1. MANAJEMEN MUTU

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MANAJEMEN MUTU
(Quality Management)
Part One
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
Presentation 30 minutes
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.
Module 2 Slide * of 26
WHO - EDM
Quality Management
TUJUAN MATERI
Untuk memahami isu-isu penting dalam quality assurance (jaminan mutu) dan quality control (pengawasan mutu).
Untuk memahami ketentuan khusus mengenai organisasi, prosedur, proses dan sumber daya.
Untuk mengembangkan berbagai tindakan untuk mengatasi masalah yang terjadi.
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.
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Part One
Quality Management
Komponen dasar:
Tindakan sistematis untuk menjamin secara meyakinkan bahwa produk/jasanya memenuhi syarat kualitasnya.
Keseluruhan tindakan sistematis ini disebut Jaminan Mutu (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.
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Part One
Quality Management
Istilah lain
Konsep Quality Assurance (QA), Good Manufacturing Practices (GMP) and Quality Control (QC) merupakan aspek-aspek yang saling terkait dalam Quality Management.
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!
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Quality Management
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.
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Konsep bercakupan luas (Wide-ranging)
Mencakup semua hal yang secara individu maupun kolektif mempengaruhi mutu suatu produk
Totalitas dalam penyusunannya
Untuk menjamin bahwa obat mempunyai kualitas yang benar sesuai tujuan penggunaannya
Quality Assurance memuat GMP
Termasuk desain produk dan pengembangannya
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.
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2. Mengidentifikasi tanggungjawab manajerial
4. Mengorganisasi suplai dan penggunaan bahan baku yang benar
5. Menetapkan kontrol atas semua tahap pengolahan dan pengemasan
Quality Assurance
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.
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Quality Assurance
Syarat-syarat Suatu Sistem QA
Menjamin produk jadi diproses dan dikontrol dengan benar sebelum dilepas ke pasaran
7. Menjamin produk yang dilepas ke pasaran telah dikaji ulang oleh SDM yang tepat
8. Mengawasi penyimpanan dan distribusi
9. Mengorganisasi inspeksi diri (self-inspection)
Part One 1.2 a-j
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.
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Menjamin produk diproduksi dan dikontrol secara konsisten
Mengurangi resiko yang tidak dapat dikontrol melalui pengujian produk
Cross-contamination (kontaminasi silang)
Mix-ups (tercampur)
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.
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Ketentuan Dasar
1. Proses produksi didefinisikan secara jelas dan dikajiulang secara benar
2. Tahap-tahap kritis proses produksi divalidasi
3. Sumberdaya utk memproduksi produk yg bermutu mencukupi:
- SDM, bangunan, peralatan, bahan baku
4. Prosedur produksi tertulis dengan jelas
5. Operator terlatih
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.
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Ketentuan Dasar
6. Proses produksi terdokumentasi dan ada investigasi kegagalan jika ada masalah kualitas
7. Penyimpanan dan distribusi produk memadai
8. Ada sistem recall (penarikan kembali) jika ada masalah pd produk yg dipasarkan
9. Ada prosedur penanganan keluhan (complaint)
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.
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Quality Control
Departemen QC
Harus ada
Tidak dipengaruhi bidang produksi maupun bidang QA
Dipegang oleh orang yang berpengalaman dan kompeten
The following QC slides illustrate that quality control is part of good manufacturing practice.
There is a handout to accompany these slides on quality control.
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This means:
Adequate laboratory facilities or access to them e.g. government or contract laboratories
Appropriately qualified, trained and experienced personnel
Approved written procedures.
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Sampling
Inspecting
Monitoring of all materials and environmental conditions in the factory
Releasing or rejecting materials for production use and finished products
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Starting materials
Packaging materials
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Quality Control
Ketentuan Dasar
2. Metode uji divalidasi
5. Mengevaluasi penyimpangan & kegagalan
6. Bahan yang digunakan memenuhi ketentuan registrasi
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.
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Quality Control
Ketentuan Dasar
8. Wadah sesuai
9. Pelabelan benar
10. Bets produk dilepas ke pasaran oleh SDM yang tepat
11. Ada sampel pertinggal (retained samples) untuk bahan baku dan produk
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.
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2. Mengevaluasi, menjaga & menyimpan baku pembanding (reference standards)
3. Pelabelan yang benar
5. Menginvestigasi keluhan
6. Memantau lingkungan
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.
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Kondisi produksi
Catatan pembuatan
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.
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Akses SDM QC
SDM QC harus mempunyai akses ke daerah produksi untuk sampling dan investigasi
Kecuali ruang pengisian aseptis dan area dgn toksisitas tinggi
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.
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Human resources terbatas
Proses tidak divalidasi dengan benar
Dokumentasi batch standar atau SOP jelek
Lebih mempertimbangkan cost daripada quality
Family members tidak kompeten dan pada posisi penting pemegang otoritas
Problem yang sering ditemui
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 :
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Ketidakmampuan re-export bahan substandar
Korupsi
Problem yang sering ditemui
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?

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1. MANAJEMEN MUTU