Manufacturing Pharmacy

MODULE 5: MANUFACTURING PHARMACY I.

INTRODUCTION A. MANUFACTURING  Large scale production drug product  Preparation, processing, packaging, labeling, repacking, and changing the container, wrapper or label of any drug product

MANUFACTURING ACTIVITIES 1. Primary Manufacturing  Manufacture of APIs and excipient 2. Secondary Manufacturing  Manufacture of finished dosage forms 3. Tertiary Manufacturing  Packaging, labeling or repacking of bulk finished product 4. Toll Manufacturing  An arrangement whereby a competent company manufactures the products for another company B. DEPARTMENT IN A MANUFACTURING PLANT 1. Research and Development Department  FORMULATES new product  Reformulate existing product  Does chemical pharmaceutical and physiological research  Facilities o Library o Animal house o Pilot plant

2. Production Department  Manufactures product according to schedule  Includes warehousing and storage 3. Quality Assurance Department  Assures all operation meet the required standards of safety and efficacy  Ensures compliance CGMP  Conducts quality audit and monitoring  Cooperates with regulatory agencies  Prepare SOP (Standard Operating Procedure) 4. Quality Control Department  Test compliance of RM, PM and finished product  Conduct sampling of materials  Performs IPQC and environmental testing 5. Marketing Department  Studies current market trends, consumer behavior and product status in the market  Advertisement and promotion 6. Regulatory Department  Ensures compliance of the company and its product with all pertinent regulations & law about drugs and their marketing  LTO initial: 2yrs, Renew: 3yrs  Certificate Product Registration (CPR)

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7. Engineering Department  Install, maintain and repairs equipment and premises  Ensures safety (employee) 8. Medical department  Concerned w/ the physical examination and medical treatment of employee  Perform clinical studies  Publishes house organ/ paper (Clinical Research)

 Theoretical yield: Actual yield (not written ≠ not happen) 6. Standard Operating Procedures (SOPs)  Step-by-step instructions for performing operational task or activities 7. Manufacturing Order  Gives instruction to the production department of manufacturing product

C. TERMS TO REMEMBER 1. Batch  A specific quantity of product having uniform character and quality produced during a single manufacturing process 2. Lot  Specific identified portion of a batch 3. Batch/ lot number  For identification and traceability of a single batch/ lot 4. Master Formula  Contains the formulation, manufacturing procedures specs, QA requirement and labeling of a finished product 5. Master Batch Record/ Batch Manufacturing Record  Ensures the batches were properly made and Q.C. test was performed

8. Overage  Addition of an active in an unstable preparation to compensate for drug loss during manufacturing/ manufacture 9. Quarantine  Designated area for holding of incoming components prior to acceptance testing and qualification for use (Yellow Label)  Green = Passed  Red = Failed (double lock) 10. Validation  Documented evidence that a system does what is it supposed to do  (3 batches)  HVAC system (Heating Ventilation Aircon)  Cleaning

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II. PACKAGING, LABELING AND STORAGE OF DRUGS A. PACKAGING  Economic way of protecting, preparing, identifying and containing drug product  Composed of a container and its closure TYPES OF PACKAGING 1. Primary Packaging  Immediate container  Direct contact w/ the product  Affect stability  May be used for administration  Pharm. Coil: o Cotton in the drug product o To prevent rattling  Desiccant – prevent absorption of moisture

c.

Hermitic  Impervious to air or any other gas (Parenteral)

d.

Light-Resistant  Protect from photochemical degradation (amber bottle = 100% protection against light)

e.

Child resistant  Difficult for children under 5 yrs. of age  Press down and turn  Align the arrows  Latch tap

f.

Tamper resistant  Uses an indicator which if breached or missing can provide evidence that tampering has occurred o Shrink seal/ wrap o Breakable cap o Tape seal o Bottle seal o Aerosol – only true tamper resistant, packaging

2. Secondary Packaging  Outer packaging  Encloses 1 or more primary packaging  Not always present e.g. box, inserts

2. According to Quality Held

B. CLASS OF CONTAINERS 1. According to protection ability a.

Well closed container  Protect from extraneous solid

b.

Tight  Protect from extraneous solid, liquid or vapors

a.

Single Unit      

Hold a single dose only Non-resealable No-antimicrobial agent Water: SWFI or WFI USP limit: 1,000 mL E.g ampule, pre-filled syringe

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b.

Multiple-unit  Holds more than a single dose  reseal able  w/ antimicrobial agent  water BWFI  USP limit 30 mL 3. According to material used

a.   



Glass Most widely used Major component SiO2 Adv: o Strength and rigidity o Inertness o Barrier protection Disadv: o Fragility o Heavily o Leaching of alkali (+buffer)

 TYPE 3 SODA LIME GLASS  Low resistance  For reconstituted by dry solid and non-aqueous liquids  NP: o General purpose soda lime glass o For oral solid and liquid & dosage form and external preparation b. Plastic  Organic polymer of HMW  Adv: o Durability o Light weight o Low cost  Disadv: o Permeability o Environmental o Leaching of additives

TYPES OF GLASS

TYPES OF PLASTIC

 TYPE 1 HIGHLY RESISTANT BOROSILICATE  Highly resistance  For buffered and non-buffered aqueous parenteral solution  Powdered glass

 THERMO PLASTIC  Soft when heated and hard when cooled  Flexible and squeezable (water bottle)

 TYPE 2 TREATED SODA-LIME GLASS  Surfaced it is treated w/ SO2 → dealkalized  For buffered acidic aqueous solution  Water attack test

 THERMOSET  Permanently hard  Rigid (monoblock)

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Polymer for Plastic No. 1

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Polymer Polyethylene Terephthalate (PET) High-density Polyethylene (HOP)

C. LABELING (A.O. 55) Description For beverage

Hard thermoset for solid dosage form Polyvinyl -For blister chloride pack -Least resistant to permeation Low density Thermoplastic Polyethylene for squeeze (LOP) bottles and medicine dropper Polypropylene -High temp (PP) resistance -For auto clave material

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c. Foils, Films and Laminates  Low film cost, flexibility, heatsealability decoration  Ex: strip & blister pack, sachets, liners for large container d.

e.

Rubber  Ex: o Stopper for vial o Bulb for pipet o Plug for syringes Metal  Aluminum (inert)  Tin (lighter, cheap)  Ex: collapsative/ collapsible tube aerosol can, crimp for vials

 Label o Display of written, printed or graphic matter on the immediate container (Principal Display Panel (POP) 40% most shown front part)  Labeling – material o All label and other written (printed or graphic matter upon any item or its container)  PRINCIPAL DISPLAY PANEL (POP) 1. Name of product (generic and brand name)  Helvetica medium, universe medium – font if BN has a special font 2. Dosage form and strength 3. Pharmacologic category 4. Rx symbol in case of prescription drug (Rx 1/5 of label) 5. Name and address of manuf, trader (reg. owner) or distributor (importer – from other country → local, exporter – from local → international, whole saler – local source, local distribution)

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6. Net content  Other info: 1. Formulation 2. Indication 3. Contraindication, precaution, warning 4. Directions for use 5. Batch/ lot number 6. Expiration & Mfg. date & cosmetic = 36 months’ shelf life 7. Registration number (DR#) 8. Storage condition D. STORAGE CONDITIONS 1. Cold: nmt 8© a. Freezer – 20 to -10© b. Refrigerator – 2-8© 2. Cool: 8-15© 3. Room temp: temp prevailing in the area 4. Controlled room temp: 20-25© 5. Warm: 30-40© 6. 7. Excessive heat: >40© III. MANUFACTURING OF TABLETS A. TABLET COMPONENT 1. APIs  Excipients → consider compatibility w/ the API(s)

2. Diluent/ filler  Inert substance added to increase tablet size which is practical for compression  Lactose o Stearic acid (check)  ≠ mg stearate (most common lubricant  ≠ anime drugs  ≠strong oxidizers  Sucrose and flucose  Starch  Dibasic CaHPO4  Anhydrose/ spray-bried lactose (free-flowing)  Microcrystalline cellulose (MCC) – Avicel ® (Freelyflowing – direct compression) 3. Binder  Imparts cohesiveness to powders causing them to form granules o Starch paste (common binder wet granulation) o Acacia o Tragacanth o Gelatin o Sucrose o Cellulose  CMC – carboxymethylcellulose  HPMC o PVP 4. Disintegrant  Facilitate the break-up of tablet when in contact with water in GIT

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 MOA: swelling (starch paste), wicking (avicel ® MC)  TYPES: o Internal – added prior to granulation o External – added prioir to compression 5. Super disintegrant  Newer class of disintegrants which are effective at much lower levels o Sodium starch glycolate o Croscarmellose Na o Crospovidone 6. Antifrictional/ Flowactivator  Hydrophobic powders added prior to compression to reduce friction and improve flow properties  Included at concentration <1%  Roles: o LUBRICANT – facilitates ejection from die cavity o ANTI-ADHERENT – reduces sticking to the punch faces or die walls o GLIDANT – enhance flow o Mg stearate – most common 3 roles o Purified talc – antiadherent/ lubricant o Colloidal talc – glidant o Colloidal SiO2 (Cab-O-Sil®) – glidant o Mg & Ca silicate – glidant o PEG & lauryl sulfate – hydrophilic lubricant

7. Colorants Classes: a. Dyes  Water soluble colorants used as solutions b. Lakes  Water-insoluble dye that have been absorbed on hydrous oxide usually alumina used as dry powders – (external use) FD&C DYES       

Blue no.1 – brilliant blue Blue no. 2 – indigoine (indigo) Green no. 3 – fast green Red no. 40 – allura red Red no. 3 – erthrosine (pink) Yellow no. 5 – tartrazine (yellow) Yellow no. 6 – sunset yellow (orange)

8. Flavors a. Salty – cinnamon, orange, cherry, butterscotch b. Bitter – chocolate, cherry, raspberry, mint c. Sour – raspberry, lemon, fruity d. Oily – mint, lemon, orange e. Unpleasantly sweet – vanilla, fruity

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9. Sweeteners  Artificial sweeteners a. Sucralose – 1000x b. Saccharin – 500x c. Na Saccharin – 300x (magic sugar) d. Acesulfame K – 180-200x e. Aspartame – 180-200x f. Na cyclamate – 30x  (SuSaNa AcAsNa)  Nela charade G. Puno (FDA director General)  Francisco Doque (DOH)

ISSUES:  Weighing accuracy  Dust control (negative pressure airflow (solid), (+) pressuresterile)  Lot control of each ingredient  Material movement  MILLING  Particle size reduction, sizing, crushing, grinding pulverization  OBJECTIVE: easier and more uniform mixing EQUIPMENTS:

1. CUTTER MILL  Cute particles using knives  For fibrous material

B. PROCESS IN TABLET & MANUFACTURE DISPENSING→ MILLING → MIXING→ GRANULATION→ TABLETING→ COATING

 DISPENSING  First-step in any manufacturing process  Weighing and measuring  OBJECTIVE: Accuracy of weight → uniform dose

2. EDGE RUNNER MILL  Crushes the materials by 2 rotating wheels  COMPRESSION (principle involve) 3. HAMMER MILL  Use a high speed rotor to which swinging hammer are fixed  IMPACT (PE)

METHODS:  Hand scooping and weighing  Weighing w. material lifting assistance  Automated dispensaries

4. FLUID ENERGY MILL  Use air w/ very high pressure  IMPACT

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5. ROLLER MILL  Consist of rotating cylindrical rolls  FRICTION

b. Fixed shell mixer i. Ribbon blender  Helical shaped  Not commonly used

6. BALL MILL  Consist of a rotating cylindrical roll filled with balls

ii.

Sigma blade mixer  Preferred for mixing acid material

 MIXING  Process of blending material together into 1 mess  OBJECTIVE: obtain dosage unit each of which contains the same amount of API & UNIFORM DOSE

iii.

Planetary mixer  Baking

iv.

Vertical impeller mixer  Screw shaped

EQUIPMENTS: 1. BATCH TYPE MIXER

2. CONTINUOUS  High volume products  Materials enter through the charging port to the discharge nozzle

 All ingredients are loaded together, mixed and discharged as a single type

 GRANULATION  Powder size enlargement  OBJECTIVE: ↑ flowability and ↑ compressibility

2 types: a. Tumbling mixer/ Rotating Shell i. Drum type blenders  Cylindrical-shaped  Horizontal axis  Poor crossflow – remedy: baffles, put mixture slanted (45°) ii.

Double cone blender  Good crossflow

iii.

V-shell blender  Twin-shell blender  Solid-solid blending  Alternately combines and draw apart the materials

TYPES: a. Good granules  Passed through sieve # 20 but not through sieve # 40 b. Fine granules  Pass through sieve # 40  Limited to 10%  To fill interparticulate spaces METHODS: 1. Wet granulation  Addition of liquid binder to powder  Most common method 9

 Cohesive of powder  Disadv: o Labor intensive o Time consuming o Not for moisture or heatsensitive drug

 Disadvantage: dusty and uneven colored PROCESS: a. Slugging – formation of slugs → large flat tablet (1inch)  Oscillating granulation b. Roller compaction – formation of sheets  Chilsonator roller compactor (machine)

WET GRANULATION STEPS 1. Blending of dry ingredients 2. Addition of liquid binder 3. Screening the damp mass (sieve no. 6 or 8) 4. Drying the granulation (alter drying moisture content: 0.5-1%) 5. Screening the dry granules (sieve no. 12-20 (90%)) 6. Addition of lubricant and external disintegrant  Under wet → too soft  Over wet → too hard  Moisture content → 31-35%  Sieve no. 6 or 8 2. Fluid bed granulation  Can accomplish both dry mixing and wet granulation efficiently and in much less time compared to traditional method 3. Dry granulation  Double compression or precompression method  Powder mixture is compacted into large pieces and subsequently broken down into granules  For moisture and heat sensitive material

 TABLETING  Compression of tablet component within a die cavity by the pressure exerted by the movement of 2 punches PARTS OF TABLETING MACHINE 1. Hopper – holds the material 2. Feed shoe/ teeth frame – transfer the material into the die 3. Die – defines the size and shape of the tablet 4. Punches – compress the material w/ in the die 5. Cam tracks – guide the movement of punches TYPES OF TABLETING MACHINE 



SINGLE STATION  Involves compression of the upper punch only MULTIPLE STATION  Involves movement of both punches

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REQUIREMENTS 1. Flowability – facilitates transfer  Flow problem o Arching/ bridging  Arch-shaped obstruction forms above the hopper outlet o Rat-holing  Discharge takes place only above the hopper outlet 2. Compressibility – form a stable, compact mass when pressure is applied DIRECT COMPRESSION  Tablet processing w/o granulation  Require a very critical selection of excipients → good flowability and compressibility  Ex: KCl, NaCl, and Na Br  Diluents: anhydrous lactose/ avicel TABLET DEFECTS: 1. Capping  Partial or complete separation of the top or bottom crown 2. Lamination  Separation into 2 or more distinct horizontal layers 3. Chipping  Removal of small portion (tablet edges)  Very dry granulation 4. Cracking  Fine cracks on the surface  Due to concave punches

5. Sticking  Adhesion to die wall 6. Picking  Adhesion to punch surfaces (pinholes) 7. Double impression  Due to free rotation of the punches w/ engraving on the faces 8. Mottling  Uneven color distribution  COATING  Application of coating material to a moving bed of solid w/ concurrent use of heated air EQUIPMENT 1. Standard coating pan  Consist of a rotating circular metal pan w/ ducts  Ex: Pellegrini Pan – immersion tube/ sword system a. Pan pouring  Problem: surface erosion  For viscous solution b. Pan spraying  More efficient → allows control 2. Perforated coating pan  Exhausting is through the perforation  Ex: Accela-cota pan, Driacoater, Glatt coater 3. Fluid bed coater  Air-suspension coating or wurster process

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2 TYPES OF COATING 1. Sugar-coating  Oldest method  Disadvantage o Large increase in weight (MT 50%) o Time consuming o Require expertise STEPS OF SUGAR COATING     

Sealing Subcoating Smoothing Color coating Polishing

1.   

SEALING Water proofing Strengthens tablet core AGENTS: o Shellac o Cap or PVAP (cellulose acetate phthalate) (polyvinyl acetate phthalate) o Zein

2.   

SUBCOATING Round off the tablet edges Most critical step Steps that adds most weight (↑ 50-100%)  Agent: alternate layer of gum (acacia/ gelatin) ↑ dusting powder → to prevent from sticking

3. SMOOTHING  Smoothes out the sub coated surface  Agent = 60-70% syrup solution 4. COLOR COATING  Critical step → color & elegance  AGENT: 60-70% syrup + colorant  STEPS: o 4.1 Grossing – develops color o 4.2 Heavy syruping – build up color o 4.3 Regular syruping – final color 5. POLISHING  Produces gloss/ shine  AGENTS: o Beeswax o Carnauba wax o Candelila wax o Hard paraffin wax 2. FILM COATING  ADV: o Minimal increase in weight (thin polymer) o Easier and faster (single step)  Film coating component 1. Film former  Smooth, thin films  Ex: cellulose, methacrylate, PVA, PVP

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2. Plasticizer  Flexibility and elasticity  Ex: castor oil, glycerin, phthalate esters 3. Surfactant  Spreadability  Ex: polyoxyethylene sorbitan derivation (TWEEN)  (SPAN: sorbitan ester)  (cleaning & polishing) 4. Allotting substance  Water solubility/ permeability  Ex: PEG 5. Glossant  Luster or shine  Ex: beeswax

7. Wrinkling  Due to improper drying/ film former defect 8. Orange peel  Rough, non-glossy film surface  Inadequate spreading IV.

CAPSULES A. HARD GELATIN CAPSULE (HGC)  HGC shells are manufactured in a separate operation from filling o PIN METHOD/ RECIPROCATING DIE METHOD: Most common

STEPS IN FILLING HGC 

6. Volatile solvent/ vehicle  Ex: alcohol + acetone COATING DEFECTS 1. Mottling  Uneven color distribution 2. Sweating  Oily film or droplet of liquid 3. Bridging  Marking or obscured 4. Blooming  White spots on the surface or dull film  Under humid condition 5. Flaking  Due to rapid drying 6. Blistering  Reduced adhesion of film

   



Supply (incorporation of raw material capsule filling machine – hopper) o Capsule filling machine  Lily  Parke davig  Farmatic  Macofar Rectification Separation Filling (Tamping and disclosing) Joining/ closing – cluger or spindle dosing, stroking in or dribbling in accogel process (powders) Finishing o Pan-polishing o Cloth dusting (caps rub w/ cloth) o Brushing

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SPECIAL TECHNIQUE 1. Sealing a. Gelatin banding  Seals w/ a band of gelatin b. Heat welding  Fuses cap to body through double wall thickness  Thermal coupling c. Thermal coupling  Uses liquid wetting agent to lower melting point 2. Imprinting  Empty capsules 3. Coating  Modifies solubility (ex: shellac, CAP, salol (phenyl salicylate)  Enteric absorption

VI.

1.

INCORPORATION METHOD  Used of ointment roller mills to mix heat sensitive ointment bases  Water removable base  Water soluble base

2.

FUSION  Use of steam – jacketed kettles to melt anhydrous ointment bases and cooling gradually until congested  Constant stirring while cooling

MANUFACTURE OF LIQUID DOSAGE FORM A. EQUIPMENT

B. SOFT GELATIN CAPSULE  Formea, filled and seated in single operation methods 1. Plate process  Oldest method which was gelatin sheets 2. Rotary die process  Uses gelatin ribbons brought together between 2 rotating dyes 3. Reciprocating die process  Uses different filling method V.

MANUFACTURE OF SEMI-SOLID DOSAGE FORM A. OINTMENTS

1.

Mixing tank  Usually made of stainless steel, jacketed and have built in agitation system  GRADES (stainless steel) o SS 304 o SS 316 – most inert

2.

Mixer a. Mechanical stirrer  Mixers w/ various impellers mounted on shafts b. Colloid mill  For comminution of solids or dispersion of suspension c. Homogenizer  Compresses the liquid w. high pressure by a strong spring mechanism  Rotor and stator 14

d. Ultrasonifier  Uses ultrasonic energy to produce emulsion  Limited output, more expensive B. COMPONENTS API’s Solvent or vehicle Buffers Viscosity enhancer Humectants – (↑stability = ↑palatability) 6. Colorants: flavors, sweeteners and perfumes 7. Stability enhancers

b. Antioxidants  TRUE antioxidants o Read w/ free radicals o Ex: vit. E, BHT – Butylated Hydroxy Toluene, BHA Butylated Hydroxy Anisole, akyll gallates  Reducing agent o Ex: Vit. C, Sulfites

1. 2. 3. 4. 5.

1. Stability Enhancers

a. Preservatives  Prevent microbial growth  Paraben (endocrine destructors  Methyl paraben – molds  Propyl paraben – yeast & inhibit bacteria  Benzyl acid  Benzoic acid and Na, Benzoate  Sorbic acid & K sorbate  Chlorbutanol  Benzalkonium Cl  Thimerosal & phenyl mercuric acid

 Antioxidant synergist o React w. heavy metals o Ex: EDTA, citric acid, tartaric acid C. MANUFACTURING PROCEDURE     

Dispensing Mixing Storage and aging Titration Filling

2. MIXING  Dissolution of solutes  ↑ solubility  Speed of agitation  Temperature  Particle size  pH  Complexation C 3. Storage and aging  Optional step  Improves flavor or odor of volatile oils

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4. Filtration  TYPES: o Parallel – passes thru 1 filler medium o Series – 2 or more filter media  Filter media o Filter paper/ cloth – non-sterile products o Membrane filter – sterile product o QC TEST: Bubble point test  METHODS o Gravity – used in the lab. (small scale) o Vacuum – large scale o Pressure – large scale 5. Filling  METHODS o Gravimetric – large container and high viscosity o Volumetric – constant volume using piston action o Constant level – container is used to control the fill D. SUSPENSION FORMULATION:

2. Wetting agent  Displaces air from crevices of hydrophobic solids to allow penetration of H2O  Ex: glycerin, PPG, PEG, syrup 3. Flocculating agents  Decrease Zeta potential causing aggregation to avoid formation of cake (optional)  Ex: NaCl, KCl  Caking – formation of cement like substance at the bottom of the suspension  Deflocculated = ideal FORMATION 1. Precipitation method  By organic solvent  By changing pH  By double decomposition 2. Dispersion method  Common method  Suspension are wetted first before dispersing into the vehicle F. EMULSIONS TYPES

1. Suspending agent:  Viscosity enhancers  Ex: acacia, tragacanth, cellulose, bentonite, magma, veegum, agar, carrageenan, gelatin

1. Natural  Acacia, tragacanth, cellulose, agar, pectin, gelatin, wool fat 2. Finely divided solid  Bentonite, mg(OH)2, Al(OH)3, Mg Trisilicate 16

 3. Synthetic surfactant  Most common

2. Creaming  ↑ internal phase 3. Breaking/ cracking  Separation into a layer due to coalescence of internal phase  Irreversible

a. Anionic – effective at basic pH  Ex: soap, alkyl SO4, sarcosinates, SLES (sodium lauryl ethyl sulfate) b. Cationic effective at acidic pH  Anti-microbial agent  Ex: benzalkonium Cl, cetremonium Cl c. Amphoteric soap – both anionic and cationic  Ex: betaine, lecithin d. Non-ionic – not affect by pH  Span ® (lipophilic) – sorbitein ester  Tween ® (hydrophilic) – polysorbate (PEG)  Acetyl alcohol  Cocamide DEA

4. Phase inversion  w/o → o/w or vice versa  irreversible IV.

MANUFACTURE OF STERILE DOSAGE FORMS A. Sterilization method 1.

Moist heat  Autoclave or steam under pressure  MOA: protein coagulation  BI: Bacillus Stearothermophilus

2.

Dry heat  Oven (160-170© for 2-4 hours)  MOA: oxidant  BI: Bacillus subtilis

3.

Membrane filtration  For heat-labile solution  MOA: physical separation

4.

Gas Plastic container Ethylene oxides or Bpropiolactone MOA: alkylation BI: Bacillus subtilis

CONSIDERATION:     

Emulsion are unstable Internal phase = 40-60% Oil phase → high grade mineral oil Ideal mixing temp→ 70-77© If perfume is to added: o o/w → 43-45© o w/o → near RT

INSTABILITIES 1. Sedimentation  ↓ internal phase

   

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5.

Ionizing radiation  Gamma or cathode rays  MOA: DNA mutation  BI: Bacillus pumilus

2. Buffer area  For staging of supplies & equipment (class 10,000) 3. Compounding area (critical site)  Class 100/ ISO class 5 (highest)  Laminar air flow hood – vertical(preferred) or horizontal  Barrier isolator – for hazardous material  NMT 100,000 particles (>0.5 um) per cubic foot of air

B. DEPYROGENATION OVEN SETTING  180© for 4hrs  250© for 45mins  600© for 1min

C. STERILE PRODUCTION AREA  Clean rooms  Rooms in which the conc. of airborne particles is controlled  Positive pressure airflow  HEPA filters – removes 99.97% of particles (≥ 0.3 um) from the air (high efficiency particulate air) o Parts: pre-filter, blower, electro static precipitator  QC test: Dioctyl Phthalate test  Airlock – space with interlocked doors

4. Aseptic filling area  Packaging (class 100) 5. Quarantine area  For staging prior to testing 6. Finishing area D. MANUFACTURING PROCEDURE 1. 2.

COMPOUNDING  Sterile solid  Spray drying (not heat labile product)  Freeze drying (if aqueous solution through sublimation)/ lyophilization

3.

FILTRATION  Sterile solution o Clarification – 2-3um o Cold filtration – 0.2-0.3um

 PARTS 1. Ante-room  For cleaning & wearing of PPE (class 100,00/ ISO class 8)  Personal protecting equipment (PPE)

DISPENSING & CLEANING

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4.

FILLING  Sterile solids – net weight filling  Sterile liquids o Volumetric filling – most common o Gravimetric filling

5.    

SEALING Vials – siliconization or halogenization Ampule Tip/ Bead sealing – melt the tip to form a bead Pull sealing – melt below the tip then pull away (commonly use) ------END----

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