by them, but ensuring samples are representative
2. Validated test methods accurate, precise, robust, specific, linear…
3. Records of sampling, inspecting, testing, of incoming materials, intermediates, bulk and packaged finished products
4. Review and evaluation of production documentation for release: not only test results
5. Failure investigations for all deviations
6. Ingredients comply with the marketing authorization
Let’s look at some of these basic requirements for quality control in greater detail:
1. Sampling should be undertaken by methods and personnel approved by the QC department. We described a little earlier the key issues around sampling. It is not a requirement that all sampling needs to be done by quality assurance or quality control personnel. The important point is that it is carried out in such a way that it is representative of the batch and in accordance with an SOP. QC personnel must have access to the production area to undertake sampling when necessary.
2. Validated test methods should be applied. The validation of test methods includes verification of: accuracy, precision, linearity, repeatability, robustness, specificity. This means that the test methods should be challenged to be able to demonstrate that the tests are able to give an accurate result on a repeatable basis. The methods must be capable of being applied with precision. The results obtained must be linear over a range of acceptable responses. Finally, the results must be repeatable over a number of identical tests.
3. Records for sampling, inspecting, testing of materials, intermediates and bulk and finished products need to be kept. It is essential too that the inspector assesses the records of the work done during processing. This means that there will be traceability on what happened.
4. The QC department should review and evaluate the relevant production documentation. This review needs to cover all quality aspects. As part of the documentation procedure, it is important that the quality control department approves all the documentation. This ensures that the manufacturing documentation and the quality assurance documentation are in harmony.
5. The QC department should generate or review records for deviations and failure investigations. As batches are produced, it is important that all deviations from the normal manufacturing procedure are recorded or documented. Any impact on product quality must be assessed. It may be that additional product testing is required. It may be that additional stability testing is necessary.
6. Ingredients must comply with the qualitative and quantitative composition of the finished product as approved in the marketing authorization. It is most important that the materials used in manufacture comply with the details registered in the marketing authorization. It is on this basis that the product was developed and that all the stability testing has been carried out. All the clinical trials have also been completed using materials of a consistent specification. The product has been registered using those sources and quality of materials.

45. Basic Requirements for QC - III
7. Ingredients are of the required purity
8. Proper containers compatibility!
9. Correct labelling mislabelling = life-threatening error
10. Release of batches by the authorized person who has the right – predetermined persons with adequate qualification and experience
11. Retained samples of starting materials and products
Successful quality control also requires that:
7. Ingredients are of the required purity. We have already talked about the reasons for ensuring that the starting materials are of the specified quality. Without it the company will be unable to ensure that the rest of the process can be carried out with success.
8. Proper containers are used. During development of the product, care will have been taken to test the compatibility of the product with the container. Testing will have been undertaken to determine the effectiveness of the container in ensuring that product stability is maintained. The use of non-compliant or non-approved containers would mean that the product shelf-life cannot be guaranteed.
9. Labelling of in-house materials and finished product is correct. In some countries more than half of all product recalls are caused by incorrect printed components. These failures can be due to a variety of causes. These range from mix-ups in the printed components during printing or labelling and packing, to text errors in the printing which have not been identified. These same errors can also occur in-house if insufficient care is taken.
10.Batches are released by the authorized person. Release of batches of finished product should only occur after the authorized person has certified that production and quality control have been completed in accordance with the requirements of the marketing authorization.
11. Samples of starting materials and products and retained. Sufficient retention samples of the starting materials and the finished product in its final pack should be kept for one year past the expiry date. This is to allow for an evaluation of the product after it has been distributed should there be a need. It will also allow ongoing stability trials to be done. These samples help to control that the product conforms with the requirements during the entire shelf-life.

46. Other Duties of the QC Department
1. Establish QC procedures and validation in the first time then its „release”
2. Reference standards and their storage! Mainly test results rely on the comparison with the reference standards…
3. Correct labelling
4. Stability testing
5. Complaint investigations
6. Environmental monitoring
In addition to those already mentioned, the QC department has other duties to carry out, including:
1. Establishing, validating and implementing all QC procedures. All QC procedures need not only to be established in the first instance but also to undergo exactly the same critical review and maintenance process as operating procedures in all other areas.
2. Evaluating, maintaining, storing reference standards. Reference standards are among the most critical materials that QC has to handle. After all, the results of much testing rely upon comparison with an analytical reference standard. If that reference standard has not been looked after properly then all the test results may be incorrect.
3. Ensuring correct labelling of containers of materials and products. We have already mentioned just how critical this activity is. The major difficulty is the problem of seeing that an error has occurred. You are looking at a situation where there are thousands of components often being processed at high speed. It is nearly impossible for operators to see that an error has occurred. Systems must be in operation as the main safeguard. If equipment such as bar code readers are in operation it must be regularly checked for effectiveness.
4. Stability testing of active ingredients and finished products. A stability-testing programme should be developed for all products, described in the form of an SOP. Stability of active pharmaceutical ingredients should be monitored. Active ingredients should be regularly tested within their shelf-life to confirm suitability for continued use. The quality control department should have a very clear role in ensuring that samples are taken for the ongoing stability testing programme and that analysis is undertaken at the right time.
5. Participating in complaint investigations. We will be devoting a whole module to the importance of complaint and recall handling. It is worth repeating that complaints offer an opportunity for the company to learn from mistakes or product design failures. In this way actions can be taken to prevent re-occurrence.
6. Participating in environmental monitoring. There are many sides to environmental monitoring. With regard to products, the environment that we are referring to here is that which can immediately affect product quality. E.g.., swab testing and settle plates in a sterile area, testing of temperature and humidity control. There is another environment that needs to be looked at. External environment checks may be needed.

47. Assessment of Finished Products
Should embrace all relevant factors (not only the QC test results!). For example:
production conditions
in-process test results
manufacturing documentation
compliance with finished product specification
examination of the finished pack
Assessment of finished products should embrace all relevant factors, including the production conditions, the results of in-process testing, the manufacturing (including packing), documentation, compliance with the specification for the finished product, and an examination of the finished pack.

48. QC Access
QC Personnel MUST have access to production areas for sampling and investigation
As appropriate! E.g. not appropriate: entering in aseptic filling suites, or where highly potent dangerous materials are present…
QC personnel must have access to production areas for, for example, sampling and inspection. However, this must be balanced because it may not be appropriate, for instance, to have QC staff enter aseptic filling suites, or areas where there is highly potent dangerous material such as oncology (or cytotoxic material) or anovulent hormones.

49. QC - Summary QC is part of GMP sampling specifications authorization
testing
release procedures
recalls and complaints
decision-making in all
quality matters
authorization
definition of product quality
laboratory operations
release decisions
investigation and reporting
Quality control is the part of GMP that is concerned with sampling, specifications, testing and with organization, documentation and release procedures, using validated methods implemented by trained and experienced personnel.
The quality control process is not confined to laboratory operations, but must be applied to all decisions concerning the quality of a product. Quality control staff must therefore sign all manufacturing procedures that are relevant to product quality. Quality control staff will also monitor environmental conditions that have an effect on product quality. Each holder of a manufacturing licence should have a quality control department. This department must have staff who are clearly responsible for all quality control activities. They must have access to suitable facilities to perform all the testing that is required.
The independence of quality control from production is considered fundamental. This means that the quality control manager should not report to the production manager. Likewise, the production manager should not report to the quality control manager. Legislation in different countries deals with this issue in different ways. Quality control departments need sufficient resources to carry out their responsibilities.
Adequate resources should include:
sufficient numbers of trained and experienced staff
an appropriately designed laboratory, suitably equipped to enable all the quality control functions to be carried out in accordance with specifications.
Ideally, the head of the quality control department should report directly to the managing director of the company. This means that for key decisions on product quality there is no interference from manufacturing staff. An alternative to this, which might in some circumstances be preferable, is that the quality controller reports to a professionally qualified technical director who is also responsible for production activities. This position does rely on the professionalism of the jobholder. The advantage of this second arrangement is that it encourages a scientific and professional review of the product quality against the standards and product use. This scientific evaluation of the product may not be possible for a chief executive who has no scientific background.
All samples must be taken by methods and trained personnel approved by the quality control department. Records must be made of all sampling and testing and any deviations fully recorded and investigated. Samples (when taken) must be representative of the whole batch under consideration. The samples must be taken in accordance with a sampling plan, and in such a way as not to change the quality of the material being sampled. When containers have been sampled, they need to be labelled as such. The equipment used for sampling should be carefully cleaned between use, to ensure that it has no adverse affect on the result of the testing to be done. This cleaning will also assist in preventing cross-contamination. All activities relating to sampling should be described in a SOP, together with the safety precautions required.
The quality control department should authorize all documentation that has an effect on product quality. This will include all SOPs as well as master documents for production and quality control batch documentation. A complete review of all batch documentation, relating to production and quality control, should be undertaken before the decision to release the product for sale is taken by the authorized person. The authorized person must check that the product conforms to the established specifications and the registered product details before releasing the product for distribution.
The quality control department must retain sufficient samples of all materials in the batch and of the finished product, as described in the relevant SOP. The retained sample is used for ongoing stability testing and to permit, as necessary, a future examination of the product in case of a product complaint or recall. The quantity of the product to be retained will be determined by reference to the stability testing programme and the extent of testing required. Generally, the quantity is at least twice that required for full testing.
The quality control department has the responsibility for handling all product complaints and recalls, including the management of any recall procedure, which must be available in the form of a written SOP. This area of activity deals with the less positive aspects of quality management. However, professional handling of any complaints or recalls is extremely important. There is a complete module devoted to this issue in this training programme.

50. Quality management also means: identification assessment
cotrol (keeping under control)
presentation (to all interested persons)
of any risk factor that may affect the quality of the medicine

51. Quality Management Group session II
Imagine you are inspecting a pharmaceutical company for compliance with GMP
Consider the situations in the next slides which may 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 _____________.

52. Quality Management Issues 1
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 :

53. Quality Management Issues 2
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.

54. Before starting: definitions
In this session, we are going to deal with an area of importance to the good functioning of a pharmaceutical factory, sanitation and hygiene.
This will be a quarter-day session with the following approximate timings:
Presentation 45 minutes
Group session 45 minutes
Group feedback minutes
Test paper minutes
(Timings are approximate and should be adjusted to suit the class and the course structure.)

55. Definitions 1 In-process control IPC: QC during the production
Campaign working: separated in time
Quarantine: separation of the the incoming or newly manufactured product until the release

56. Definition 2
Release: decision on a batch: whether it meets the requirement (or not), based on both QC results and batch production records
Key persons: head of production, head of QC/QA + the qualified person QP if different from the latter

57. Definitions 3
Standard Operating Procedure SOP: description of a technological procedure
Intermedier product: product between the starting materials and the final product
Bulk: starting materials and intermediates as well as final products e.g. in barrels

58. Definitions 4
Yield in synthesis: based on the chemical formulas, molecular weights, the reaction equation and the measured-in quantities
Yield in dosage-form production: based on the measured-in quantities and the quantitative composition of one tablet
Never 100%!

59. 2. Sanitation and Hygiene
In this session, we are going to deal with an area of importance to the good functioning of a pharmaceutical factory, sanitation and hygiene.
This will be a quarter-day session with the following approximate timings:
Presentation 45 minutes
Group session 45 minutes
Group feedback minutes
Test paper minutes
(Timings are approximate and should be adjusted to suit the class and the course structure.)

60. Sanitation and Hygiene
Objectives
Review measures to ensure good sanitation in:
premises
equipment
processes
To review measures to ensure good personnel hygiene
There are three main objectives to this session:
Firstly, we are going to look at the measures that need to be taken to ensure good sanitation during manufacturing. These relate primarily to the premises, the equipment and the process to prevent any type of contamination.
Secondly, we are going to look at the measures that need to be taken to ensure that good levels of hygiene are achieved during manufacturing. These relate primarily to the personnel.
Finally, we are going to relate everything back to the issues particularly relevant to your country. During the group session, you will be looking at the key factors that you need to be aware of during your inspections. We will be presenting you with some photographs to list all the sanitation and hygiene problems that you can.

61. Sanitation and Hygiene, scope
All aspects of manufacturing
Personnel who enter the manufacturing area
Premises the level of attention will depend on the nature of the operation carried out there
Equipment
Apparatus
Production materials and container if not handled properly can contribute to dirt
Products for cleaning and disinfection but cleaningagents also controlled = they do their job but do not contaminate the product. Also cleaning tools e.g. brushes
All potential sources of cross-contamination
The WHO GMP refers to sanitation and hygiene in part one, section 4. It makes the point that all aspects of manufacturing are affected by one or both of these factors.
Consideration must be given to all personnel, both direct operators and other staff who enter the manufacturing area for whatever purpose.
Then there are the premises in which manufacturing takes place. The level of attention to this aspect will vary with the operation that is carried out.
All equipment and apparatus used in manufacturing must be controlled, together with production materials and the containers in which they are held.
Production materials (if not handled properly) and the containers (if not properly cleaned) can contribute to dirt and contamination in the factory.
Secondary materials, such as cleaning agents and disinfectants, must be controlled to ensure that they do the job for which they are designed but do not cause any contamination to the product. Cleaning tools, such as mops and brushes, must also be controlled.
To summarize, the aim of sanitation and hygiene measures is to eliminate all potential sources of contamination and cross-contamination from all areas where the product is at risk.

62. Design of Premises - I Design
Walls, floors, ceilings, ledges, drains, air supply, dust extraction
Prevention of build-up of dirt and dust to avoid unnecessary risks of contamination
Cleaning programme, appropriate cleaning (e.g. cleaning a warehouse differs from cleaning a sterile area), its frequency, cleaning records
Sanitation is covered as part of the general discussion of premises in part one, section 11 of the WHO GMP text.
As discussed (or will be discussed) in the module on premises, the design of any area depends on the activities that are going to be performed there. However, in general terms, all areas should be designed in such a way that prevents the build-up of dirt and dust. This includes the absence of ledges and unnecessary surfaces, sealing of all joints in ceilings, coving at floor and ceiling and installation of a ventilation system that provides an appropriate flow of air.
There are a number of aspects to be covered in looking at cleaning. An effective programme should be designed that covers both cleaning and disinfection. The frequency of each will vary with the function of each area and the particular activities undertaken there. There must be a written procedure (SOP) covering the programme, who is responsible for carrying it out, the materials to be used and methodology. The procedure should be appropriate to the area being cleaned. For example, the procedure for cleaning the warehouse would not be appropriate for cleaning a sterile area.
There should also be a written record of cleaning that has been performed.
While drains are inevitable in some manufacturing areas, they should be kept to a minimum and should certainly not be located in sterile areas. Their design must prevent the possibility of back-flow. Open channels should be easy to clean and disinfect.
There should be maximum protection against the entry of insects or other animals. In loading bays in particular, there needs to be protection against the weather.

63. Design of Premises - II Effective cleaning and disinfection
choice of materials and chemicals, validation
Drains no back-flow, in sterile areas: at a minimum,
Protection from insects, vermin and weather
from receipt of raw materials to despatch of released product
Sanitation is covered as part of the general discussion of premises in part one, section 11 of the WHO GMP text.
As discussed (or will be discussed) in the module on premises, the design of any area depends on the activities that are going to be performed there. However, in general terms, all areas should be designed in such a way that prevents the build-up of dirt and dust. This includes the absence of ledges and unnecessary surfaces, sealing of all joints in ceilings, coving at floor and ceiling and installation of a ventilation system that provides an appropriate flow of air.
There are a number of aspects to be covered in looking at cleaning. An effective programme should be designed that covers both cleaning and disinfection. The frequency of each will vary with the function of each area and the particular activities undertaken there. There must be a written procedure (SOP) covering the programme, who is responsible for carrying it out, the materials to be used and methodology. The procedure should be appropriate to the area being cleaned. For example, the procedure for cleaning the warehouse would not be appropriate for cleaning a sterile area.
There should also be a written record of cleaning that has been performed.
While drains are inevitable in some manufacturing areas, they should be kept to a minimum and should certainly not be located in sterile areas. Their design must prevent the possibility of back-flow. Open channels should be easy to clean and disinfect.
There should be maximum protection against the entry of insects or other animals. In loading bays in particular, there needs to be protection against the weather.

64. Design of Premises: avoidance of cross-contamination Definitions:
Contamination: by a foreign matter
Cross-contamination: by a material also manufactured there

65. Avoidance of Cross-contamination - I
Segregated areas
Ventilation systems and airlocks
Clothing
Closed processing systems
Cleaning and decontamination
In part two of the WHO GMP, section 15 covers the measures that need to be taken to avoid cross-contamination.
These include:
Segregated areas
Ventilation systems and airlocks
Clothing
Closed processing systems
Cleaning and decontamination

66. Avoidance of Cross-contamination - II
Segregated areas and separate facilities for
live vaccines and other biological materials
penicillin products
campaign processing
Certain products, such as live vaccines and other biological materials need to be produced in separated areas. In particular, penicillin should be produced in a separate facility.
The trainer should also give emphasis to the WHO clause (a) on campaign processing. The question of campaign batches and what cleaning may be appropriate is a matter of some controversy and many countries have different requirements.

67. Avoidance of Cross-contamination - III
Ventilation systems and airlocks
design of ventilation system
incoming air should be filtered
pressure differentials and air extraction positive pressure
airlocks
airflow patterns and equipment design
recirculation versus 100% fresh air supply
An important measure against cross-contamination is the design of the ventilation system. All incoming air should be filtered to an appropriate standard to achieve the grades of cleanliness specified for the room being supplied. The use of appropriate pressure differentials and air extraction, together with airlocks, is one of the main ways of achieving control over cross-contamination. (Airflow patterns and equipment design are other considerations.) Additionally, the recirculation of air must be examined carefully. If a ventilation system supplies 100% fresh air, then different rooms can be used for different products at the same time. However, if a system includes recirculation, then all rooms supplied by that system must be processing the same product, or the air must be filtered to an appropriate standard. If no filters are installed, then all ductwork will have to be cleaned during product changeover.

68. Avoidance of Cross-contamination - IV
Clothing
protection of operator and product
highly potent products or those of particular risk - need for special protective clothing
personnel should not move between areas producing different products
garments need to be cleaned
Clothing relates to the protection of both the operator and the product. For highly potent products or those that create a particular risk of cross-contamination, special protective clothing needs to be worn. Decontamination processes for these clothes need to be in place. For all manufacturing areas where there is any risk of the product contaminating the clothing, the simple precaution of not moving between areas producing different products should be adopted.

69. personnel in different coloured garments

70. Avoidance of Cross-contamination - V
Closed processing systems, i.e.
totally enclosed water purification systems
tanks fitted with appropriate filtration - without
removable lids
present special cleaning difficulties, sometimes use
clean-in-place (CIP)
Increasingly, facilities are being designed with closed processing systems. This trend is obviously one that should be encouraged, as it is a major element in the avoidance of cross-contamination.

71. Avoidance of Cross-contamination - VI
Cleaning and decontamination
procedure for removing soil and dirt
remove all cleaning chemical residues or disinfectant residues
must remove or reduce micro-organisms
Cleaning should be a procedure for removing soil and dirt. It should not add or leave behind anything, including cleaning, chemical or disinfectant residues.
It must remove or reduce micro-organisms.
Cross reference to the module on validation can be mentioned if questions arise on how and what is cleaning validation.

72. Product Operations – Sanitation 1
Work-flow
designed to avoid potential contamination
access restricted to authorised persons exclusively
operators
QC staff
warehouse staff
maintenance personnel
cleaners
the more critical the more restriction!
The work-flow has to be designed in such a way as to avoid any potential contamination. Access to production areas should be restricted to authorized personnel only. These will include direct operators, QC staff, warehouse staff, maintenance personnel and cleaners. The more critical the area, the fewer the people that should be in there during processing operations.

73. Production Operations – Sanitation 2
Simultaneous operations
not permissible to process different products in different areas with a common ventilation system
permissible to carry out secondary packaging activities for different products within a packing hall with adequate physical separation
Processing of different products simultaneously within a single room or area supplied by the same ventilation system must not be carried out unless there is no risk of cross-contamination. Hence, it is permissible to dispense materials for different products within adjacent down-flow booths in a dispensary. This is because each booth creates its own protected environment. That is, it is not permissible to process different products in different parts of a tabletting facility, if the area is supplied by a single unfiltered recirculating air system It is also permissible to carry out secondary packaging activities for different products within a packing hall, provided there is adequate physical separation, such as a partition, since the product is sealed and there is no risk of airborne contamination. However, it is not permissible to process different products in different parts of a tabletting facility, if the area is supplied by a single recirculating air system, unless appropriate air filtration is used. .

74. Production Operations – Sanitation 3
Area clearance checks
Process of checking
all materials and documentation from the previous batch removed
all plant and equipment thoroughly cleaned and appropriate status labelling
checklist useful
The first step in any batch processing operation is the area clearance check. This is the process of checking that all materials and documentation from the previous batch have been removed, and that all plant and equipment has been thoroughly cleaned.
A useful group exercise is to use a flipchart to get the trainees to list all the requirements for a cleaning status label. Items can include: name of the equipemnt, cleaned or not clean, date cleaned, who cleaned, who passed, how long will the cleaned equipment remain clean before rrequiring recleaning, etc.,

75. Production Operations - Sanitation 4
Area clearance checks a)
The area clearance check should be carried out by two people
between batches of same product, acceptable for both checks to be carried out by production personnel it is the first manufacturing/packaging step!
The area clearance check should be carried out by two people (one performing the check and the other confirming the result). Between batches of the same product, it is acceptable for both checks to be carried out by production personnel. However, where there has been a product changeover as well, the second check should be carried out by QC staff. All checks should be carried out in accordance with a written SOP and the results recorded on the batch documentation and cleaning record. A checklist is very useful for this purpose.
Discuss with the trainees the requirement for QC to do the second check for the area clearance check.

76. Production Operations – Sanitation 5
Area clearance checks b)
The area clearance check should be carried out by two people
for product changeover, second check carried out by QC staff
all checks carried out in accordance with written SOP and results recorded on the batch documentation
The area clearance check should be carried out by two people (one performing the check and the other confirming the result). Between batches of the same product, it is acceptable for both checks to be carried out by production personnel. However, where there has been a product changeover as well, the second check should be carried out by QC staff. All checks should be carried out in accordance with a written SOP and the results recorded on the batch documentation and cleaning record. A checklist is very useful for this purpose.
Discuss with the trainees the requirement for QC to do the second check for the area clearance check.

77. Production Operations - Sanitation 6
Cleaning and cleaning validation
degree of cleaning depends on whether consecutive batches are of same or different product
Check cleaning agent is fully removed
If possible hot water alone used for cleaning
all cleaning and disinfecting solutions carefully prepared and expiry dated
Final rinse with purified water, or water for injection (for sterile products)
Full records kept
We have already talked about cleaning of premises. Another important point is the cleaning of the equipment in which products are manufactured. The degree of cleaning will depend on whether consecutive batches are of the same product or of different products. It is important that any cleaning agent introduced is also fully removed so that it does not contaminate the product. Wherever possible, hot water alone should be used for cleaning. The final rinse should be with purified water or water for injection in the case of equipment used for processing sterile products.
A validation programme should be based on the worst case situation, e.g. a relatively insoluble material that is active at low levels of concentration. Additionally, full records should be kept of cleaning and sanitation.

78. Production Operations – Sanitation 7
Water systems
Water - major constituent of most products
SOP for cleaning and sanitisation of the water purification system should include distribution pipework
Validation and removal of disinfectant before reuse
The sanitation of water systems is particularly important, as water is such a major constituent of most products. Water heated >75oC and recirculated is a good sanitising agent. Water for Injection is usually stored at much higher temperatures.
There should be a written standard procedure for cleaning and prevention of contamination, which should include not just the purification system but also the distribution pipework. The procedure should be validated, especially the removal of disinfectant before the system is put back into use. This is important because formaldehyde and peracetic acid are often used to disinfect water systems

79. Production Operations – Sanitation 8
Maintenance and repair
activities inevitable in manufacturing area.
Should present no risk to product
Whenever possible, all planned maintenance outside normal operating hours
Emergency work in working area followed by thorough clean down and disinfection before manufacturing recommences
Area clearance by QC
Repair and maintenance activities are inevitable in a manufacturing area. However, they should be carried out in a way that does not present any risk to the product. Therefore, whenever possible, all planned maintenance should be done outside of normal operating hours. Any emergency work in a working area should be followed by a thorough clean down and disinfection of the area before manufacturing recommences, AND area clearance by QC

80. ! Personnel Hygiene 1 Health examinations Training - check
On recruitment for direct operators , repeated on regular basis
Training - check
induction training for new operators includes basic personal hygiene training
written procedures - to wash hands before entering a manufacturing area
signs in changing rooms to reinforce hand washing !
Having dealt with sanitation, we now move on to the hygiene of the personnel involved in manufacturing. This is covered in the WHO GMP texts in part one, section 10.
The recruitment process for direct operators in particular should include a medical examination. This should be repeated on a regular basis during the employment period. The definition of “regular” will obviously depend on the activities being undertaken and the products being processed.
Induction training for new operators should include basic training in personal hygiene and should state the level of hygiene that is required for working in manufacturing areas. There should be written procedures covering the need to wash hands before entering a manufacturing area. In addition, signs should be posted in the changing rooms to reinforce this.
Staff who have an illness or open lesions that are likely to present a risk to the product, should not be allowed to carry out operations that involve handling of starting materials, intermediates or finished products until the condition has cleared up. Since not all illnesses are going to be obvious, operators must be trained to recognize such risks themselves and be willing to report any illness to the area supervisor.

81. Personnel Hygiene 2 Illness
staff with illness or open lesions should not handle starting materials, intermediates or finished products
Staff who have an illness or open lesions that are likely to present a risk to the product, should not be allowed to carry out operations that involve handling of starting materials, intermediates or finished products until the condition has cleared up. Since not all illnesses are going to be obvious, operators must be trained to recognize such risks themselves and be willing to report any illness to the area supervisor.

82. Personnel Hygiene 3 Adverse conditions
operators trained to recognize risks
willingness to report illness to the area supervisor easy? What happens? People can be motivated to the opposite!
Staff who have an illness or open lesions that are likely to present a risk to the product, should not be allowed to carry out operations that involve handling of starting materials, intermediates or finished products until the condition has cleared up. Since not all illnesses are going to be obvious, operators must be trained to recognize such risks themselves and be willing to report any illness to the area supervisor.

83. Personnel Hygiene 4 Contact between product and operator
avoid direct contact
if direct handling unavoidable, gloves should be worn
check glove disinfection (for sterile production) and disposal
Direct contact between the operator and the product should be avoided wherever possible. If direct handling is unavoidable, then gloves should be worn and, if appropriate, these should be disinfected after being put on.

84. Personnel Hygiene 5 Clothing and changing facilities a)
check changing rooms (handwashing, towels or hot air hand dryers) opening taps
check if used clothing stored in separate closed containers while awaiting cleaning
Clothing and changing facilities are covered in a number of the modules on this course. The type of clothing required and the changing procedure will obviously vary with the activities being carried out. They need also to apply to visitors. Used clothing must be stored in separate closed containers while awaiting cleaning.
The laundering of clean area clothing must be carried out according to a written procedure and in an appropriate facility. If necessary, there should also be a procedure for sterilizing and storing clothing for use in the sterile area.

86. Personnel Hygiene 6 Clothing and changing facilities b)
laundering of clean area clothing must be to SOP and in appropriate facility
check for procedure for sterilizing and storing clothing for use in sterile area
Clothing and changing facilities are covered in a number of the modules on this course. The type of clothing required and the changing procedure will obviously vary with the activities being carried out. They need also to apply to visitors. Used clothing must be stored in separate closed containers while awaiting cleaning.
The laundering of clean area clothing must be carried out according to a written procedure and in an appropriate facility. If necessary, there should also be a procedure for sterilizing and storing clothing for use in the sterile area.

87. Personnel Hygiene 7
Smoking, eating and drinking should not be allowed in any manufacturing area, including laboratories and storage rooms
Chewing of gum should be banned
Smoking, eating and drinking should not be allowed in any manufacturing area, including laboratories and storage rooms. Chewing of gum should also be banned. There should be no plants kept inside any factory areas.
Rest and refreshment areas should be separate from manufacturing areas. Toilets should not open directly into production or storage areas. However, there should be a reasonable access procedure. This should be taken into consideration when setting up changing procedures for entry to manufacturing areas.

88. Personnel Hygiene 8
There should be no plants kept inside any factory areas.
Rest and refreshment areas should be separate from manufacturing areas.
Toilets should not open directly into production or storage areas.
Smoking, eating and drinking should not be allowed in any manufacturing area, including laboratories and storage rooms. Chewing of gum should also be banned. There should be no plants kept inside any factory areas.
Rest and refreshment areas should be separate from manufacturing areas. Toilets should not open directly into production or storage areas. However, there should be a reasonable access procedure. This should be taken into consideration when setting up changing procedures for entry to manufacturing areas.

89. Sanitation and Hygiene
Group Session
You are inspecting a new factory. What are the key issues for sanitation and the key issues for personnel hygiene that the company should have in place?
We are now going to move into the group session.
In your groups, you should discuss the subjects of sanitation and hygiene as they relate to the pharmaceutical industry in your country.
Use your experience from inspections that you have made and give concrete examples wherever possible to illustrate the key issues that you are to check in a new manufacturing facility.

90. Sanitation and Hygiene
Possible Issues – Sanitation 1
Mixed production
Penicillins
Product versus batch changeovers
Water systems
How long should a “cleaned” status last for?
If production demand is high, there may be resistance from the managers of the factory to spending time carrying out effective cleaning.
Production of different products in the same area can cause serious cross-contamination.
The issue of decontamination of a factory that has been used for the manufacture of penicillins needs to be addressed carefully.
In an older building, the design may not be suitable for effective cleaning. For example, there may not be false ceilings, walls may be covered in tiles, etc.
The design of the ventilation system needs to be reviewed, particularly with respect to standards of filters and recirculation. Cleaning of ductwork should also be discussed.
Procedures for a changeover from one product to another should be more stringent than the procedure between batches.
There should be written procedures for regular cleaning and prevention of contamination of the water system.
The procedure for cleaning and prevention of contamination should include details of who is responsible, what they have to do and where it is recorded.

91. Sanitation and Hygiene
Possible Issues – Sanitation 2
What should happen if a clearance check is required when no QC personnel are on duty?
Procedures and records
If production demand is high, there may be resistance from the managers of the factory to spending time carrying out effective cleaning.
Production of different products in the same area can cause serious cross-contamination.
The issue of decontamination of a factory that has been used for the manufacture of penicillins needs to be addressed carefully.
In an older building, the design may not be suitable for effective cleaning. For example, there may not be false ceilings, walls may be covered in tiles, etc.
The design of the ventilation system needs to be reviewed, particularly with respect to standards of filters and recirculation. Cleaning of ductwork should also be discussed.
Procedures for a changeover from one product to another should be more stringent than the procedure between batches.
There should be written procedures for regular cleaning and prevention of contamination of the water system.
The procedure for cleaning and prevention of contamination should include details of who is responsible, what they have to do and where it is recorded.

92. Sanitation and Hygiene
Possible Issues – Hygiene
Personal hygiene
Health checks
Dealing with health problems
Personal responsibility
Training records
Frequency of handwashing
Personal hygiene is always a sensitive matter. However, the company must be able to ensure that operators not only understand hygiene requirements, but also fulfil them.
Health checks should be carried out on all new operators and periodically on all staff during employment. This could be a problem if the managers are reluctant to carry the expense.
There should be trained staff who can deal with issues relating to health problems. The operators must feel that they can report these problems in confidence without risking their jobs.
As with any aspect of pharmaceutical manufacture, the final quality of the product depends, to a large extent, on the willingness of the operators to take personal responsibility for such issues as hygiene.
Training should include references to procedures for cleaning and hygiene requirements, which should be included in written training records.

93. Exam topic

94. Sanitation and hygiene in GMP
Design of premises (walls, ceilings, floors, drains, cleaning programme, protection from external factors)
Avoidance of cross-contamination (mention measures)
Campaign working versus dedicated manufacture areas for certain drugs (examples!).
Clothing
Health measures
Cleaning