Karakteristik khusus sediaan parenteral :Aman secara toksikologi Steril Bebas dari kontaminasi bahan pirogenik Bebas partikel partikulat asing Stabil , tidak hanya secara fisika dan kimia tapi juga secara mikrobiologiIsotonis Kompatibel dengan obat lain , jika diberikan dalam bentuk intravena admixture Farmasetika II (Teknologi Sediaan Steril)

Tantangan Umum :Relatif hanya sedikit eksipien yang dapat diterima dalam formulasi dan dapat digunakan untuk sediaan injeksi

Selama proses pembuatan sediaan injeksi , produk hrs dilindungi dari kontaminasi personil .

Kebanyakan sediaan injeksi diberikan oleh para profesional (dokter dan perawat).

Tantangan Mikroorganisme dan kontaminasi lain Kontaminasi mikroba dapat berasal dari bahan baku dan eksipien. Mikroba dapat memasuki sediaan selama proses manufaktur (peralatan, operator, udara dan material pengemas), selama penyimpanan dan penggunaan. Untuk bahan baku dicantumkan dalam USP microbial limit testSediaan injeksi (terutama voleme besar) harus bebas pirogen dan endotoksin. Pengujian pirogen secara in vivo dan in vitro.Sediaan injeksi jika disuntikkan dalam bentuk larutan harus bebas dari partikel partikulat.

Tantangan Stabilitas Sediaan injeksi biasanya diberikan dalam bentuk larutan air dan sistem dispersi (suspensi, emulsi, liposom atau sistem partikulat lain). Secara umum sediaan injeksi bermasalah dalam hal stabilitas kimia, fisika dan mikrobiologi.Kimia : hidrolisis, oksidasi, rasemasi dan fotolisisFisika : pada sediaan injeksi protein, cendrung terbentuk self- aggregate yang selanjutnya akan mengendap, kekeruhan, penurunan kelarutan dan pertumbuhan kristal.

Stabilitas mikrobiologi : kontaminasi mikrorganisme selama proses pembuatan dan penyimpanan. Dpt diatasi dengan pengunaan kemasan yang tepat dan penambahan bahan pengawet. Pengujian kompatibilitas anatara sediaan injeksi dengan kombinasi cairan sediaan intravena lain (NaCl, dektrosa dan laktat ringeri) atau sediaan injeksi lain diperlukan untuk mencegah hal yang tidak diinginkan pada pasien pengguna sediaan .

Tantangan kelarutan Kebanyakan senyawa obat memiliki kelarutan yang terbatas dalam air, seperti ; steroide, fenitoin, diazepam dan digoksin. Masalah kelarutan dapat diatasi dengan beberapa cara :

Pembentukan garam Pengaturan pHPenggunaan kosolven Penambahan surfaktan Pembentukan kompleks inclusi dengan beta cyclodextrinFormulasi sediaan mikroemulsi, liposom, mixed miccele

Tantanagan Kemasan Formulasi sediaan injeksi harus kompatibel dengan sistem kemasan dan penutup kemasan .

Kemasan yg paling luas digunakan vial gelas dan penutup karet.Kriteria penutup karet sangat penting diperhatikan krn dapat mengadsorpsi bahan aktif dan bahan eksipien. Atau leaching material pengemas ke dalam larutan injeksi

PIROGEN PIROGEN : SUATU PRODUK MIKROORGANISME, TERUTAMA BAKTERI GRAM NEGATIF DAN DAPAT BERUPA ENDOTOKSIN DARI BAKTERI INI. ENDOTOKSIN INI TERDIRI ATAS SENYAWA KOMPLEKS YANG MERUPAKAN SUATU SENYAWA LIPOPOLISAKARIDA PYROGEN BERASAL DARI KATA PYRO = KEADAAN ATAU BENTUK YANG BERHUBUNGAN DENGAN PANAS, GEN = MENGHASILKAN

SUBSTAN DAN PREPARAT YANG HARUS BEBAS PIROGEN :

AIR UNTUK INJEKSI LARUTAN INFUS ANTIBIOTIKAGARAM ASAM ORGANIKPRODUK-PRODUK HEWANI : CHORIONIC GONADOTROPIN, GELATIN DAN HEPARINOBAT TETES DAN SUBSTAN LAIN, YANG DIBERIKAN I.V UNTUK MAKSUD DIAGNOSTIK, INULIN, INDIGOCARMINPRODUK-PRODUK DARAH ; HUMAN ALBUMIN

1923 SEIBERT MEMBUKTIKAN BAHWA PIROGEN ADALAH SUBSTANCE YANG BERSIFAT :

TIDAK TERSARINGTHERSTABILNON VOLATILE

SUMBER PIROGEN :PELARUT OBAT SUNTIKOBAT ITU SENDIRIPERALATAN CARA PENYIMPANAN

ADANYA PIROGEN DALAM LARUTAN INJEKSI BISA MENJADI HAL SERIUS JIKA OBAT SUNTIK DALAM JUMLAH BESAR (MISAL INFUS), INI DISEBABKAN KARENA :

INJEKSI VOLUME BESAR AKAN MENGANDUNG PIROGEN YANG BANYAK PULA INJEKSI VOLUME BESAR , BIASANYA DIBERIKAN INTRAVENA, AKIBATNYA PIROGEN AKAN MEMBERIKAN EFEK YANG CEPAT PASIEN YANG MENERIMA CAIRAN INFUS INI BIASANYA PASIEN GAWAT, BILA TERJADIKENAIKAN TEMPERATUS TUBUH BISA BERAKIBAT FATAL.OLEH KARENA ITU, LARUTAN INFUS (INJEKSI VOLUME BESAR) HARUS BEBAS PIROGEN, BPC MENSYARATKAN VOLUME OBAT SUNTIK YANG LEBIH BESAR DARI 10 ML HARUS BEBAS PIROGEN

SIFAR SIFAT PIROGEN :

THERMOSTABIL, UNTUK MENGHANCURKAN PIROGEN DIBUTUHKAN TEMPERATUR YANG LEBIH TINGGI DARI TEMPERATUR BIASA, YANG DIGUNAKAN UNTUK PROSES STERILISASI (> 200 O C)LARUT DALAM AIR, TIDAK DAPAT DIHILANGKAN DENGAN PENYARING BAKTERI TIDAK DIPENGARUHI OLEH BAKTERISIDA YANG BIASA TIDAK MENGUAPBERAT MOLEKUL ANTARA 15.000 4.000.000 DA UKURAN UMUMNYA 1 -50 MIKRON, YANG DAPAT DITENTUKAN SECARA DIALISA

PENENTUAN PIROGEN PENENTUAN KWANTITATIF PIROGEN SECARA FISIKO KIMIA :

DENGAN FOTOKOLORIMETRIPOLAROGRAFIELEKTROFORESA SPEKTROFOTOMETRI

PENENTUAN SECARA KWALITATIF SECARA BIOLOGIS :PENGUKURAN TEMPERATUR BADDAN HEWAN PERCOBAAN :HEWAN PERCOBAAN YANG DIGUNAKAN : KELINCI , KARENA KELINCI ADALAH HEWAN YANG SANGAT PEKA TERHADAP PIROGEN PRINSIP : MENGUKUR KENAIKAN TEMPERATUR TUBUH KELINCI, BILA DIINJEKSIKAN DENGAN LARUTAN OBAT SUNTIK YANG MENGANDUNG PIROGEN SECARA INTRAVENA DITELINGA KELINCI , PENGUKURAN TEMPERATUS TUBUH DILAKUKAN PADA DAERAH DUBUR.KELINCI YANG DIGUNAKAN, HARUSLAH SELAMA SEMINGGU SEBELUM PENGUJIAN TIDAK MENUNJUKKAN PENURUNAN BERAT BADAN. ALAT : TERMOMETER DENGAN KETELITIAN 0,1 DERAJAT DAN DAPAT DIMASUKKAN KE DALAM DUBUR SEDALAM LEBIH KURANG 5 CM.

SEDIAAN UJI : ZAT UJI DILARUTKAN ATAU DIENCERKAN DENGAN LARUTAN NATRIUM KLORIDA P. STERIL BEBA S PIROGEN

PERHITUNGAN SEL DARAH PUTIHINJEKSI LARUTAN OBAT SUNTIK YANG MENGANDUNG PIROGEN PADA PEMBULUH DARAH BALIK KELINCI AKAN MENYEBABKAN TERJADINYA PERUBAHAN SEL-SEL DARAH PUTIH. EX. PENURUNAN LIMFOSIT DAN MENAIKAN NETROFIL.TEST LIMULUS PRINSIP : LYMULUS AMOBOCYTES LYSATE YANG BERUPA EKSTRAK CAIR SEL-SEL DARAH KEPITING LADAM KUDA (LIMULUS POLYPHEMUS) AKAN MENGGUMPAL (MEMBENTUK GEL) DENGAN ADANYA PIROGEN

CAIRAAN LIMFA DAN DARAH KEPITING INI MENGANDUNG AMOEBOCYTEN (MENGANDUNG PROTEIN YANG DAPAT MENGGUMPAL /PROCOAGULANTIN) = LAL ( LIMULUS AMOBOCYTES LYSATE)BAKTERI GRAM NEGATIF BEREAKSI DENGAN EKSTRAK SEL DARAH KEPITING LIMULUS POLYPHEMUS. METODE LAL SANGAT SENSITIF DAN AKURAT UNTUK PENGUJIAN PIROGEN SECARA KWALITATIF ; BAGIAN LIPID A DARI MOLEKUL ENDOTOKSIN DAPAT BEREKSI MENJADI PENGGUMPALAN (GEL)DENGAN LIMULUS LYSATE .

Penghilangan Pirogen Ada beberapa metode untuk menghilangkan pirogen :

Cara Penyulingan :biasanya digunakan untuk membebaskan pirogen dari air. Dilakukan penyulingan bertingkat, dengan alat destilasi tertutup. Pada saat penyulingan dapat ditambahkan bahan kimia dan absorbensia ex. 0,5 % KMnO4, atau dengan bubuk pemutih . Cara pemanasan larutan : waktu dibutuhkan 6-8 jam, suhu 120 derajat, 30 menit 1 jam suhu 140 derajat. (autoclave)dalam keadaan kering : untuk alat dan bahan yang tahan pemanasan : selama 30 menit 250 derajat, 2 jam 200 derajat.

3. Cara Penyerapan pirogen dapat dihilangkan dg cara adsorpsi dengan menggunakan f ilter asbes aktif atau karbon aktif. Pirogen dapat diserap secara kimia dan fisika. Bentuk saringan : asbes aktif dan norit aktif (0,1 0,3 %)

Bentuk bubuk : carbo adsorben, asbes aktif (1 %)

Small Volume Parenteral : Sterile, pyrogen free injectable product which are packaged in volume s up to 100 ml (Avis et al. 1984).SVP product can be classified into one or more of the following categories :

Market Inventory and Projected Sales. A combination of product inventory and projected sales determine in large measure when and how much the product is to be made by a production department.Planning and scheduling activities are the key to the successful production of small volume parenterals.

Materials Management

This group of personnel is responsible for providing the materials necessary to manufacture the product.

Materials management personnel coordinate the activities :

chemical stock, package component warehouse, printing, and purchasing so that there are sufficient supplies of chemicals, package components, and printed components to keep up with the needs of production, and makes certain that these supplies are available in a timely manner.

Personnel Management

The key factor in the large-scale manufacturing of high-quality products is a properly motivated production staff .Documentation Control

Documentation is the control and verification of the critical activities in a pharmaceutical process production and control cycle.

The elements of good documentation include the following:

Master fileBatch recordsProcess logsMaterial IogsDistribution records ComPlaint filesRetained sample storage area recordsReturn good records

The master file is a perpetual record of the production and control cycles on all batches of a particular product.

The batch record is the complete record of the manufacture, control, and distributiott of a single batch of a product.

Process logs are written verification by a responsible person that the facilities and equipment used during a pharmaceutical process have been cleaned, maintained,calibrated, and/or operated in an acceptable manner.

Material logs are a verification that the raw materials used in a pharmaceutical process are acceptable

Distribution records are maintained so that the manufacturer can determine the location of all manufactured products at all times.

In addition, a complaint file is maintained as a backup to in-house monitoring of product performance. Complaint files include inquiries or complaints on product and,/or package defects or adverse product reactions.

A retained sample storage area is maintained as a comparative reference source to assist in the reply to product inquiries and complaints.

The returned goods record is a record of products returned to the manufacturer as a result of complaints or products exceeding their shelf life before being consumed. In any case, returned goods are an important indicator of product market demand and acceptance of a product.

The majority of formulation fall into three pharmaceutical products :

SolutionSuspensions/dispersionsSolid for constitution

Sterile solution is the most common small volume parenteral dosage forms.

Composition of a sterile solution :

Soluble drugOsmotic pressure adjusters (sodium chloride or mannitol)Bacteriostatic agents (required for multiple dose containers such as benzyl alcohol)Buffering agents (phosphates, acetate and citrate salt)pH adjausters (such as sodium hydroxide and hydrochloric acid)Antioxidants (such as bisulfite, ascorbate and citrate )Chelating agent (EDTA)

Dosage10 mg Soluble drug Active drug8,3 mgSodium phosphate mono basicBuffering agent11,29 mg Sodium phosphate dibasicBuffering agent9,0 mg Benzyl alcohol Parenteral preservativeQs pH 6,8 - 7Sodium hydroxide pH adjusterAd 1 mlWater for injection Solvent

Figure I : operation I Nonsterile Formulation

Place WFI (in excess of 10 % of the final volume) into stainless steel tankHeat WFI (121 C 20 min), cool to 60 CRemove and place WFI (30 %) in separate container, save for final volume adjustmentDissolve with stirring the buffering agent with remaining WFI (60 C)Allow the solution to cool (at room temperature 25 30 C), dissolve active drug and preservative, check the pH of the solution, if required, adjust with 1 N sodium hydroxide solutionBring the bulk to final volume with WFI and mix well.

Figure I : operation II Sterilization

Sterilize the bulk solution by filtration methodCollect the sterile filtrate

Figure I : operation III Sterile Subdivision

Aseptically subdivide the sterile bulk into appropriate sterile containerAseptically apply sterilized closure systems to the container and sealInspect for sterility and volume fill check during filling operationInspect all units for defect and particulate matterSubmit samples to the quality control laboratory for release assays

The blue zone (Dan Buettner, 2008)

Figure 2 : operation I nonsterile formulation of the vehicle

Place WFI (in excess of 10 % of the final volume) into stainless steel tankHeat WFI (121 C 20 min), cool to 60 CRemove and place WFI (30 %) in separate container, save for final volume adjustmentDissolve with stirring the buffering agent with remaining WFI (60 C)Seal the tank for autoclaving

Figure 2. Operation II thermal sterilization of the vehicle

Autoclave both of the vessel from operation I for 30 min at 121 C

Figure 2. Operation III aseptic formulation of the active and preservative

Cool the sterile vessel from OP II to room temperature, aseptically add and dissolve active drug and preservative Aseptically check and adjust the pH 6,8 7 if requiredAseptically bring the bulk to final volume with WFI

Figure 2. operation IV Filtration

Figure 2. operation V sterile subdivision

Formulation for a sterile injectable suspension

Dosage800 mg Insoluble drug Active drugO,2 mgPolysorbate 80 USPSurface active agent6,67 mg Sodium Chloride USP Tonicity adjuster 5,0 mg Sodium Carboxymethyl celluloseViscosity building agent9,0 Benzyl alcoholParenteral preservativeAd 1 mlWater for injection Solvent

Sterile suspensions for injection are more complicated in composition than a sterile solutions. Consequently, they are more difficult to process and sterilize than solutions. Solid active ingredient may be sterilized prior to compounding into a suspensions in a numer of ways , dry heat, autoclave, radiation, sterile precipitation or crystallization.

Dry heat sterilization ; low melting point , heat sensitivity of active drug. Autoclaving of suspensions : increased solubility of active drug , induce degradation and recrystallization when is cooled.

Alter the crystal form , habits, or sizes of solid drug Ethylene oxide : residuals of toxic gas, react with the active drug

Radiation : radiation energy can break chemical bonds and or form a new one. The most practical method of preparing a sterile solid for suspension : sterile crystallization and precipitation .

Active drug dissolve in a solvent (organic solvent and co-solvent), then sterilized by filtration through a sterilizing membran with porosity 0,2 mikron or less,

Collected in a sterile vessel containing a sterile liquid in which the dug is insoluble.

The active drug precipitates as crystalline or amorphous mass.

Some sterile solids may have to be aseptically milled to reduce particle size or break up hard aggregates of solid if the crystallizing or precipitation process does not produce a uniform particle size

Preparation of Packaging Components Sterile package consist of :

Primary packaging component (ampuls, vial, syringes, rubber or plastic stopper Secondary packaging component (Box and shrink wrap)Preparation and sterilization of primary packaging component for parenteral and other sterile products are very important steps in the overall manufacturing process. Primary component must be clean and sterile

Rubber Components Vial stoppers, syringe parts, opthalmic dropper bulbsFIFO inventory inventory control for packaging component are critical.Processing of rubber component involves the following operations :

Washing Sterilization Siliconization

Rubber component are generally sterilized by autoclaving (moist heat) because of the rapid heat penetration (121 C 30-60 min)

Siliconization of rubber component is usually necessary to facilitate insertion of the rubber component into container openings via high speed automatic filling and sealing machine.

Silicon oil is used to siliconize SVP rubber component.

Glass Component Vials , ampuls, bottles , syringe are chemically stable than rubber component and therefore may be stored at higher temperature and high humidities for s longer period of time.Processing :

Washing Sterilization Siliconization

Glass component are sterilized by dry heat, dry heat is the process of choice for sterilizing glass component.