Quality by Test (QbT) was the only way to guarantee quality of drug products before FDA

launching current Good Manufacturing Practice (cGMP), which is an approach without clear
understanding of the processes. In order to solve this problem, FDA generalized Quality by Design
(QbD) in the field of pharmacy. Inpharmaceutical industry, QbD brings cost-efficiency and simplicity
of manufacturing process into reality. Several tools are utilized to make QbD system easily applied to
pharmaceutical field, namely design of experiment (DoE), risk assessment and process analytical
technology (PAT). QbD is based on the thorough understanding of how materials and process
parameters affecting the profile of final products. The following parameters are defined to describe
those characteristics: Quality target product profile (QTPP); critical quality attributes (CQAs); critical
material attributes (CMAs) and critical process parameters (CPPs).
Quality by design (QbD) encompasses designing and developing formulations and
manufacturing processes which ensures predefined product specifications. The concept of quality
by design (QbD) has been recently adopted in the pharmaceutical industry through several
initiatives {e.g., ICH Q81, Q92 and Q103, and the new regulatory documents, Process Analytical
Technology (PAT)5, FDAs cGMP for the 21st Century}. The general aim is to switch from the
quality by testing (QbT) paradigm previously implemented in the pharmaceutical industry to a
development aimed at improving the understanding of the processes and the products and
hence improving product quality, process efficiency and regulatory flexibility.
While medicine is well known as special goods, the development of pharmaceutical industry is
based on innovation and manufacturing. However, there are lots of complaints from pharmaceutical
industry about the strict rules. In current quality by test (QbT) system (Fig. 1a), product quality is
ensured by following a sequence of steps, including rawmaterial testing, fixed drug product
manufacturing process, and end product testing. It is only when all the specifications of the FDA or
other standards are complied with that the materials can be used for manufacturing or come into
market. If not, they need to be reprocessed. Root causes for failure are usually not well understood
due to the poor process understanding and uncertainty about how characteristics of substances
impacts target product profile. As a result, the manufacturers have to restart the procedure until the
root causes of failure are understood and addressed or FDA approves supplements to revise (e.g.,
widen) the acceptance criteria to pass the previously failed batches. This causes poor cost-efficiency
and product variation, which may lead to poor drug safety.
The applications of DoE and PAT in pharmaceutical field are discussed in details. DoE
combines parameters such as CPPs, CMAs and CQAs into QbD system, which is a reasonable method
to determine the relationship between the input and output of a process. In addition, full factorial
design, Plackett-Burman (PB) screening design, fractional factorial statistical design, central
composite–face centered–response surface design and Box–Behnken design can be used to establish
a design space (DS) for given a process to guarantee the quality of final products. In addition to DoE,
PAT is also an important tool of QbD, by obtaining technological and material parameters on-line,it
plays a role in real-time monitoring of pharmaceutical process without interruption.In order to
achieve successful PAT implementation, there are three-step-process (namely design, analyze and
control) and four PAT toolsin the design and optimization of drug formulations and manufacturing
process, the four PAT tools are as follows: (1) multivariate tools for design, data acquisition and
analysis; (2) process analyzers; (3) process control tools; (4) continuous improvement and knowledge
management tools. In conclusion, with the assistance of DoE and PAT together with other QbD tools,
thorough understanding of pharmaceutical process can be achieved and stable quality of products
can be assured.
 Over the last two decades, there have been an increased number of pharmaceutical products,
and a greater role of medicines in healthcare. The number of foreign applications has increased,
along wtih the globalization of the pharmaceutical industry. The rate of increase in regulatory
submissions has outpaced the rate of growth of the review resources. These pharmaceutical and
regulatory environmentchanges, a priori mentioned technical and regulatory issues with QbT and
the old pharmaceutical assessment system, along with advancements in manufacturing sciences,
have accelerated the need for a modern regulatory framework that encourages risk and science-
based, cost-efficient, continously improved pharmaceutical development and regulatory quality
assessment.
In 2002, the FDA announced a new initiative (cGMPs for the 21th Century: A Risk-Based
Approach). This initiative intended to modernize the FDAs regulation of pharmaceutical quality, and
establish a new regulatory framework focused on quality by design (QbD), risk management, and
quality systems. The initiative challenged the industry to look beyond QbT for ensuring product
quality and performance.
The aim of pharmaceutical development is to design a quality product and its manufacturing
process to consistently deliver the intended performance of theproduct. The information and
knowledge gained from pharmaceutical developmentstudies and manufacturing experience provide
scientific understanding to support theestablishment of the design space, specifications, and
manufacturing controls. Information from pharmaceutical development studies can be a basis for
quality risk management. It is important to recognize that qualitycannot be tested into products; i.e.,
quality should be built in by design. Changes in formulation and manufacturing processes during
development and lifecycle management should be looked upon as opportunities to gain additional
knowledge and further support establishment of the design space. Similarly, inclusion of relevant
knowledge gained from experiments giving unexpected results can also be useful.

Quality by design is an essential part of the modern approach to pharmaceutical quality.

This is a concept that can and is replacing the traditional approach, and is firmly taking roots
in the industry. QbD, if properly implemented and taken together with the current world
wide harmonization of regulations and risk should be taken for what it has to offer, rather
than what its concerns. It’s important to know the emphasis on the importance of the
Quality Target Product Profile (QTPP) in articulating quantitative performance targets for
QbD , identification of critical material attributes (CMAs) that provide a mechanistic link of
the product quality to the manufacturing process, clarification that critical process
parameters (CPPs) are operating parameters and should be combined with critical material
attributes (CMAs) to describe the relation between unit operation inputs and outputs, the
role of the control strategy as the mechanism for incremental implementation of QbD
elements into practice. QbD is the future of product and process improvement, and as such
leads to continuous improvement and innovation in products and processes.
The fast growth of interest in QbD and its tools indicates that the approaches are not
fashionable phenomena but responses to the demands of modern manufacturing process. QbD is a
cost and time efficient approach in design and manufacturing, with DoE, risk assessment, and PAT as
its tools to achieve a better understanding on the materials and processes, which make the QbD
available and feasible to the pharmaceutical field.With its broad implementation in the
pharmaceutical manufacture, drug products with high and reproducible quality can be anticipated.
Moreover, QbD has become a broadly applicable manufacturing model and is going far beyond
pharmaceutical (or related) areas.
ICH Q8 defines quality as “The suitability of either a drug substance or drug product for its intended
use. This term includes such attributes as the identity, strength, and purity”. ICH Q8 guideline states
that Quality by Design (QbD) is a systematic approach to development that begins with predefined
objectives and emphasizes product and process understanding and process control, based on sound
science and quality risk management. which is in accordance with FDA’s current drug quality system
ideology of ‘quality cannot be tested into products; it should be built-in or should be by design’.
Product testing alone is not sufficient to assure that a process consistently produces a product with
predetermined specifications. Adequate process design; knowledge and control of factors that
produce process variability and successful validation studies, in conjunction with product testing,
provide assurance that the process will produce a product with the required quality characteristics.

Fortunately, with the development of the concept “Quality by Design (QbD)”, there will be a
significant transformation in pharmaceutical quality regulation, from an empirical process to a more
scientific and risk-based approach. QbD (Fig. 1b) is a systematic risk-based, proactive approach to
pharmaceutical development that begins with predefined objectives and emphasizes product and
process understanding and process control based on sound science and quality risk management.
Comparison between QbT and QbD procedures is shown in Fig. 1.

There are several statements about the elements of QbD, the most widely accepted is that,
QbD consists of the following parameters:
1. Quality Target Product Profile (QTPP): including dosage form, delivery systems,
dosage strength(s), etc. It is a prospective summary of quality characteristics of a
drug product to be achieved, taking into account dosage strength(s) and container
closure system of the drug product, together with the attributes affecting
pharmacokinetic characteristics (e.g., dissolution, aerodynamic performance) and
drug product quality criteria (e.g., sterility, purity, stability and drug release)
appropriate for the intended marketed product.
2. Critical Quality Attributes (CQAs): including physical, chemical, biological, or
microbiological properties or characteristics of an output material including finished
drug product. Potential drug product CQAs derived from the QTPP and/or prior
knowledge are used to guide the product and process development and they should
be within an appropriate limit, range, or distribution to ensure the desired product
quality.
3. Critical Material Attributes (CMAs): including physical, chemical, biological, or
microbiological properties or characteristics of an input material. CMAs should be
within an appropriate limit, range, or distribution to ensure the desired quality of
that drug substance, excipient, or in-process material.
4. Critical Process Parameters (CPPs): parameters monitored before or in process that
influence the appearance, impurity, and yield of final product significantly.

During the QbD process, product design and understanding include the identification of
CMAs, which are different from CQAs. CQAs are for output materials while CMAs are for
input materials including drug substance, excipients, in-process materials. The CQA of an
intermediate may become a CMA of the same intermediate for a downstream
manufacturing step. While process design and understanding include the identification of
CPPs and a thorough understanding of scale-up principles, linking CMAs and CPPs to CQAs is
of special importance. From the viewpoint of QbD, CMAs and CPPs can vary within the
established Design Space without significant influence on CQAs, and as a result, the quality
of the final product will meet the QTPP.
The concept of QbD has two components – the science underlying the design and the
science of manufacturing. Upon understanding the elements of QbD and the steps for QbD
implementation, it is important to be familiar with the commonly used tools in QbD,
including Risk Assessment, Design of Experiment (DoE), and Process Analytical Technology
(PAT).
1. Risk Assessment
There are three components of Risk Assessment, that is:
1. Risk Identification: The systematic use of information to identify potential sources of
harm (hazards) that are referring to the risk question or problem description, which
can include historical data, theoretical analysis, informed opinions, and the concerns
of stakeholders;
2. Risk Analysis: The estimation of the risk associated with the identified hazards;
3. Risk Evaluation: The comparison of the estimated risk to given risk criteria using a
quantitative or qualitative scale to determine the significance of the risk. The above
components
ICH Q9 provides a non-exhaustive list of 9 common risk management tools as follows: (1)
Basic risk management facilitation methods (Ishikawa fishbone diagram, flowcharts, check
sheets, etc.); (2) Fault tree analysis; (3) Risk ranking andfiltering; (4) Preliminary hazard
analysis; (5) Hazard analysis and critical control points; (6) Failure mode and effects analysis
(FMEA); (7) Failure mode, effects, and criticality analysis (FMECA); (8) Hazard operability
analysis; (9) Supporting statistical tools.
2. Design of Experiment (DoE)
To carry out the design of experiment, the risk assessment should be taken into function
first. A structured, organized method for determining the relationship between factors
affecting a process and the output of that process is known as “Design of Experiments”
(DoE). DoE is an excellent tool that allows pharmaceutical scientists to systematically
manipulate factors according to a pre-specified design. A good design is based on sound
cognition of product and effective management of whole process during manufacturing. DoE
studies work together with mechanism-based studies to achieve better product and process
understanding.
3. Process Analytical Technology (PAT)

PAT is defined as “Tools and systems that utilize real-time measurements, or rapid
measurements during processing, of evolving quality and performance attributes of in-
process materials to provide information to ensure optimal processing to produce final
product that consistently conforms to established quality and performance standards”. ICH
Q8 [9]identifies the use of PAT to ensure that the process remains
within an established Design Space.

Quality by Test (QbT) adalah satu-satunya cara untuk menjamin kualitas produk obat
sebelum FDA meluncurkan Good Manufacturing Practice (cGMP) saat ini, yang merupakan
pendekatan tanpa pemahaman yang jelas tentang proses. Untuk mengatasi masalah ini, FDA
menggeneralisasi Kualitas dengan Desain (QbD) di bidang farmasi. Industri farmasi, QbD
menghadirkan efisiensi biaya dan kesederhanaan proses pembuatan menjadi kenyataan.
Beberapa alat digunakan untuk membuat sistem QbD mudah diterapkan pada bidang
farmasi, yaitu desain eksperimen (DoE), penilaian risiko dan proses teknologi analitis (PAT).
QbD didasarkan pada pemahaman menyeluruh tentang bagaimana bahan dan parameter
proses mempengaruhi profil produk akhir. Parameter berikut didefinisikan untuk
menggambarkan karakteristik tersebut: Profil produk target kualitas (QTPP); atribut kualitas
kritis (CQA); atribut material kritis (CMA) dan parameter proses kritis (CPP).
(Lan Zhang, Shirui Mao, Applications of quality by design (QbD) and its tools in drug delivery,
Asian Journal of Pharmaceutical Sciences (2015). Shenyang Pharmaceutical University,
Shenyang 110016, China. )
Kualitas dengan desain (QbD) mencakup perancangan dan pengembangan formulasi
dan proses pembuatan yang memastikan spesifikasi produk yang telah ditentukan. Konsep
kualitas dengan desain (QbD) baru-baru ini diadopsi di industri farmasi melalui beberapa
inisiatif {misalnya, ICH Q81, Q92 dan Q103, dan dokumen peraturan baru, Process Analytical
Technology (PAT) 5, FDA cGMP untuk Abad ke-21} . Tujuan umum adalah untuk beralih dari
paradigma kualitas dengan pengujian (QbT) yang sebelumnya diterapkan di industri farmasi
ke pengembangan yang bertujuan untuk meningkatkan pemahaman tentang proses dan
produk dan karenanya meningkatkan kualitas produk, efisiensi proses dan pengTURn
fleksibilitas.
(Jadhav, J.B., Girawale, N.N., and Chaudhari, R.K., 2014. Quality by Design (QBD) Approach
used in Development of Pharmaceuticals. International Journal of Pure & Applied
Bioscience. ISSN: 2320 – 7051 Int. J. Pure App. Biosci.2 (5): 214-223.)
Ketika obat-obatan dikenal sebagai barang khusus, perkembangannya industri farmasi
didasarkan pada inovasi dan manufaktur. Namun, ada banyak keluhan dari farmasi industri
tentang aturan ketat. Dalam kualitas saat ini sistem uji (QbT) (Gbr. 1a), kualitas produk
dipastikan dengan mengikuti urutan langkah-langkah, termasuk pengujian bahan baku,
diperbaiki proses pembuatan produk obat, dan pengujian produk akhir. Hanya ketika semua
spesifikasi FDA atau standar lainnya dipatuhi bahwa bahan dapat digunakan untuk
manufaktur atau masuk pasar. Jika tidak, mereka perlu diproses ulang. Penyebab root untuk
kegagalan biasanya tidak baik dipahami karena proses yang buruk, pemahaman dan
ketidakpastian tentang bagaimana karakteristik zat mempengaruhi profil produk target.
Akibatnya, pabrikan harus memulai kembali prosedur sampai akar penyebab kegagalan
dipahami dan yang dialamatkan atau FDA menyetujui suplemen untuk direvisi (mis.,
memperlebar) kriteria penerimaan untuk lulus yang sebelumnya gagal kumpulan. Ini
menyebabkan buruknya efisiensi biaya dan variasi produk, yang dapat menyebabkan
keamanan obat yang buruk.
(Lan Zhang, Shirui Mao Application of quality by design in the current drug development.
asian journal of pharmaceutical s c i e n c e s . Shenyang Pharmaceutical University,
No.103,Wenhua Road, Shenyang 110016, China)
Aplikasi DoE dan PAT dalam bidang farmasi dibahas secara terperinci. DoE
menggabungkan parameter seperti CPP, CMAs dan CQAs ke dalam sistem QBD, yang masuk
akal metode untuk menentukan hubungan antara input dan output dari suatu proses. Selain
itu, faktorial penuh desain, desain penyaringan Plackett-Burman (PB), desain statistik
faktorial pecahan, wajah komposit pusat desain permukaan tengah-respons dan desain
Kotak-Behnken dapat digunakan untuk membangun ruang desain (DS) untuk diberikan
proses untuk menjamin kualitas produk akhir. Selain DoE, PAT juga merupakan alat penting
QbD, dengan memperoleh parameter teknologi dan material secara on-line, ia berperan
dalam pemantauan waktu nyata proses farmasi tanpa gangguan. Untuk mencapai
keberhasilan implementasi PAT, ada proses tiga langkah (yaitu desain, analisis dan kontrol)
dan empat alat PAT dalam desain dan optimalisasi formulasi obat dan proses pembuatan,
empat alat PAT adalah sebagai berikut: (1) alat multivariat untuk desain, akuisisi dan analisis
data; (2) analisis proses; (3) alat kontrol proses; (4) terus menerus perbaikan dan alat
manajemen pengetahuan. Sebagai kesimpulan, dengan bantuan DoE dan PAT bersama
sama dengan alat QbD lainnya, pemahaman menyeluruh tentang proses farmasi dapat
dicapai dan kualitas stabil produk bisa terjamin.
(Lan Zhang, Shirui Mao, Applications of quality by design (QbD) and its tools in drug delivery,
Asian Journal of Pharmaceutical Sciences (2015). Shenyang Pharmaceutical University,
Shenyang 110016, China.)
Selama dua dekade terakhir, ada peningkatan jumlah produk farmasi, dan peran obat-
obatan yang lebih besar dalam perawatan kesehatan. Jumlah aplikasi asing telah meningkat,
seiring dengan globalisasi industri farmasi. Tingkat peningkatan pengajuan peraturan telah
melampaui tingkat pertumbuhan sumber daya tinjauan. Perubahan lingkungan farmasi dan
peraturan ini, yang disebutkan sebelumnya sebagai masalah teknis dan peraturan dengan
QbT dan sistem penilaian farmasi lama, bersama dengan kemajuan dalam ilmu manufaktur,
telah mempercepat kebutuhan akan kerangka kerja peraturan modern yang mendorong
risiko dan berbasis ilmu pengetahuan, hemat biaya, terus meningkatkan pengembangan
farmasi dan penilaian kualitas peraturan.
Pada tahun 2002, FDA mengumumkan inisiatif baru (cGMP untuk Abad ke-21:
Pendekatan Berbasis Risiko). Inisiatif ini dimaksudkan untuk memodernisasi regulasi FDA
tentang kualitas farmasi, dan membangun kerangka kerja regulasi baru yang berfokus pada
kualitas berdasarkan desain (QbD), manajemen risiko, dan sistem kualitas. Inisiatif ini
menantang industri untuk melihat melampaui QbT untuk memastikan kualitas dan kinerja
produk.
Tujuan pengembangan farmasi adalah merancang produk yang berkualitas dan proses
pembuatannya secara konsisten memberikan kinerja produk yang diinginkan. Informasi dan
pengetahuan didapat dari studi pengembangan farmasi dan pengalaman manufaktur
memberikan pemahaman ilmiah untuk mendukung pembangunan ruang desain, spesifikasi,
dan kontrol manufaktur. Informasi dari studi pengembangan farmasi dapat menjadi dasar
untuk manajemen risiko kualitas. Ini penting untuk menyadari bahwa kualitas tidak dapat
diuji ke dalam produk; Yaitu, kualitas harus dibangun dengan desain. Perubahan dalam
formulasi dan proses manufaktur selama pengembangan dan manajemen siklus hidup harus
dipandang sebagai peluang untuk mendapatkan pengetahuan tambahan dan selanjutnya
mendukung pembentukan ruang desain. Demikian pula, dimasukkannya pengetahuan yang
relevan yang diperoleh dari eksperimen yang memberi tak terduga hasilnya juga bisa
bermanfaat.

Kualitas dengan desain adalah bagian penting dari pendekatan modern terhadap kualitas
farmasi. Ini sebuah konsep yang dapat dan sedang menggantikan pendekatan tradisional, dan
dengan kuat berakar di industri. QbD, jika diimplementasikan dengan baik dan diambil bersama
dengan harmonisasi peraturan di seluruh dunia saat ini dan risiko harus diambil untuk apa yang
ditawarkan, bukan apa yang menjadi perhatiannya. penting untuk mengetahui tentang penekanan
pada pentingnya Profil Produk Target Kualitas dalam mengartikulasikan kuantitatif target kinerja
untuk QbD, identifikasi atribut material kritis yang menyediakan tautan mekanistik kualitas produk
untuk proses pembuatan, klarifikasi parameter proses kritis parameter operasi dan harus
dikombinasikan dengan atribut material kritis untuk menggambarkan hubungan antara input dan
output operasi unit, peran strategi kontrol sebagai mekanisme untuk implementasi tambahan
elemen QbD ke dalam praktik. QbD adalah masa depan produk dan proses peningkatan, dan dengan
demikian mengarah pada peningkatan dan inovasi yang berkelanjutan dalam produk dan proses.

Pesatnya pertumbuhan QbD dan alat-alatnya menunjukkan hal itu pendekatannya bukan
fenomena yang modis, melainkan respons untuk tuntutan proses manufaktur modern. QbD adalah
biaya dan pendekatan waktu yang efisien dalam desain dan manufaktur, dengan DoE, penilaian
risiko, dan PAT sebagai alat untuk mencapai yang lebih baik pemahaman tentang bahan dan proses,
yang membuat QbD tersedia dan layak untuk bidang farmasi implementasi luas dalam pembuatan
farmasi, obat-obatan produk dengan kualitas tinggi dan dapat diproduksi ulang dapat diantisipasi.
Apalagi QbD sudah menjadi yang berlaku luas model manufaktur dan jauh melampaui
farmasi (atau terkait) area.
ICH Q8 mendefinisikan kualitas sebagai “Kesesuaian suatu zat obat atau produk obat
untuk tujuan penggunaannya. Istilah ini mencakup atribut seperti identitas, kekuatan, dan
kemurnian”. Pedoman ICH Q8 menyatakan itu Kualitas oleh Desain adalah pendekatan
sistematis untuk pengembangan yang dimulai dengan tujuan dan menekankan pemahaman
produk dan proses dan kontrol proses, berdasarkan pada ilmu pengetahuan dan kualitas
suara manajemen risiko. Pengujian produk saja tidak cukup untuk memastikan bahwa suatu
proses secara konsisten menghasilkan suatu produk dengan spesifikasi yang ditentukan
sebelumnya. Desain proses yang memadai; pengetahuan dan kontrol faktor-faktor yang
menghasilkan variabilitas proses dan studi validasi yang berhasil, dalam hubungannya
dengan pengujian produk, menyediakan jaminan bahwa proses akan menghasilkan produk
dengan karakteristik kualitas yang diperlukan .

Untungnya, dengan pengembangan konsep "Kualitas oleh Desain (QbD) ”, akan ada transformasi yang
signifikan di regulasi kualitas farmasi, dari proses empiris untuk pendekatan yang lebih ilmiah dan berbasis
risiko. QbD (Gbr. 1b) adalah pendekatan sistematis proaktif berbasis risiko untuk farmasi pengembangan yang
dimulai dengan tujuan yang telah ditentukan dan menekankan pemahaman dan proses produk dan proses
kontrol berdasarkan ilmu pengetahuan dan manajemen risiko kualitas. Perbandingan antara prosedur QbT dan
QbD ditunjukkan pada Gambar. 1.