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Rancangan dan PengembanganRancangan dan PengembanganFormula
Teuku Nanda Saifullah Sulaiman
Laboratorium Teknologi FormulasiLaboratorium Teknologi Formulasi
Fakultas Farmasi UGM
Daftar PustakaDaftar Pustaka
Pharmaceutical Preformulation and FormulationPharmaceutical Preformulation and Formulation
(A Practical Guide from Candidate Drug Selection to Commercial Dosage Form)Selection to Commercial Dosage Form)
edited by Mark Gibson
Informahealthcare
Biopharmaceutical Support inFormulation DevelopmentFormulation Development
• The pharmaceutical formulation plays an important role in the delivery of a drug to the body.
• The clinical benefit of a drug molecule can thereby be optimized by delivering the right amount at the right rate to the right site at the right time.
• The pharmaceutical possibilities for improving clinical utility may be extended to include site‐specific drug delivery systems that reach systemic targets, such as cancer cells and the central nervous
t (CNS) d li t ll l isystem (CNS), or gene delivery to cell nuclei.
• To achieve the potential clinical benefits that can be provided by a formulation
• Biopharmaceutical input is needed from the start of preformulation, through formulation development, to documentation for regulatory applications.
The key activities are as follows:The key activities are as follows:
Bi h ti l t t th d i• Biopharmaceutical test methods in formulation development, such as:
EtEtc.
IN VITRO DISSOLUTIONPurposes of dissolution testing in research and
d l f lldevelopment are as follows:
• Dissolution Apparatus
The choice of dissolution apparatus will be specific for h f l i d h f ll i f h ld beach formulation, and the following factors should be
considered:• Correlation to in vivo data• Correlation to in vivo data• Risk for hydrodynamic artifacts• Regulatory guidelinesg y g• Drug solubility
Choice of Agitation Intensity
Choice of Dissolution Test MediaChoice of Dissolution Test Media
The choice of dissolution medium is highly dependent on the purpose of the dissolution study, but the following aspects should always be considered:
1. Correlation to in vivo data
2 Resemblance of physiological conditions in the GI tract2. Resemblance of physiological conditions in the GI tract
3. Regulatory and pharmacopoeial recommendations
4. Drug solubility and stability properties at different pH values
5. Known sensitivity of the formulation function for different medium factors
Data Analysis ?Data Analysis ?
Th t i h th t t d f filThe percent error is zero when the test and reference profiles are identical and increases proportionally with the dissimilarity between the two profiles”.
The f2 value between 50 and 100 suggests that the dissolution profiles are similar.
Dissolution efficiency (DE)
mean dissolution time (MDT)mean dissolution time (MDT)
BIOAVAILABILITY STUDIESBIOAVAILABILITY STUDIES
Bioavailability studies are performed during formulation development at different stagesand for several reasons to :
• obtain and verify the desirable dissolution and releaseobtain and verify the desirable dissolution and release properties,
• study the influence of physiological factors such as foodfood,
• establish bioquivalence between clinical trial and commercial formulations after changes of a f l iformulation,
• develop and validate IVIVCs for in vitro dissolution test methods.
Product OptimizationThe traditional approach to product development, that the following keyoutputs should be obtained from this stage of development:
EXCIPIENT AND PACK OPTIMIZATION CONSIDERATIONS
• The International Pharmaceutical Excipients Council (IPEC) has defined a pharmaceutical excipient as any substance other than the active drug or prodrug thatsubstance other than the active drug or prodrug that has been appropriately evaluated for safety and is included in a drug delivery system to:
1. aid processing of the system during manufacture or2 prote t s pport or enhan e stabilit bioa ailabilit or2. protect, support, or enhance stability, bioavailability, or patient acceptability or
3. assist in product identification or3. assist in product identification or4. enhance any other attribute of the overall safety and effectiveness of the drug product during storage or use.
Raw Material Specifications
Pack SelectionPack Selection
1 Product compatibility1. Product compatibility
2. Protection from environmental condition to achieve the desired shelf lifeachieve the desired shelf life
3. Package and product integrity through the di ib i h ldistribution channel
4. Resistence to children and tamperers
5. Government Role ?
SOURCES OF INFORMATION ?SOURCES OF INFORMATION ?
Stability to Support Product License lApplications
PROCESS DESIGN, PROCESS OPTIMIZATION, AND SCALE‐UP
PENELITIAN DAN PENGEMBANGAN
1 REGISTRASI PENELITIAN1. REGISTRASI‐PENELITIAN
‐ Penyusunan berkas regristrasi produk baru
‐ Penyusunan desain kemasan
‐Monitoring registrasi produk
‐ Studi pustaka/info ilmiah untuk penyusunan master formula
2. PENELITIAN & PENGEMBANGAN PRODUK BARU
‐ Formulasi produk baru
‐ Reformulasi‐ Reformulasi
‐ Analisa produk baru
‐ pengembangan analisa yang telah ada
‐ kerjasama penelitian dg pihak luar
‐ pengujian stabilitas produk
PENELITIAN DAN PENGEMBANGAN
3 PENELITIAN & PENGEMBANGAN OBAT BAHAN ALAM3. PENELITIAN & PENGEMBANGAN OBAT BAHAN ALAM
‐ Optimasi proses ekstraksi
‐ Penyusunan formula obat bahan alam
‐ Pengembangan metode analisa produk barubahan alam
‐ Kerjasama penelitian dengan pihak luar
‐ pengujian stabilitas produk obat bahan alam
FORMULASI
• TAHAP PRE FORMULASI
• TAHAP FORMULASI SKALA LAB.
• TAHAP PENGUJIAN STABILITAS
• TAHAP FORMULASI SKALA TRIAL PRODUCT
• TAHAP SKALA PRODUKSI (TRIAL SKALA PRODUKSI/TRIAL UP)PRODUKSI/TRIAL UP)
• MASTER FORMULA
Ide FRPB
FIP Studi Lit. Ketersed. bhn
Perc.skala lab.(tahap A)( p )Formula terpilih
Perc.stab.fisik (tahap B)f pFormula terpilih
Jml.diperbanyak (tahap C)Stab.kimia & fisika
Formula terpilih
Formula terpilih
P t j k Sk l P d k iPetunjuk Skala Produksi
Skal prod /Sc up (tahap D) Min 3 batchSkal prod./Sc.up (tahap D) Min. 3 batch
Hasil Skala ProduksiHasil Skala Produksi
Petunjuk Produksi Rutin(standard Operasional produksi)
FRPB f li d k bFRPB= formulir rancangan produk baruFIP= formulir informasi produk
TAHAP PREFORMULASI
• SURVEY TERHADAP PRODUK SEJENIS
• STUDY PUSTAKA TENTANG SIFAT FIS‐KIM Z A, SEDIAAN,
FORMULA SERTA METODE PRODUKSIFORMULA, SERTA METODE PRODUKSI
• INFORMASI SUPPLIER BAHAN BAKU
• INFO SIFAT FISIKA‐KIMIA BAHAN BAKU DARI SUPPLIER
(BANDINGKAN)( )
TAHAP FORMULASI SKALA LABORATORIUM
Dibuat beberapa formula dari hasil rancangan penelitian/study pustaka
Formula dibuat skala lab. Kira‐kira 5‐10 kg bahan tiap batch sebanyak 3 batchbatch, sebanyak 3 batch.
Untuk sediaan cair kira‐kira 500 ml
Analisa hasil apakah memenuhi parameter yang p p y gditetapkan
Hasil baik jika tiap batch yang dibuat memenuhi t dit t kparameter yang ditetapkan
Dipilih formula yang terbaik
TAHAP PENGUJIAN STABILITASTAHAP PENGUJIAN STABILITAS
Formula terpilih (beberapa formula) akan dilakukan ujiFormula terpilih (beberapa formula) akan dilakukan uji
stabilitas fisik‐kimia, apabila hasil baik (tidak terjadi
ketidakstabilan secara fisika dan kimia, maka akan dilanjutkan
trial produksi
Tahap Formulasi Skala Trial Product
Formula yang terbaik skala laboratorium, dilakukan trialFormula yang terbaik skala laboratorium, dilakukan trial
dalam skala yang lebih besar dg ukuran batchmasing‐
masing minimal sepersepuluh batch skala produksimasing minimal sepersepuluh batch skala produksi
Hasil dikatakan baik jika batch yang dibuat memenuhi
parameter yang ditetapkan
Tahap Skala ProduksiTahap Skala Produksi(trial skala produksi/trial up)
Bila hasil trial product baik, maka dilakukan peningkatan kapasitas menjadi 3 batch
Hasil dikatakan baik jika ke 3 batchmemenuhi parameter yang ditetapkanparameter yang ditetapkan
Pada tahap ini dilakukan validasi proses dan uji stabilitas produk yang dihasilkan
Butuh waktu lama
MASTER FORMULA
Setelah trial sukses, bag. R&D dan QC memuat Master Formula berisi :Master Formula, berisi :
Nama produk
K i i f l k i b hKomposisi atau formula untuk tiap batch
Daftar spesifikasi bahan baku yang digunakan
Daftar spesifikasi bahan pengemas yang digunakanDaftar spesifikasi bahan pengemas yang digunakan
Prosedur pengolahan dan pengemasan
Daftar peralatan yang digunakanp y g g
IPC yang harus dilakukan selama pengolahan dan pengemasan
Tindakan yang harus dilakukan bila timbul masalah
Semisolid FormulationlDevelopment
How to Select the Topical Dosage Form ?
• Disease (dosage form may be selected basedDisease (dosage form may be selected based on compatibility with the disease state)
• Target product profle• Target product profle
• Skin penetration characteristics,
• Stability and/or compatibility data
• Cosmetic properties, consumer testing and p p , gmarketing considerations.
Physicochemical criteria for dermatological formulations
A successful topical dermatological formulation can be considered
1) Physically and chemically stable (adequate shelf life))
2) releases API from the formulation and delivers it into the skin as required for the targetindication
) ll l d bl3) cosmetically elegant and acceptable to patients4) contains only excipients that are necessary, FDA‐
approved oracceptable from a regulatoryapproved oracceptable from a regulatory perspective, and acceptable fo the disease state
5) is easy to apply and compatible with the desired y pp y ppackaging
6) can be manufactured with a process that is scalable to commercial levelsscalable to commercial levels.
The Need for Multiple Excipients