国生 图秋生 3.Formulation of parenteral products 3.Formulation of parenteral products ·Solutions Parenteral Dosage Forms Manufacture: -Dissolving drugs and excipients ·Solutions -Adjusting the pH -Sterile filtering ·Suspensions w remove particulates and microorganisms prefiltrate in large-scale production to prevent clogging ·Emulsions select suitable filter material to avoid absorption loss -Aseptic filling ·Dry Powders Fill volume should be greater than the exact labeled dose -Autoclaving 国丛生一 圈上达生 7 3.Formulation of parenteral products 3.Formulation of parenteral products Parenteral Dosage Forms Parenteral Dosage Forms ·Suspensions ·Suspensions -Very difficult to formulate and produce -Components >Excellent stability:ships without 》Active ingredients caking/settling 》aqueous vehicle Critical rheological properties: >surfactant for wetting syringeability:from container to syringe Preservatives injectability:from syringe to vein 》buffers 国活人生 圈人生 3.Formulation of parenteral products 3.Formulation of parenteral products .Parenteral Dosage Forms .Parenteral Dosage Forms ·Suspensions ·Emulsions -Two basic methods: -Rarely used as parenteral products Sterile vehicle powder aseptic Excellent stability requirement, combination; >Particle size<lum,homodispersity; Sterile solutions are combined first and Very limited selection of stabilizers in situ crystallization emulsifiers, 1
1 Shanghai Jiao Tong University 3. Formulation of parenteral products • Parenteral Dosage Forms • Solutions • Suspensions • Emulsions • Dry Powders Shanghai Jiao Tong University 3. Formulation of parenteral products • Solutions • Manufacture: – Dissolving drugs and excipients – Adjusting the pH – Sterile filtering » remove particulates and microorganisms » prefiltrate in large-scale production to prevent clogging » select suitable filter material to avoid absorption loss – Aseptic filling » Fill volume should be greater than the exact labeled dose – Autoclaving Shanghai Jiao Tong University 3. Formulation of parenteral products • Parenteral Dosage Forms • Suspensions – Very difficult to formulate and produce » Excellent stability: ships without caking/settling » Critical rheological properties: syringeability: from container to syringe injectability: from syringe to vein Shanghai Jiao Tong University 3. Formulation of parenteral products • Parenteral Dosage Forms • Suspensions – Components » Active ingredients » aqueous vehicle » surfactant for wetting » Preservatives » buffers Shanghai Jiao Tong University 3. Formulation of parenteral products • Parenteral Dosage Forms • Suspensions – Two basic methods: » Sterile vehicle & powder aseptic combination; » Sterile solutions are combined first and in situ crystallization Shanghai Jiao Tong University 3. Formulation of parenteral products • Parenteral Dosage Forms • Emulsions – Rarely used as parenteral products » Excellent stability requirement; » Particle size<1um, homodispersity; » Very limited selection of stabilizers & emulsifiers;
图人生 国生 3.Formulation of parenteral products 3.Formulation of parenteral products Parenteral Dosage Forms Parenteral Dosage Forms ·Emulsions ·Dry Powders -w/o,allergy test,SB -Purpose:To overcome the intrinsic -o/w,sustained-release,depot,IM instability of the drug,be reconstituted -o/w,nutrient emulsion,IV before use. o/w type,use triglycerides as central ·Production Method: core,phospholipid as emulsifier,to -Freeze-drying provide essential fatty acids and calories -Aseptic crystallization and dry powder filling -Spray-drying 圈默人丝 圈上人生 7 3.Formulation of parenteral products 3.Formulation of parenteral products Parenteral Dosage Forms ·Freeze-drying Parenteral Dosage Forms -Advantages Freeze-drying:Under low pressure,under the Avoid damage to heat-sensitive drugs High specific surface are facilitating complete triple point of water,water was removed by rehydration sublimation. Improvement in filling accuracy -Disadvantages: ·sublimation:ice→vapor directly Protective agents needed xStability changing,crystalline/amorphous Triple point of water three phases coexisting High-cost and complicated in equilibrium 国生 国大烧 Process of freeze-drying 3.Formulation of parenteral products .Freezing Parenteral Dosage Forms ·Primary drying Aseptic crystallization ·Secondary drying -The drug is dissolved in a suitable solvent ·Capping -Sterile filtered -A second solvent is then added -Crystallization and precipitation of the drug -Collected and washed -Dried by vacuum drying -Milled and blended -Filled into vials 2
2 Shanghai Jiao Tong University 3. Formulation of parenteral products • Parenteral Dosage Forms • Emulsions – w/o, allergy test, SB – o/w, sustained-release, depot, IM – o/w, nutrient emulsion, IV » o/w type, use triglycerides as central core, phospholipid as emulsifier, to provide essential fatty acids and calories Shanghai Jiao Tong University 3. Formulation of parenteral products • Parenteral Dosage Forms • Dry Powders – Purpose: To overcome the intrinsic instability of the drug, be reconstituted before use. • Production Method: – Freeze-drying – Aseptic crystallization and dry powder filling – Spray-drying Shanghai Jiao Tong University 3. Formulation of parenteral products • Parenteral Dosage Forms • Freeze-drying – Advantages » Avoid damage to heat-sensitive drugs » High specific surface are facilitating complete rehydration » Improvement in filling accuracy – Disadvantages: » Protective agents needed » Stability changing, crystalline/amorphous » High-cost and complicated Shanghai Jiao Tong University 3. Formulation of parenteral products • Parenteral Dosage Forms • Freeze-drying: Under low pressure, under the triple point of water, water was removed by sublimation. • sublimation : ice vapor directly • Triple point of water : three phases coexisting in equilibrium Shanghai Jiao Tong University • Process of freeze-drying • Freezing • Primary drying • Secondary drying • Capping Shanghai Jiao Tong University 3. Formulation of parenteral products • Parenteral Dosage Forms • Aseptic crystallization – The drug is dissolved in a suitable solvent – Sterile filtered – A second solvent is then added – Crystallization and precipitation of the drug – Collected and washed – Dried by vacuum drying – Milled and blended – Filled into vials
国生 国丛丝 3.Formulation of parenteral products 3.Formulation of parenteral products Parenteral Dosage Forms Parenteral Dosage Forms ·Spray-drying -A solution of drug is sterile filtered -An aerosol of small droplets of liquid is created by Limitations of aseptic crystallization an atomizer -Solvent evaporates quickly by contacting with a -Batch-to batch variance stream of hot sterile gas -Drug is collected as a powder in the form of -Hard to maintain asepsis uniform hollow spheres -Filled into vials -Fill weight uniformity 国生一 圈秋生一 3.Formulation of parenteral products ©4.Packaging Parenteral Dosage Forms Limitations of spray-drying .Container components for parenteral -Sterile filtration of very large volumes of air products must be considered an integral -Constructing and maintaining a spray dryer that can be readily sterilized part of the product because they can -Aseptic transfer of powder from the spray dramatically affect product stability, dryer to the powder-filling line -precise control of the drying conditions to potency,toxicity,and safety. prevent overheating of the product 国生 国我生一 4.Packaging ④4.Packaging Small volume parenterals(SVPs) Small volume parenterals(SVPs) ·Ampoules ·Ampoules -heat sealed after filling Glass vials sealed with rubber stoppers .Plastic ampoules(blow-fill-seal) ·Pre-filled syringes Needle-free injection 3
3 Shanghai Jiao Tong University 3. Formulation of parenteral products • Parenteral Dosage Forms • Limitations of aseptic crystallization – Batch-to batch variance – Hard to maintain asepsis – Fill weight uniformity Shanghai Jiao Tong University 3. Formulation of parenteral products • Parenteral Dosage Forms • Spray-drying – A solution of drug is sterile filtered – An aerosol of small droplets of liquid is created by an atomizer – Solvent evaporates quickly by contacting with a stream of hot sterile gas – Drug is collected as a powder in the form of uniform hollow spheres – Filled into vials Shanghai Jiao Tong University 3. Formulation of parenteral products • Parenteral Dosage Forms • Limitations of spray-drying – Sterile filtration of very large volumes of air – Constructing and maintaining a spray dryer that can be readily sterilized – Aseptic transfer of powder from the spray dryer to the powder-filling line – precise control of the drying conditions to prevent overheating of the product Shanghai Jiao Tong University 4. Packaging • Container components for parenteral products must be considered an integral part of the product because they can dramatically affect product stability, potency, toxicity, and safety. Shanghai Jiao Tong University 4. Packaging • Small volume parenterals (SVPs) • Ampoules • Glass vials sealed with rubber stoppers • Plastic ampoules (blow-fill-seal) • Pre-filled syringes • Needle-free injection Shanghai Jiao Tong University 4. Packaging • Small volume parenterals (SVPs) • Ampoules – heat sealed after filling
国生一 国坠生 ④4.Packaging 图4.Packaging Small volume parenterals(SVPs) Small volume parenterals(SVPs) Glass vials sealed with rubber stoppers Plastic ampoules (blow-fill-seal) 邑www.vial-bottie.com Extrusion-Molding Finahed Product 图秋生 圈秋生一 ④4.Packaging ④4.Packaging Small volume parenterals(SVPs) ·Pre-filled syringes Small volume parenterals(SVPs) -reducing the degree of manipulation required -facilitating administration in an emergency situation Needle-free injection Prefilled Syringes 国人生 国生一 ©4.Packaging ④4.Packaging Single-dose container Large volume parenterals(LVPs) A hermetic container holding a quantity of Glass bottles sealed with rubber stoppers sterile drug intended for parenteral administration as a single dose;when opened, Plastic bags it cannot be resealed with assurance that sterility has been maintained. Multi-dose container .A hermetic container that permits withdrawal of successive portions of the contents without changing the strength,quality,or purity of the remaining portion. 4
4 Shanghai Jiao Tong University 4. Packaging • Small volume parenterals (SVPs) • Glass vials sealed with rubber stoppers Shanghai Jiao Tong University 4. Packaging • Small volume parenterals (SVPs) • Plastic ampoules (blow-fill-seal) Shanghai Jiao Tong University 4. Packaging • Small volume parenterals (SVPs) • Pre-filled syringes – reducing the degree of manipulation required – facilitating administration in an emergency situation Shanghai Jiao Tong University 4. Packaging • Small volume parenterals (SVPs) • Needle-free injection Shanghai Jiao Tong University 4. Packaging • Large volume parenterals (LVPs) • Glass bottles sealed with rubber stoppers • Plastic bags Shanghai Jiao Tong University 4. Packaging • Single-dose container • A hermetic container holding a quantity of sterile drug intended for parenteral administration as a single dose; when opened, it cannot be resealed with assurance that sterility has been maintained. • Multi-dose container • A hermetic container that permits withdrawal of successive portions of the contents without changing the strength, quality, or purity of the remaining portion
国生 国生 ④5.Stability 6.Sterilization methods .90%to 95%activity of medicament Sterilization means destruction of all living ·Other considerations organisms and their spores or their Adsorption of preservative to a rubber closure complete removal from the preparation ·Physical stability 国我生 国生一 6.Sterilization methods 6.Sterilization methods Steam ·Steam Steam sterilization is conducted in an ·Dry heat autoclave and employs steam under pressure. ·Filtration This method is preferred to other sterilization methods if the product and ·Gas container can withstand it. Autoclave 国建一 6.Sterilization methods ·Steam .The usual temperature and the approximate length of time required is 121C for 15 to 30 minutes,depending on the penetration time of moist heat into the load. 5
5 Shanghai Jiao Tong University 5. Stability • 90% to 95% activity of medicament • Other considerations • Adsorption of preservative to a rubber closure • Physical stability Shanghai Jiao Tong University 6. Sterilization methods • Sterilization means destruction of all living organisms and their spores or their complete removal from the preparation. Shanghai Jiao Tong University 6. Sterilization methods • Steam • Dry heat • Filtration • Gas Shanghai Jiao Tong University 6. Sterilization methods • Steam • Steam sterilization is conducted in an autoclave and employs steam under pressure. • This method is preferred to other sterilization methods if the product and container can withstand it. Autoclave Shanghai Jiao Tong University 6. Sterilization methods • Steam • The usual temperature and the approximate length of time required is 121oC for 15 to 30 minutes, depending on the penetration time of moist heat into the load
国生 国生 6.Sterilization methods 6.Sterilization methods ·Dry heat ·Dry heat .The transfer of energy from dry air to the Less effective heat transfer than for object that is sterilized.The transfer steam sterilization occurs through conduction,convection .Higher temperature and longer time are and radiation. required -160C for more than 2 hours 国我丛生 圈上人生 6.Sterilization methods 6.Sterilization methods ·Dry heat 。Filtration Substances that are not effectively Sterilization by filtration depends on the sterilized by steam physical removal of microorganisms by Glassware and surgical instruments adsorption on the filter medium or by a sieving mechanism. For heat-sensitive solutions 国生一 国生一 6.Sterilization methods 6.Sterilization methods ·Filtration ·Filtration .The filtration process might be affected ·Depth filters by adsorption. The integrity of the filters has to be proven ·Membrane filters Avoid filters that cause particles (0.22m) .Test the filters so that they do not give extractable 6
6 Shanghai Jiao Tong University 6. Sterilization methods • Dry heat • The transfer of energy from dry air to the object that is sterilized. The transfer occurs through conduction, convection and radiation. Shanghai Jiao Tong University 6. Sterilization methods • Dry heat • Less effective heat transfer than for steam sterilization • Higher temperature and longer time are required – 160oC for more than 2 hours Shanghai Jiao Tong University 6. Sterilization methods • Dry heat • Substances that are not effectively sterilized by steam • Glassware and surgical instruments Shanghai Jiao Tong University 6. Sterilization methods • Filtration • Sterilization by filtration depends on the physical removal of microorganisms by adsorption on the filter medium or by a sieving mechanism. • For heat-sensitive solutions Shanghai Jiao Tong University 6. Sterilization methods • Filtration • Depth filters • Membrane filters (0.22 μm) Shanghai Jiao Tong University 6. Sterilization methods • Filtration • The filtration process might be affected by adsorption. • The integrity of the filters has to be proven • Avoid filters that cause particles • Test the filters so that they do not give extractable
国生一 国生 6.Sterilization methods 6.Sterilization methods ·Gas .Ethylene oxide(ETO)is widely used as a Validation of sterility sterilant in hospitals and industry for items that cannot be sterilized by steam. Regardless of the method, It is often diluted with carbon dioxide,or pharmaceutical preparations required to sometimes fluorocarbons,to overcome its flammable and explosive nature. be sterile must undergo tests to confirm Post treat procedure:to remove the residual the absence of microorganisms. ETO and its byproducts 国我生一 圈上人生 6.Sterilization methods 6.Sterilization methods .Validation of sterility .Validation of sterility Biological indicator ·Biologic indicator ·Fo value -A characterized preparation of specific microorganisms resistant to a particular sterilization process. -Added to the product or strips of filter paper 国人生 国我生 6.Sterilization methods ©7.Quality assurance .Validation of sterility Core meaning:To build the quality into the product ·Fo=D12 (logNo-logN) -D2 is the time required for a one-log .Especially significant for parenteral products,sterility, reduction in the microbial population absence of pyrogens,freedom from extraneous exposed to a temperature of 121C particles -No is the initial microbial population Testing of raw materials,packaging components,and -N,is the final microbial population after final product sterilization Written operating procedures,personnel training,record keeping,and facility design and monitoring 7
7 Shanghai Jiao Tong University 6. Sterilization methods • Gas • Ethylene oxide (ETO) is widely used as a sterilant in hospitals and industry for items that cannot be sterilized by steam. • It is often diluted with carbon dioxide, or sometimes fluorocarbons, to overcome its flammable and explosive nature. • Post treat procedure: to remove the residual ETO and its byproducts Shanghai Jiao Tong University 6. Sterilization methods • Validation of sterility • Regardless of the method, pharmaceutical preparations required to be sterile must undergo tests to confirm the absence of microorganisms. Shanghai Jiao Tong University 6. Sterilization methods • Validation of sterility • Biological indicator • F0 value Shanghai Jiao Tong University 6. Sterilization methods • Validation of sterility • Biologic indicator – A characterized preparation of specific microorganisms resistant to a particular sterilization process. – Added to the product or strips of filter paper Shanghai Jiao Tong University 6. Sterilization methods • Validation of sterility • F0 =D121(logN0-logNt ) – D121 is the time required for a one-log reduction in the microbial population exposed to a temperature of 121oC – N0 is the initial microbial population – Nt is the final microbial population after sterilization Shanghai Jiao Tong University 7. Quality assurance • Core meaning: To build the quality into the product • Especially significant for parenteral products, sterility, absence of pyrogens, freedom from extraneous particles • Testing of raw materials, packaging components, and final product • Written operating procedures, personnel training, record keeping, and facility design and monitoring
国生一 国丛生 ④7.Quality assurance ④7.Quality assurance Regulatory and Compendial Requirements GMP:Good Manufacturing Practice ·Monitoring Programs -Organization and personnel -Buildings and facilities ·Process facilities -Control of drug components,packaging,and Production areas materials -Production and process control ·Personnel -Equipment -Packaging and labeling control Environmental monitoring -Holding and distribution -Laboratory control -Records and reports 国我生 圈上人生 7.Quality assurance ④7.Quality assurance Product testing and evaluation .Product testing and evaluation Sterility testing ·Sterility testing ·Pyrogen testing -Direct method:culture tube ·Leaker testing -Indirect method:membrane Clarity testing and particulate analysis ·Labeling 国生 国我生一 ©7.Quality assurance ©7.Quality assurance Product testing and evaluation Product testing and evaluation ·Pyrogen test ·Leaker testing -Rabbit test -For sealed ampoules >under vacuum,dying method -Limulus amebocyte lysate(LAL)test ordinary pressure,high-frequency spark test 8
8 Shanghai Jiao Tong University 7. Quality assurance • Regulatory and Compendial Requirements • GMP: Good Manufacturing Practice – Organization and personnel – Buildings and facilities – Control of drug components, packaging, and materials – Production and process control – Equipment – Packaging and labeling control – Holding and distribution – Laboratory control – Records and reports Shanghai Jiao Tong University 7. Quality assurance • Monitoring Programs • Process facilities • Production areas • Personnel • Environmental monitoring Shanghai Jiao Tong University 7. Quality assurance • Product testing and evaluation • Sterility testing • Pyrogen testing • Leaker testing • Clarity testing and particulate analysis • Labeling Shanghai Jiao Tong University 7. Quality assurance • Product testing and evaluation • Sterility testing –Direct method : culture tube –Indirect method: membrane Shanghai Jiao Tong University 7. Quality assurance • Product testing and evaluation • Pyrogen test –Rabbit test –Limulus amebocyte lysate (LAL) test Shanghai Jiao Tong University 7. Quality assurance • Product testing and evaluation • Leaker testing – For sealed ampoules » under vacuum, dying method » ordinary pressure, high-frequency spark test
国生一 国丛生 ④7.Quality assurance ④7.Quality assurance Product testing and evaluation Product testing and evaluation .Clarity testing and particulate analysis .Labeling -Clarity:the state of quality of being clear or -The drug substance transparent to the eyes -Concentration/dose. -Particulate matter:extraneous,mobile,undissolved -Handling/storage condition substances unintentionally present in parenteral -Any special precautions. solutions 图丝一 Learning objectives .Concepts:Parenteral,WFI,GMP,LVP,SMP. pyrogen,Freeze-drying(lyophilization), Sterilization Routes of parenteral administration Functions of the added substances Calculation of tonicity adjustment Parenteral dosage forms .Sterilization methods 9
9 Shanghai Jiao Tong University 7. Quality assurance • Product testing and evaluation • Clarity testing and particulate analysis – Clarity: the state of quality of being clear or transparent to the eyes – Particulate matter: extraneous, mobile, undissolved substances unintentionally present in parenteral solutions Shanghai Jiao Tong University 7. Quality assurance • Product testing and evaluation • Labeling – The drug substance – Concentration/dose, – Handling/storage condition – Any special precautions. Shanghai Jiao Tong University Learning objectives • Concepts: Parenteral, WFI, GMP, LVP, SMP, pyrogen, Freeze-drying (lyophilization) , Sterilization • Routes of parenteral administration • Functions of the added substances • Calculation of tonicity adjustment • Parenteral dosage forms • Sterilization methods