Introduction to COMPOUNDING PRACTICES

By Gunawan Setiyadi, S.Si., Apt.

@ta collection

Pharmacists
Profesi

yang unik Terlatih dalam ilmu alam, fisik, dan medis Memiliki pengetahuan dan keterampilan yang tidak tergantikan oleh profesi lain Perannya: meracik (compounding) dan menyerahkan (dispensing) obat, konseling pasien, meminimalkan medication errors, meningkatkan kepatuhan pasien, monitoring drug therapy, and meminimalkan biaya obat

Apoteker dalam praktik compounding

Fungsi

compounding adl utk mengindividualisasi terapi pasien Keahlian apoteker digunakan utk menyesuaikan besaran dosis, frekuensi pemberian, dan bahkan bentuk sediaan utk meningkatkan kepatuhan pasien. Apoteker harus paham akan pilihan-pilihan terapi obat yg bisa diberikan dengan praktik compounding.

.
Apoteker

bertanggung jawab utk melayani pasien mrk dan meracik sediaan obat yg diresepkan dlm kerangka praktik profesional. Meracik obat (steril atau nonsteril) merupakan hak dan kewajiban apoteker utk memenuhi kebutuhan khusus pasien.

Materi :
Definisi The technical aspects and economic impact of compounding Facilities & equipment Ingredients Steps in the compounding process Packaging & labeling Stability, expiration and beyond-use dating Records and reports

Definisi
Compounding is the act of preparing, mixing, assembling, packaging, and/or labelling of a drug or device as the result of a practitioners Prescription Drug Order or initiative based on the practitionerspatient-pharmacist relationship in the course of professional practice, or for the purpose of, or as an incident to, research, teaching, or chemical analysis and not for sale or dispensing. Compounding also includes the preparations of drugs or devices in anticipations of prescriptions drug orders based on routine, regularly observed prescribing patterns. [National Association of Boards of Pharmacy]

Produksi sediaan obat

Manufacturing

manufactured drug product expiration date, biasanya dlm tahun Extemporaneous compounding compounded drug preparation beyond-use date, biasanya dlm hari atau bulan

Manufacturing vs Compounding
Manufacturing Mass production Fixed-dose products No triad relationship physician-patientpharmacist Market autorization Stabilitas terukur Expiration date cGMP, CPOB, ISO

Compounding Limited preparation Individualized prescription/therapy Triad relationship physician-patientpharmacist Off-label Stabilitas ??? Beyond-use date Standar kompetensi apoteker (?) etika (?)

3 types of compounded prescriptions :

Isolated

prescriptions Routine prescriptions Batch prescriptions

Compounding activities

The preparation of suspensions, topicals, and suppositories The conversion of dose (e.g. oral to rectal, injection to oral) The conversion of a dosage form into another The preparation of select dosage forms from bulk chemical The preparation of intravenous admixtures and parenteral nutrition solutions

.
The

preparation of paediatric dosage forms from adult dosage forms The preparation of radioactive isotopes The preparation of cassettes, syringe and other devices with drugs for administration in the home setting Etc.

Reasons for compounding

The

impact of home healthcare Needs for individualized drug therapy Unavailable drug products Orphan drugs Veterinary compounding Biotechnology-derived products

 It

almost seems unvelievable that, as we in health care become more aware that patients are individuals, respond as individuals, and must be treated as individuals, some health care providers appear to be grouping patients into categories for treatment and categories for reimbursement from third-payers or categories for determining levels of care in managed care organizations.

Should every pharmacist compound?

Legally,

any pharmacist is qualified to compound Technically, only properly trained pharmacists should be involved in pharmaceutical compounding.

Should every pharmacist compound?

To be capable of meeting the special or advanced needs of todays patients, whether human or animal, a compounding pharmacist must:

Have access to the most recent information available Maintain an inventory and provide for proper storage of drugs and flavoring agents and be capable of obtaining any chemical within a reasonable time Be dedicated to pharmacy and willing to put forth the necessary financial and time investment

Have the appropriate physical facilities and equipment to do the job right (the extent and type of compounding may be determined or limited by the facility) Be commited to lifelong learning and continuing education, since a major advantage of compounded prescriptions is that they provide treatments that are new, undeveloped, and often not commercially available. Have a willingness to tear down walls and build bridges to share experiences with others for the good of all.

The technical aspects and economic impact of compounding

Technical considerations for compounding a prescription:

1. 2.

3.

Is the product commercially available in the exact dosage form, strength and packaging? Is the prescription rational concerning the ingredients, intended use, dose and method of administration? Are the physical, chemical and therapeutic properties of the individual ingredients consistent with the expected properties of the ordered drug product?

Technical considerations for compounding a prescription:

1.

2.

3.

4.
5.

Will this compounded product satisfy the intent of the prescribing physician and meet the needs of the patient? Is there an alternative (e.g. different dosage form, different route of administration) by which the patient will receive a benefit? Is there a bonafide prescriber-pharmacist-patient relationship? Can ingredient identity, quality and purity be assured? Does the pharmacist have the training and expertise required to prepare the prescription?

Technical considerations for compounding a prescription:

1.
2.

3. 4.

Are the proper equipment,supplies and chemicals or drugs available? Is there a literature reference that might provide information on use, preparation, satbility, administration and storage of the product? Can the pharmacist perform the necessary calculations to prepare the product? Can the pharmacist project a reasonable and rational beyond-use date for the prescription?

Technical considerations for compounding a prescription:

1.
2.

3.

4.

5.

Can the pharmacist willing to complete the necessary documentation to prepare the product? What procedure are in place for investigating and correcting failures? How long will the patient be using the product and is the expected duration of therapy consistent with an appropriate expiration Alternatively, should the product be prepared in small quantities and dispensed to the patient in short intervals? Does the patient have the necessary storage facility, if required, to ensure the potency of the product until its beyond-use date?

Economic considerations for compounding a prescription:

1.
2.

The pharmacists compensation for the service The impact of the service on health care cost

The pharmacists compensation for the service

Pharmaceutical compounding is a cognitive service. Therefore, appropriate reimbursement is justified.

The pricing of a compounded prescription should take into consideration:

Pharmacodynamic/pharmacotherapeutic decision making Formulation expertise The time involves Reimbursement for materials
Compounding prescription can be one way of lowering the cost of drug therapy : enable patient to afford the drug therapy, divide commercial product into smaller units.

Facilities & Equipment

The compounding area should be located sufficiently away from routine dispensing , counseling functions and high traffic areas The area should be isolated from potential interruptions, chemical contaminants and sources of dust and particulate matter Proper temperature & humidity control Well lighted

Facilities & Equipment

Work surface should be smooth and clean The equipment needed to compound a drug product depends upon the particular dosage form requested. Weighing equipment Measuring equipment Compounding equipment: mortar & pestles,spatula,filter, a source of heat paper,beaker,refrigerator & freezer

PERSONNEL

1.

2.
3. 4. 5. 6. 7.

Include : pharmacist and supportive personnel engaged in any aspect of the compounding procedure Training: Proper use of compounding equipment Pharmaceutical techniques needed for preparing compounded dosage form Properties of dosage form Literature in which information on stability, solubility Handling of nonhazardous and hazardous materials in the work area Pharmaceutical calculations Use and interpretation of chemical and pharmaceutical symbols

Facilities & Equipment

INGREDIENTS
Selection

may depend on the dosage form to be compounded In most cases, the prescriber specifies a particular dosage form Sometimes, the prescriber relies on the pharmacist to decide on an appropriate form

Factor to consider in selecting the dosage form include:

1.
2.

3.
4. 5. 6.

Physical & chemical characteristics of the active ingredient Possible routes of administration that will produce the desired therapeutic effect (oral or topical) Patient characteristic (age, level of consciousness, ability to swallow a solid dosage form) Specific characteristics of the disease being treated Comfort for the patient Ease or convenience of administration

Ingredients
If ingredients are liquid Should consider compounding liquid dosage form (solution,syrup,elixir) Compounding dry dosage form (divided powder,capsul) Compounding suspension, elixir,syrup

If ingredients are crystal, powder If ingredients are both liquid & dry form

Note:
Extended

release or delayed release products should not be crushed. Preservative & excipients may affect stability and bioavailability so the presence should not be ignored

Steps in the compounding process

Preparatory

Compounding Final check Sign off Clean up

Preparatory
1. 2. 3. 4. 5. 6.

Judging the suitability of the prescription in terms of its safety and intended use and the dose for the patient Performing the calculations to determine the quantities of the ingredients needed Selecting the proper equipment and making sure it is clean Donning the proper attire and washing hands Cleaning the compounding area and the equipment, if necessary Assembling all the necessary materials/ingredients to compound and package the prescription

Compounding
1.

Compounding the prescription according to the formulary record or the prescription using techniques according to the art and science of pharmacy

Final check
2.

3. 4.

Checking, as indicated, the weight variation, adequacy of mixing, clarity, odor, color,consistency and pH Entering the information in the compounding log Labeling the prescription

Sign off
1.

Signing and dating the prescription affirming that all of the indicated procedures were carried out to ensure uniformity, identity, strength, quantity and purity

Clean up
1.
2.

Cleaning and storing all equipment Cleaning the compounding area

Packaging & Labeling

Container for compounded products: a. should be appropriate for the dosage form compounded b. should not interact physically or chemically with the product (so as to alter strength, quality, purity )

Stability, expiration and beyond-use dating

The

extent to which a dosage form retains, within specified limits and throughout its period of storage and use, the same properties and characteristics that possessed at the time of its preparation.

USP-NF defines stability as the

Stabilitas obat produk manufaktur

Stabilitas obat produk manufaktur tercermin dalam expiration date Expiration date umumnya adalah tanggal ketika obat telah terdegradasi hingga 90% Expiration date merupakan hasil dari uji stabilitas berdasarkan kinetika degradasi kimiawi senyawa aktif Apoteker hrs mengelola obat produk manufaktur sesuai instruksi pd label, terutama aturan penyimpanan, dan menyampaikan informasi tsb kepada pasien saat dispensing untuk penyimpanan/penanganan oleh pasien.

Expiration date
USP 27 (2004) The expiration date identifies the time during which the article may be expected to meet the requirements of the Pharmacopeial monograph, provided it is kept under the prescribed storage conditions. The expiration date limits the time during which the article may be dispensed or used. Where an expiration date is stated only in terms of the month and the year, it is a representation that the intended expiration date is the last day of the stated month.

Stabilitas sediaan racikan (compounded preparation)

Beyond-use date
USP the dispenser shall place on the label of the prescription container a suitable beyond-use date to limit the patients use of the article based on any information supplied by the manufacturer and the General Notices and Requirements of this Pharmacopeia. The beyond-use date placed on the label shall not be later than the expiration date on the manufacturers container

 Beyond-use

date is defined as that date after which a dispensed product should no longer be used by a patient = discard-after date (the date after which a compounded preparation should be discarded).

Pertimbangan dalam menetapkan

beyond-use date

Sifat obat dan kinetika degradasinya Wadah yang digunakan untuk mengemas obat tersebut Kondisi penyimpanan sediaan Lama terapi Expiration date produk komersial serupa, sbg pedoman, jika zat aktifnya USP/NF substance Literatur terpublikasi Informasi dari produsen: printed doc, telepon

Permasalahan dlm penetapan

beyond-use date

Tidak tersedianya data stabilitas formula sediaan racikan (compounded) Banyak ketidakstabilan tidak bisa terdeteksi tanpa peralatan analitik. Berbeda dg inkompatibilitas yg bisa teramati scr visual. Formula racikan mungkin berbeda dg produk pabrik (beda konsentrasi, diluen dan eksipien lain, bahan pengemas) shg beyond-use date tidak bisa begitu saja diekstrapolasi atau diestimasi dari

expiration date.

USP Chapter <795> In the absence of stability information that is applicable to a specific drug and preparation, the following maximum beyond-use dates are recommended for non sterile compounded drug preparations that are packaged in tight, light-re sistant containers and stored at controlled room temperature unless otherwise indicated. For nonaqueous Liquids and Solid Formulations (Where the manufactured drug product is the source of active ingredient)---The beyond-use date is not later than 25% of the time remaining until the products expiration date or 6 months, whichever is earlier. (Where a USP or NF substance is the source of active ingredient)---The beyonduse date is not later than 6 months.

For Water-Containing Formulations (prepared from ingredients in solid form)--The beyond-use date is not later than 14 days when stored at cold temperature.
For All Other Formulations---The beyond-use date is not later than the intended duration of therapy or 30 days, whichever is earlier. These beyond-use date limits may be exceeded when there is supporting valid scientific stability information that is directly applicable to the specific preparation (i.e. the same drug contcntration range, pH, excipients, vehicle, water content, etc.

Contoh: Diazepam tablet digerus dan dimasukkan ke dalam kapsul. Jika tablet tsb mempunyai ED 1 tahun dari saat penggerusan (compounding), BUD maksimum diaz dlm kapsul adl 3 bulan (25% dari 1 tahun). Dengan asumsi, kapsul tsb diberikan dan disimpan di dlm wadah tertutup rapat (tight), kedap cahaya, di dalam temperatur ruang yg terkontrol.

Contoh Jika kapsul diazepam diracik dengan menggunakan serbuk diazepam murni USP, BUD maksimum adl 6 bulan, dg asumsi ED serbuk diaz lebih dari 6 bulan. Jika ED diaz kurang dari 6 bulan, maka BUD kapsul diaz tsb diperpendek. Misalnya, ED diaz = 4 bulan, maka BUD kapsul diaz adl 1 atau 2 bulan.

Contoh Jika tablet komersial yang digerus atau serbuk murni digunakan utk membuat suspensi diazepam dg medium air, maka BUD maksimum adalah 14 hari. BUD tsb berlaku dg asumsi suspensi tsb disimpan di tempat dingin (refrigerator) Utk diaz tdp banyak laporan penelitian ttg formulasinya dlm btk suspensi. Salah satu formulasi tsb stabil sampai 60 hari. Jika formula tsb digunakan maka BUD bisa diperpanjang sesuai dg laporan penelitian tsb.

Contoh Jika tablet komersial yg digerus atau serbuk murni digunakan utk membuat suppositoria diazepam, maka tdp pilihan BUD:
3 bulan (jika menggunakan tablet yg diserbuk) krn produk nonaqueous 6 bulan (jika menggunakan serbuk obat murni) krn produk nonaqueous 3 hari atau lamanya terapi krn bentuk sediaan lainnya

Tipe-tipe stabilitas obat

Menurut USP Chemical: Each active ingredient retains its chemical integrity and labeled potency, within the specified limits. Physical: The original physical properties, including appearance, palatability, uniformity, dissolution, and suspendability are retained. Microbiological Sterility or resistance to microbial growth is retained according to the specified requirements. Antimicrobial agents that are present retain effectiveness within the specified limits. Therapeutic: The therapeutic effect remains unchanged. Toxicological: No significant increase in toxicity occurs.

Potential adverse effect of instability in pharmaceutical products:

Hilang/berkurangnya

zat aktif Naiknya konsentrasi zat aktif Perubahan bioavailabilitas (perubahan F) Hilangnya keseragaman kandungan Berubahnya status mikrobiologis Loss of pharmaceutical elegance and patient acceptability Formation of toxic degradation products

Stabilitas kimiawi
Sifat

kimia obat adalah sifat yang termanifestasi oleh struktur molekul obat tersebut. Jika terjadi perubahan kimia, molekul obat asli tidak ada lagi (hilang/berkurang)

Stabilitas Kimiawi
Kriteria

menurut USP Chapter <1191> Each active ingredient retains its chemical integrity and labeled potency, within the specified limits.

Dekomposisi Kimiawi (Chemical Decomposition)

Hilangnya obat aktif (loss of active) Hilangnya pharmaceutical elegance (kepatutan farmasetis) Terbentuknya produk yang toksik

Hilangnya zat aktif (loss of active): Pada umumnya obat dikatakan tidak berkulitas bila telah mengalami penurunan zat aktif lebih dari 10% (kadar zat aktif tinggal 90%-nya) Hilangnya zat aktif bisa berakibat pada terjadinya terapi yang suboptimal

Kurva degradasi obat

Hilangnya pharmaceutical elegance (kepatutan farmasetis), seperti: timbul bau tidak enak, tengik perubahan warna, akibat reaksi kimia problema rasa, dari inert menjadi asam
Hilangnya pharmaceutical elegance bisa berpengaruh pada kepatuhan pasien dan akhirnya pada keberhasilan terapi.

Terbentuknya produk yang toksik Chemical degradation may not be extensive The product of degradation are more toxic than the original one

Contoh:
Tetrasiklin menjadi epianhidrotetrasiklin Para aminosalisilat menjadi meta aminofenol Chlorokuin dapat menjadi reaksi toksik, dll.

Stabilitas Fisis
Sifat

fisik obat/sediaan obat adalah sifat yang bisa dilihat dan diuji dengan alat fisis. Misal:
wujud (padat, cair, gas), sistem dispersi (larutan, suspensi, emulsi), adsorpsi (adsorpsi ke permukaan wadah)

Jika

terjadi perubahan fisis, senyawa/entitas kimia obat masih ada, tapi sifat fisisnya berubah.

Contoh perubahan fisis: Pembentukan polimorfi dan hidrat Hilangnya uniformitas/keseragaman, misal pada:
a. Vaporasi (sublimasi) b. Adsorbsi obat c. Mottling pada tablet d. Creaming pada emulsi e. Caking pada suspensi f. Presipitasi pada larutan, dll.

Stabilitas Fisis
Kriteria menurut USP Chapter <1191> The original physical properties, including appearance, palatability, uniformity, dissolution, and suspendability, are retained.

Stabilitas mikrobiologis
Produk

obat harus bebas dari kontaminasi mikrobiologis. Fokus perhatian pada sediaan nonsteril: bioburden total, patogen Obat-obat tertentu dipersyaratkan steril, spt: sediaan parenteral dan ophthalmic. Untuk produk obat yang labil thd pertumbuhan mikroorganisme, perlu digunakan preservatif.

Stabilitas Mikrobiologis
Kriteria menurut USP Chapter <1191> Sterility or resistance to microbial growth is retained according to the specified requirements. Antimicrobial agents that are present retain effectiveness within the specified limits.

Stabilitas mikrobiologis
Perlu

diperhatikan kualitas bahan baku, sifat peralatan, fasilitas produksi dan operasionalnya (higiene). Bahan baku yg rentan thd pertumbuhan mikroorganisme adalah bahan yg berasal dari alam (gom, pati, lecithin dll.) perlu monitoring status mikrobiologisnya

Rute-rute degradasi obat (kimiawi)

Solvolisis/hidroli sis 2. Oksidasi 3. Fotolisis 4. Pirolisis 5. Kompleksasi
1. 1.
2.

Racemisasi Epimerisasi

Hidrolisis Obat yang rentan: Ester-ester (anestetika lokal kain, spt prokain, tetrakain, lidokain; aspirin, alkaloida belladonna. Amida (penisilin) Imida (barbiturat) Tioester

Oksidasi Obat yang rentan Katekolamin (senyawa dg gugus OH terikat pd atom karbon yg terikat pd cincin aromatik, spt: epinefrin) Fenol-fenol (phenilephrine, morfin) Senyawa fenotiazin (klorpromazin, prometazin) Senyawa olefin/alkena (senyawa alifatik dg ikatan rangkap Steroid-steroid Senyawa trisiklik Senyawa tiol (senyawa sulfhidril, spt: captopril) Lain-lain (amfoterisin B, Na nitroprusida, nitrofurantoin, tetrasiklin, furosemid, ergotamin, sulfasetamid dll)

Kompleksasi Tetrasiklin dengan ion logam multivalen (Ca2+, Mg2+, Fe2+, Al2+) EDTA Kompleks teofilin dg etilendiamin membentuk aminofilin adalah kompleks yg dikehendaki utk meningkatkan kelarutan. Permasalahan justru muncul jika teofilin keluar dari kompleks, terutama pd sediaan injeksi.

 Rasemisasi

Epinefrin: enantiomer-l (l-epinefrin) 15-20 kali lebih poten daripada enantiomer-d (d-epinefrin) Anestetik lokal: mepivacaine, bupivacaine

Faktor-faktor yang mempengaruhi stabilitas produk obat

USP Chapter <1191> Each ingredient, whether therapeutically active or pharmaceutically necessary, can affect the stability of drug substances and dosage forms. The primary environmental factors that can reduce stability include exposure to adverse temperatures, light, humidity, oxygen, and carbon dioxide. The major dosage form factors that influence drug stability include particle size (especially in emusions and suspensions), pH, solvent system composition (i.e. percentage of free water and overall polarity), compatibility of anions and cations, solution ionic strength, primary container, specific chemical additives, and molecular binding and diffusion of drugs and excipients.

Faktor-faktor yang mempengaruhi stabilitas produk obat

Ingredient

(aktif, eksipien) Lingkungan (suhu, cahaya, kelembaban, oksigen, dan karbondioksida) Bentuk sediaan/formula (ukuran partikel, pH, komposisi solven, kompatibilitas anion dan kation, kekuatan ionik, pengemas primer, bahan tambahan kimia ttt, ikatan molekuler obat dan eksipien.

Cara praktis estimasi waktu kadaluwarsa obat

T 90(awal) T 90(baru) T/10 Q

T90: waktu kadaluwarsa Q : harga yg didasarkan pada energi aktivasi (Ea) dari persamaan Arrhenius. Harga Q = 3 merupakan harga yang cukup reasonable. T : perubahan suhu

Contoh Suatu larutan antibiotika mempunyai waktu kadaluwarsa 96 jam dlm almari pendingin (5oC). Jika larutan tsb harus digunakan dg ambulatory pump pada suhu mendekati suhu badan (30oC) selama 6 jam akankah kadar senyawa bertahan setidaknya 90% dari kadar mulamula selama durasi pemberian tsb?

Penyelesaian: Langkah 1. Hitung perubahan suhu yg akan dialami oleh larutan tsb T = 30oC 5oC = 25oC Langkah 2. Hitung waktu kadaluwarsa pada temperatur yang baru (dlm ambulatory pump)
96 jam jam 96 T 5 jam 6 , 16 90(baru) 25 /10 2 , 3 3

Langkah 3. Bandingkan waktu kadaluwarsa yg baru dengan durasi pemakaian T90 = 6,16 jam; lama pemakaian: 6 jam; maka jawabannya adalah: ya.

Contoh Sebuah resep diterima utk larutan ophthalmic yg waktu kadaluwarsanya 4 jam pada suhu kamar (25oC). Sediaan obat tsb akan digunakan di ruang dokter pada jam 12.00 keesokan harinya. Dapatkah larutan tersebut disiapkan malam sebelum pemakaian (jam 20.00) dan masih mempertahankan setidaknya 90% kadar zat aktifnya jika disimpan di dalam kulkas (5oC)?

Penyelesaian Langkah 1. Hitung perubahan suhu yg akan dialami oleh larutan tsb. T = 5oC 25oC = -20oC Langkah 2. Hitung waktu kadaluwarsa pada temperatur yang baru
4 4 jam jam T . 36 49jam jam 90(baru) 20 /10 2 3 3

Langkah 3. Bandingkan waktu kadaluwarsa yg baru dg lama simpan di dlm kulkas T90 = 36 jam; Lama di dlm kulkas = 16 jam; maka jawabannya: ya, bisa.

Contoh Suatu antibotika hasil rekonstitusi mempunyai waktu kadaluwarsa pd suhu kamar 3 hari. Berapa lama sediaan itu akan stabil jika disimpan di dalam kulkas (dg estimasi berdasarkan T90)?

Penyelesaian Langkah 1. Hitung perubahan suhunya T = 5oC 25oC = - 20oC Langkah2. Hitung waktu kadaluwarsa pada suhu yang baru

3 3 hari hari T . 39 hari hari 27 90(baru) 20 /10 2 3 3

Sekian dan Terima Kasih

Daftar Pustaka
United States Pharmacopeia Allen Jr. LV (2002), The art, science, and technology of pharmaceutical compounding, 2nd ed., American Pharmaceutical Association, Washington DC Thompson JE (1998), A practical guide to contemporary pharmacy practice, 2nd ed., Lippincott Williams & Wilkins Allen Jr. LV

Homework
Berapa

lama beyond-use date sediaan sirup parasetamol yang sudah dikonsumsi bbrp kali tapi belum habis dan disimpan pada suhu kamar?

Records and reports

1.
2. 3. 4.

Formulation records Compounding records SOPs Ingredients records

Thank you..