pengprod - pertemuan 1
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Pengembangan Produk (ProductDevelopment)Najma Annuria Fithri, S.Farm.,M..Sc., Apt.
Universitas SriwijayaGemap 2013/2014
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What is it?The creation of products with new ordifferent characteristics that offer new oradditional benefits to the customer.
Product development may involvemodification of an existing product or its
presentation, or formulation of an entirelynew product that satisfies a newly definedcustomer want or market niche.
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Introduction What are we gonna learn in the next 8 weeks ahead?
1. Novel drug delivery system (DDS) and itsimplementation
Iontophoresis/Transdermal pH sensitive DDS Liposome/dendrimer/micelles Nanotechnology Mucoadhesive hydrogels Floating systems
2. Design of experiment how to startexperimenting your formula. How to create a designfor the experiment
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Drug Discovery and Development
How are drugs discovered and developed?
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Why are new drugs needed? unmet medical need ; new diseases (BSE; AIDS,
Alzheimers; obesity); low efficacy (dementia, cancer);side effects (antidepressants, antipsychotics)
downstream health costs ; (Alzheimers; spinal injury )
cost of therapy ; (Viagra, Interleukins)
costs to individual/country ; (depression)
sustain industrial activity ; pharmaceutical industryemploys thousands and makes a massive contribution tooverseas earnings); patent expiry
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Choose a disease Choose a drug target Identify a bioassay
bioassay = A test used to determine biologicalactivity.
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Find a lead compound
lead compound = structure that has some activityagainst the chosen target, but not yet good enoughto be the drug itself.
If not known, determine the structure of the lead
compound
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Synthesize analogs of the lead Identify Structure-Activity- Relationships (SARs)
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Does it all work? Of course not. Trial and error is commonin drug and product developmentEx: Roche development of GABA agonist
Benzodiazepine
RO 48-8684
RO 48-6791
Flumazenil (RO 15-1788)
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Identify the pharmacophore
pharmacophore = the structural features directlyresponsible for activity Optimize structure to improve interactions with
target
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Determine pharmacodynamics and pharmacokinetics
of the drug. Pharmacodynamics explores what a drug does to the body, whereas pharmacokinetics explores what the body does to the drug.
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In vivo testing: important to find out onset,duration, efficacy, potency and toxicity of activecompound in living organism (preferablymammal)
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Patent the drug Continue to study drug metabolism Continue to test for toxicity
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Designing a dosage form usage of design
experiment (mixture design, factorial design,etc) Creating formula and analysis of dosage form Builds a knowledge on in vivo in vitro
correlation
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Design a manufacturing process Carry out clinical trials Market the drug
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Choosing a Disease
Pharmaceutical companies
will also (most of the time)avoid products that would beconsumed by individuals oflower economic status (i.e. a
disease which only affectsthird world countries)
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Choosing a Disease (cont.) Most research is
carried out on diseases which afflict first world countries: (e.g.cancer, cardiovasculardiseases, depression,
diabetes, flu, migraine,obesity).
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The Orphan Drug Act
The Orphan Drug Act of 1983 was passed toencourage pharmaceutical companies to developdrugs to treat diseases which affect fewer than200,000 people in the US
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Under this law, companies who develop such adrug are entitled to market it without competition
for seven years. This is considered a significant benefit, since the
standards for patent protection are much morestringent.
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Identifying a Drug Target
Drug Target = specific macromolecule, or biological system, which the drug will interact with
Sometimes this can happen through
incidental observation
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Identifying a Drug Target (cont.)
Example: In addition to their being able to inhibit the uptakeof noradrenaline, the older tricyclic antidepressants wereobserved to incidentally inhibit serotonin uptake. Thus, it wasdecided to prepare molecules which could specifically inhibitserotonin uptake. It wasn t clear that this would work, but it
eventually resulted in the production of fluoxetine (Prozac).
NH2
NH
HO
serotonin
O
HN
prozac
N
N CH3
H3C
Imipramine(a classical tricyclic antidepressant)
F3C
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Having the genetic code for the production of anenzyme or a receptor may enable us to over-express that protein and determine its structure
and biological function. If it is deemed importantto the disease process, inhibitors (of enzymes), orantagonists or agonists of the receptors can be
prepared through a process called rational drugdesign.
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Selectivity is Important!
e.g. targeting a bacterial enzyme, which is notpresent in mammals, or which has significantstructural differences from the correspondingenzyme in mammals
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The Standards are Being Raised
More is known about the biological chemistry ofliving systems
For example: Targeting one subtype of receptormay enable the pharmaceutical chemist to avoidpotentially troublesome side effects.
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Problems can arise
Example: The chosen target, may over time, loseits sensitivity to the drug
Example: The penicillin-binding-protein (PBP)known to the the primary target of penicillin inthe bacterial species Staphylococcus aureus hasevolved a mutant form that no longer recognizespenicillin.
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Choosing the Bioassay
Definitions: In vitro : In an artificial environment, as in a test
tube or culture media In vivo : In the living body, referring to tests
conductedin living animals Ex vivo : Usually refers to doing the test on a tissue
taken from a living organism.
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Choosing the Bioassay (cont.)
In vitro testing Has advantages in terms of speed and requires
relatively small amounts of compound Speed may be increased to the point where it ispossible to analyze several hundred compounds in asingle day (high throughput screening)
Results may not translate to living animals
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Choosing the Bioassay (cont.)
In vivo tests More expensive May cause suffering to animals Results may be clouded by interference with other biological systems
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Reducing animal usage ethic About 50-100 million vertebrate animals/year used in
procedures around the globe Likely to increase; more research, more targets, genetic
capability
3Rs REPLACEMENT : use non-animal tests if possible(cheaper, less trouble, less variable but not possible foreverything at this time)
REDUCTION : get the statistics right, dont replicate work unnecessarily, dont overbreed
REFINEMENT : reduce suffering and severity ofprocedure, pay attention to housing, stress, husbandry andrich environments, proper analgesia and pre- and post-operative care
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Finding the Lead
Screening Natural Products Plants, microbes, the marine world, and
animals, all provide a rich source of
structurally complex natural products.
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It is necessary to have a quick assay for thedesired biological activity and to be able to
separate the bioactive compound from theother inactive substances Lastly, a structural determination will need to be made
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Finding the Lead (cont.)
Screening synthetic banks Pharmaceutical companies have prepared
thousands of compounds
These are stored (in the freezer!), catalogedand screened on new targets as these newtargets are identified
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Finding the Lead (cont.)
Enhance a side effect
O
NH
SO
O
NH
tolbutamide
NH2S
O
O
H2N
sulphanilamide(an antibacterial with the side effect of lowering glucose levels in the blood and alsodiuretic activity)
(a compound which has been optimized to onlylower blood glucose levels. Useful in the treatment
of Type II diabetes.)
SNH
N
O O
SO
OH2N
Cl
Chlorothiazide
(a compound which has been optimized to only display diureticactivity.)
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Use structural similarity to a natural ligand
N
NH2
HO
HN
N(CH 3)2
H
S
HN
O O
H3C
5-Hydroxytryptamine (5-HT)Serotonin (a natural neurotransmitter
synthesized in certain neurons in the CNS)
Sumatriptan (Imitrex)Used to treat migrain headaches
known to be a 5-HT 1 agonist
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Computer-Assisted Drug Design
If one knows the precise molecular structure of thetarget (enzyme or receptor), then one can use acomputer to design a perfectly-fitting ligand.
Drawbacks: Most commercially available programsdo not allow conformational movement in the target(as the ligand is being designed and/or docked intothe active site). Thus, most programs are somewhat
inaccurate representations of reality.
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Finding a Lead (cont.)
Sildenafil (compound UK-92,480) was synthesized by agroup of pharmaceutical chemists working at Pfizer'sSandwich, Kent research facility in England.
It was initially studied for use in hypertension (high bloodpressure) and angina pectoris (a form of ischaemiccardiovascular disease).Phase I clinical trials under the direction of Ian Osterloh
suggested that the drug had little effect on angina, but thatit could induce marked penile erections.
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Pfizer therefore decided to market it for erectile dysfunction,rather than for angina.
The drug was patented in 1996, approved for use in erectiledysfunction by the Food and Drug Administration on March 27,1998, becoming the first pill approved to treat erectile
dysfunction in the United States, and offered for sale in theUnited States later that year.
It soon became a great success: annual sales of Viagra in theperiod 1999 2001 exceeded $1 billion.
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Finding a Lead (cont.)
N
N
SO
O
N
N
N
NH
OO
viagra(Sildenafil)
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Structure-Activity- Relationships (SARs)
Once a lead has been discovered, it is important to
understand precisely which structural features areresponsible for its biological activity (i.e. to identifythe pharmacophore)
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The pharmacophore is the precise section of themolecule that is responsible for biological activity
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This may enable one to prepare a more activemolecule
This may allow the elimination of excessivefunctionality, thus reducing the toxicity and cost ofproduction of the active material
This can be done through synthetic modifications Example: R-OH can be converted to R-OCH3 to see
if O-H is involved in an important interaction Example: R-NH2 can be converted to R-NH- COR to
see if interaction with positive charge on protonated
amine is an important interaction
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Next step: Improve PharmacokineticProperties Improve pharmacokinetic properties.
pharmacokinetic = The study of absorption,distribution, metabolism and excretion of a drug(ADME).
Metabolism of Drugs
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Metabolism of Drugs The body regards drugs as
foreign substances, notproduced naturally.
Sometimes such substancesare referred to asxenobiotics
Body has goal of removing such xenobiotics
from system by excretion in the urineThe kidney is set up to allow polar substancesto escape in the urine, so the body tries tochemically transform the drugs into more polar
structures.
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Metabolism of Drugs (cont.)
Phase 1 Metabolism involves the conversionof nonpolar bonds (eg C-H bonds) to morepolar bonds (eg C-OH bonds).
A key enzyme is the cytochrome P450 system, which catalyzes this reaction:
RH + O 2 + 2H+ + 2e ROH + H 2 O
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Mechanism of Cytochrome P450
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Phase I metabolism may eitherdetoxify or toxify.
Phase I reactions produce a more polarmolecule that is easier to eliminate.
Phase I reactions can sometimes result in asubstance more toxic than the originallyingested substance.
An example is the Phase I metabolism ofacetonitrile
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The Liver
Oral administration frequently brings thedrugs (via the portal system) to the liver
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Metabolism of Drugs (cont.)
Phase II metabolism links the drug to still morepolar molecules to render them even more easy toexcrete
O O
OHHO
OH
HO
O PHO
O
O
P
HO O
O O
HO
OH
N
NH
O
O
R OH
O O
OHHOOH
HO
O
R
Glucuronic Acid
UDP Glucuronic Acid
More easily excreted than ROH itself
glucuronosyltransferaseenzyme
Drug
Drug
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Metabolism of Drugs (cont.)
Another Phase II reaction is sulfation (shown below)
R OHO N
N
N
N
NH2
OHO
OP
O
O -
OS
O
O
O-
PO O -
O -
3'-Phosphoadenosine-5'-phosphosulfate
DrugR O
SO 3-
Sulfated Drug(more easily excreted)
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Phase II Metabolism Phase II reactions most commonly detoxify Phase II reactions usually occur at polar sites,
like COOH, OH, etc.
Manufacture of Drugs
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Manufacture of Drugs
Pharmaceutical companies must make a profit to continue to exist Therefore, drugs must be sold at a profit One must have readily available, inexpensive starting materials
One must have an efficient synthetic route to the compound As few steps as possible Inexpensive reagents
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The route must be suitable to the
scale up needed for the production ofat least tens of kilograms of finalproduct
This may limit the structuralcomplexity and/or ultimate size (i.e.mw) of the final product
In some cases, it may be useful todesign microbial processes whichproduce highly functional, advancedintermediates. This type of processusually is more efficient than trying toprepare the same intermediate usingsynthetic methodology.
Toxicity
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Toxicity
Toxicity standards are continually becoming
tougher Must use in vivo (i.e. animal) testing to screen for
toxicity Each animal is slightly different, with different metabolic
systems, etc. Thus a drug may be toxic to one species and not to
another
E l Th lid id
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Example: ThalidomideThalidomide was developed by German pharmaceutical
company Grnenthal. It was sold from 1957 to 1961 in almost50 countries under at least 40 names. Thalidomide waschiefly sold and prescribed during the late 1950s and early1960s to pregnant women, as an antiemetic to combatmorning sickness and as an aid to help them sleep. Before itsrelease, inadequate tests were performed to assess the drug'ssafety, with catastrophic results for the children of women whohad taken thalidomide during their pregnancies.
Antiemetic = a medication that helps preventand control nausea and vomiting
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Birth defects
caused by use of thalidomide
Example: Thalidomide
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Example: ThalidomideFrom 1956 to 1962, approximately 10,000 children were born withsevere malformities, including phocomelia, because their mothers had
taken thalidomide during pregnancy. In 1962, in reaction to the tragedy,the United States Congress enacted laws requiring tests for safety duringpregnancy before a drug can receive approval for sale in the U.S.
N
O
O
NH
O
O
Thalidomide
Phocomelia presents at birth very short or absent long bonesand flipper-like appearance of hands and sometimes feet.
E l Th lid id
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Example: ThalidomideResearchers, however, continued to work with the drug. Soonafter its banishment, an Israeli doctor discovered anti-inflammatory effects of thalidomide and began to look for usesof the medication despite its teratogenic effects.
He found that patients with erythema nodosum leprosum, apainful skin condition associated with leprosy, experiencedrelief of their pain by taking thalidomide.
Teratogenic = Causing malformations in a fetus
Th lid id
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ThalidomideFurther work conducted in 1991 by Dr. Gilla Kaplan at Rockefeller
University in New York City showed that thalidomide worked inleprosy by inhibiting tumor necrosis factor alpha. Kaplanpartnered with Celgene Corporation to further develop thepotential for thalidomide.
Subsequent research has shown that it is effective in multiplemyeloma, and it is now approved by the FDA for use in thismalignancy. There are studies underway to determine the drug'seffects on arachnoiditis, Crohn's disease, and several types ofcancers.
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Literature
Haffner Marlene E; Whitley Janet; Moses Marie Two decades of orphanproduct development. Nature reviews. Drug discovery (2002), 1(10),821-5. Link
Franks Michael E; Macpherson Gordon R; Figg William D Thalidomide.Lancet (2004), 363(9423), 1802-11. Link
Abou-Gharbia, Magid. Discovery of innovative small moleculetherapeutics. Journal of Medicinal Chemistry (2009), 52(1), 2-9. Link Paul, S. M. et al. How to improve R&D productivity: the pharmaceutical
industrys grand challenge. Nature Reviews Drug Discovery (2010), 9:203-214.
Jorgensen, W. L. The many roles of computation in drug discovery. Science
(2004) 303: 1813-1818. Butcher, E. C. et al. Systems biology in drug discovery. Nature biotechnology (2004) 22(10): 1253-1259.
http://web.ebscohost.com/ehost/detail?vid=1&hid=104&sid=6e2232b5-8dbf-4d2c-81c8-4e68d93e297d@sessionmgr104&bdata=JmxvZ2lucGFnZT1Mb2dpbi5hc3Amc2l0ZT1laG9zdC1saXZlJnNjb3BlPXNpdGU=http://web.ebscohost.com/ehost/detail?vid=1&hid=104&sid=5ed122a3-8dbb-473c-aeba-e95c82356395@sessionmgr104&bdata=JmxvZ2lucGFnZT1Mb2dpbi5hc3Amc2l0ZT1laG9zdC1saXZlJnNjb3BlPXNpdGU=http://pubs.acs.org/doi/full/10.1021/jm8012823?source=chemporthttp://pubs.acs.org/doi/full/10.1021/jm8012823?source=chemporthttp://web.ebscohost.com/ehost/detail?vid=1&hid=104&sid=5ed122a3-8dbb-473c-aeba-e95c82356395@sessionmgr104&bdata=JmxvZ2lucGFnZT1Mb2dpbi5hc3Amc2l0ZT1laG9zdC1saXZlJnNjb3BlPXNpdGU=http://web.ebscohost.com/ehost/detail?vid=1&hid=104&sid=6e2232b5-8dbf-4d2c-81c8-4e68d93e297d@sessionmgr104&bdata=JmxvZ2lucGFnZT1Mb2dpbi5hc3Amc2l0ZT1laG9zdC1saXZlJnNjb3BlPXNpdGU= -
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2/18/2014
KOMPETENSI FARMASIS DALAM
PRODUCT DEVELOPMENT
1. MEMILIKI PENGETAHUAN DALAM FORMULASI
2. MENGAPLIKASIKAN FORMULA PADA FASILITAS
PRODUKSI
3. MAMPU MENGEVALUASI, MERANCANG dan
MENENTUKAN BAHAN PENGEMAS YANG COCOK
4. MAMPU MENYUSUN DATA PENUNJANG REGISTRASI
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1. MEMILIKI PENGETAHUAN DALAMFORMULASI
Memahami dan dapat menjalankan
preformulasiDapat membuat formula sediaan
obat yang berkualitas
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2. MENGAPLIKASIKAN FORMULAPADA FASILITAS PRODUKSI
Melakukan pemilihan mesin dan prosedurpembuatan
Dapat melakukan scale-upDapat melakukan validasi prosesDapat menyiapkan master formula
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2/18/201478
3. MAMPU MENGEVALUASI,MERANCANG
dan MENENTUKAN BAHAN PENGEMAS YANGCOCOK
Dapat melakukan pemilihan , pengujian dan
penelitian bahan pengemasDapat melakukan trial pengemasan danevaluasinya
Dapat melakukan pengujian stabilitas bahan
pengemas
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4. MAMPU MENYUSUN DATA
PENUNJANG REGISTRASI
Mampu mengevaluasi data-data
penunjang proses registrasiDapat melakukan validasi proses
dan membuat rancangan kemasan
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2/18/2014KONSEP D S R
PENGEMB NG N PRODUK
MENGUBAH BAHAN BAKU MENJADI PRODUK SEDIAANFARMASI YANG BERKUALITAS MENGGUNAKANPROSEDUR FABRIKASI YANG TELAH DITETAPKAN
PRODUK SEDIAAN FARMASI YANG BERKUALITAS ?
+
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Pengembangan Produk Baru dapat
berupa : Adaptasi sederhana produk asli dan
kemasannya Adanya rancang ulang total
Penggantian produk sama sekalibaru
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KESEIMBANGAN ANTARA :
Tingginya nilai produk terkait dengan manfaatproduk total, mencakup: Produk nyata (barang secara fisik , pengepakan)
Produk tidak nyata (citra, garansi, informasi, dll)
Nilai produk Harga produk
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P R METERS OF DRUG QU LITY
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2/18/2014P R METERS OF DRUG QU LITY
1. SAFE (AMAN)TIDAK MENIMBULKAN EFEK SAMPING YANG TIDAKDIKEHENDAKI PADA PEMBERIAN DOSIS TERAPEUTIK
2. EFFECTIVE (BERKHASIAT)MENIMBULKAN EFEK FARMAKOLOGIS PADA HEWAN
ATAU MANUSIA
3. ACCEPTABLE (NYAMAN)DAPAT DITERIMA OLEH PASIEN (PENGGUNA OBAT)
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K NDUNG N SEDI N OB T
R/ Bahan obat (Zat aktif)Bahan tambahan (Eksipien)
SAFE BAHAN AKTIF
EFFECTIVE BAHAN AKTIF
ACCEPTABLE EKSIPIEN
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