temp.pptWHO - EDM
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.
Module 2 Slide * of 26
WHO - EDM
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.
Module 2 Slide * of 26
WHO - EDM
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!
Module 2 Slide * of 26
WHO - EDM
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.
Module 2 Slide * of 26
WHO - EDM
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.
Module 2 Slide * of 26
WHO - EDM
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.
Module 2 Slide * of 26
WHO - EDM
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.
Module 2 Slide * of 26
WHO - EDM
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.
Module 2 Slide * of 26
WHO - EDM
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.
Module 2 Slide * of 26
WHO - EDM
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.
Module 2 Slide * of 26
WHO - EDM
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.
Module 2 Slide * of 26
WHO - EDM
This means:
Adequate laboratory facilities or access to them e.g. government or
contract laboratories
Appropriately qualified, trained and experienced personnel
Approved written procedures.
WHO - EDM
Sampling
Inspecting
Monitoring of all materials and environmental conditions in the
factory
Releasing or rejecting materials for production use and finished
products
Module 2 Slide * of 26
WHO - EDM
Starting materials
Packaging materials
WHO - EDM
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.
Module 2 Slide * of 26
WHO - EDM
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.
Module 2 Slide * of 26
WHO - EDM
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.
Module 2 Slide * of 26
WHO - EDM
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.
Module 2 Slide * of 26
WHO - EDM
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.
Module 2 Slide * of 26
WHO - EDM
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 :
Module 2 Slide * of 26
WHO - EDM
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?