MANUF Flashcards by Zheian Daryll Taguic

small-scale preparation of drug products with reference from a prescription order for an individual patient

extemporaneous compounding

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The complete set of activities to produce a drug that comprise production and quality
control from dispensing of materials to the release for distribution of the finished
product.
LARGE-scale

manufacturing

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primary manufacturing activities

raw materials

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secondary manufacturing activities

drug delivery systems

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tertiary manufacturing activities

packaging, labelling, repacking

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Any organization or company involved in the manufacture, import, packaging and/or
distribution of drugs or medicines

Drug Establishment

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Registered owner of the drug product but subcontracts toll
manufacturers of such products to a licensed manufacturer.

Drug Trader

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any drug establishment that procures raw materials, active
ingredients and/or finished products from local establishments
for local distribution on a wholesale Basis

wholesaler

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Standard document which gives instructions to the Production Department to produce
a pharmaceutical product for distribution/sale in the market.

manufacturing order

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A specified quantity of a drug of uniform specified quality produced according to a single manufacturing order during the same cycle of manufacture

Batch

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Batch OR portion of batch having uniform specified quality and a distinctive identifying lot number

Lot

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Ensures that batches were properly made, and quality control tests were performed

Batch Manufacturing Record (BMR)

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Process of addition of an EXCESS of an active ingredient in an unstable
pharmaceutical preparation to compensate for its lost during the manufacture of the period

overages

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maximum overage limits of dry dosage forms

15%

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maximum overage limits of fluids

20%

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maximum overage limits of semisolids

25%

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maximum overage limits of vitamins

30%

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Develops new or improves existing products
Prepares the master formula; Justifies __________
Handles research activities
Facilities: _______, __________, _________

Research Department
overages
library, pilot plants, animal house

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Receives materials and supplies
Oversees warehousing and storage and shipping of the final product
Plans the production
Manufactures and packages products
Accomplishes __________________

Production Department

Batch Manufacturing Record

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Promotes the maximum volume of sales of products
Provides professional service through intelligent presentation
Handles advertising
Sponsors conventions, meetings

Marketing Department

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Performs sampling, testing, and assaying of products
Performs In-Process Quality Control and __________ _____________
Records and compiles results

Quality Control

environmental testing

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Assures that all operations meet required standards for safety and efficacy and ensures
cGMP compliance
Auditing, cGMP monitoring, environmental control
Prepares _________

Quality Assurance

SOP

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Locates, installs, repairs, and maintains equipment
Maintains ______ services

Engineering Department

Plant

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Purchases, receives, and inventories supplies

Purchasing Department

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* Conducts physical and medical examination of new employees and applicants * Performs Clinical Studies: ______ ________ ________ * Prepares literature and package inserts * Publishes house organ; Handles scholarships

Medical Department Clinical Research Associate

* Ensures compliance of company and its products with pertinent regulations and laws

Regulatory Department

An economical means of providing presentation, protection, preservation, identification, information, containment, convenience, and compliance for a drug product

Packaging

Device that holds a drug and is or may be in direct contact with the drug

Containers

direct contact w the drug ex. blister packs, bottles

primary container

indirect contact w drug ex. boxes

secondary

multiple secondary packs corrugated boxes

tertiary

Protects against extraneous solids

well closed container

* Protects from extraneous solids, liquids, or vapors * Protects from efflorescence, deliquescence, evaporation

tight containers

* Impervious to air or any other gas * Generally sterile

Hermetic container

Protects from photochemical deterioration Amber, opaque, blue

Light-resistant

Glass 1

Highly Resistant Borosilicate Parenteral Solutions

Glass 2

Treated Soda Lime Glass Parenteral solutions, buffered or acidic

Glass 3

Soda Lime Glass Dry powder for parenterals

Glass 4

General Soda Lime Glass Non-parenteral

Plastic Type 1

Polyethylene terephthalate beverages

Plastic Type 2 (PET)

High Density Polyethylene (HDPE)

Plastic Type 3

Polyvinyl Chloride (PVC) Blister pack

Plastic Type 4

Low Density Polyethylene (LDPE) Squeeze bottles

Plastic Type 5

Polypropylene (PP) Autoclavable

Plastic Type 6

Polystyrene (PS) General Purpose

Plastic Type 7

Others

freezer

-20 to -10 deg c

refrigerated

2 to 8 deg c

cold

nmt 8 deg c

cool

8 to 15 deg c

room temperature

temperature prevailing in the work area

controlled room temperature

20 to 25 deg c

warm

30 to 40 deg c

excessive heat

40 deg c

For stability testing -- I

Temperate 21 deg c or 45 RH

For stability testing -- II

Subtropical and Mediterranean 25 deg c or 65 RH

For stability testing -- III

Hot and Dry 30 deg c or 35% RH

For stability testing -- IVA

Hot and Humid 30 deg c or 65% RH

For stability testing -- IVB

Hot and Very Humid 30 deg c or 75% RH

* Size reduction occurs by fracture of particles between two sets of knives * Results in a coarse degree of size reduction * FOR: __________________

Cutter Mill fibrous crude drugs

* Series of 4 or more hammers hinged on a central shaft * FOR: ________________

Hammer Mill brittle and dry drugs

Filled up to 80% with porcelain or steel balls

Vibration Mill

Weighed pestle is turned by the friction of material passing beneath it as the mortar rotates.

End runner mill

Pestle equivalent (________) mounted horizontally and rotating against a bed of powder.

Edge runner mill muller

Crushes materials between 2 metal cylindrical rolls rotating and rubbing against each other

Roller Mill

A narrow cylinder contains balls of different diameters and rotates

Ball Mills

2 discs with closely spaced pins rotate against one another

Pin Mills

Consists of a hollow toroid where a fluid is injected as a high-pressure jet through nozzles at the bottom of the loop. Aka: ________________

fluid energy/set mills micronizer

* Cylindrical that rotates horizontally * Poor cross flow; Solve by: Baffles, Slants

Drum

Conical shaped at both ends Better cross flow

Double-cone

* Alternately combines and draws the ingredients apart. * S-S blending → most commonly used

V-shell/Twin-shell

* Consists of through-like shell with mounted spiral or helical blades * Difficult to clean

Ribbon

* Double through shaped shell with 2 sigma shaped blades fitted horizontally * Solid-liquid blending

Sigma blade

Screw type impellers rotating inside a conical shell

Vertical impeller

Paddle moves around its own axis and around the central axis

Planetary

* Most common, produces the best quality and cohesive granules * Disadvantage: NOT for moisture sensitive and heat labile; TIME-consuming

Wet Granulation

Formation of spherical particles

Spheronization

Brings together highly dispersed liquids and a sufficient volume of hot air to produce evaporation and drying of liquid droplets

Spray Drying

Melting of solids and reducing them to beads or powder by spraying molten feed into a stream of cold air or other gas

Spray Chilling / Congealing

Powders are suspended in the air through the high velocity air and granulating fluid sprayed in the powders inside the vessel

Fluidized Bed Granulator

* Used for drugs which do not compress well after wet granulation and are sensitive to moisture. * Make bigger pieces then break them down by oscillating granulator

Dry Granulation

* Formation of slugs. * Uses ___________

Slugging Tablet Press

* Formation of sheets. * Uses ____________

Roller Compaction Roller Compactor

Steps in Making Gelatin

* Manufactured in separate processes (Dipping pegs made of manganese bronze in a melted gelatin mixture) Dip-spin-dry-strip-trim-join-polish

Steps in Filling Gelatin Capsules

A. Pin Method/Reciprocating Die Method – most common B. Punch Method – small-scale 1. Rectification 2. Separation 3. Filling 4. Sealing/Joining/Closing 5. Ejection

oldest method of soft gelatin capsule

Plate Process

more efficient method of soft gelatin capsule

rotatory and reciprocating die process

reacts with free radicals ex ______________

True Antioxidants Vitamin E, BHT, BHA, Propyl Gallate

selectively oxidized instead of the drug ex ________________

Reducing Agents Vitamin C (most unstable vitamin) Hypophosphites Sulfites

Reacts with heavy metals, w/c catalyzes oxidation ex _____________________

Antioxidant Synergists Citric acid, Tartaric Acid, EDTA, Lecitin

Mixing of flavors ex _________________

blending fruit+sour

Addition of flavor whose intensity is longer and stronger ex ______________

overshadow methyl salicylate glycyrrhiza

Formation of insoluble compounds Emulsification, Increasing viscosity, Coating

Physical

Formation of chelates ex_________________

chemical caffeine + gentisic acid

Anesthetize taste buds ex ____________________

Physiological menthol, mint

A type of sweetening agent not absorbed by the small intestine

Non-nutritive

the standard nutritive sweetening agent

sucrose

sweetest sugar nutritive sweetening agent

fructose

d-glucose

dextrose

(sugar alcohol) non nutritive sweetening agents

mannitol, sorbitol, xylitol, erythritol

artificial sweetener 1000x sweeter than sucrose

sucralose

artificial sweetener 500x sweeter than sucrose

saccharin

artificial sweetener 300x sweeter than sucrose

Na saccharin

artificial sweetener 180-200x sweeter than sucrose

Acesulfame K Aspartame

artificial sweetener 30x sweeter than sucrose

Na cyclamate

a tablet colorants that is water soluble and organic

dyes

a tablet colorant that is water insoluble ; dye absorbed on a bed of inorganic oxide

Lakes

Examples of Dyes

FD&C Red 40 FD&C Yellow 6 FD&C Yellow 5 FD&C Green 3 FD&C Blue 1 FD&C Blue 2

Examples of Lakes

FD&C Red 3 D&C Yellow 10 D&C Red 22 D&C Red 28

FD&C Red 40

Allura red

FD&C Yellow 6

Sunset Yellow

FD&C Yellow 5

Tartrazine

FD&C Green 3

Fast Green

FD&C Blue 1

Brilliant Blue

FD&C Blue 2

Indigotine

FD&C Red 3

Erythrosine

D&C Yellow 10

QUINOLINE

D&C Red 22

Eosin Y

D&C Red 28

Phloxine Red

An inert substance added to increase tablet size to a manageable size

Diluents/Fillers/Bulking Agents

Most common tablet diluent/filler/bulking agent, NO reaction with most drugs 1. Anhydrous – __________ 2. Monohydrate – ______________ 3. Spray dried

Lactose direct compression wet granulation

a tablet diluent used as sweeteners

sucrose, dextrose

a tablet diluent that has good flow properties Diluent of choice : _______________

Microcrystalline Cellulose (BN: Avicel) Direct compression

sucrose based tablet diluent binder

Nutab

Only inorganic salt used as a diluent

Dibasic CaPO4

a tablet diluents used in chewable tablets

mannitol, xylitol

Used as diluent, binder, and disintegrant Modified starch: _________________

Starch Sta-Rx 1500, Cellutab

Promotes breaking of tablet after administration

Disintegrants

mechanism of disintegration: exposure to water → disintegrant swells (starch paste, alginates)

swelling

mechanism of disintegration: forms pores/spaces around tab, capillary action (MCC, calcium silicate

Wicking

mechanism of disintegration: effervescent tablets (release of what CO2

Release of Gas

Add _________ Disintegrant → ______________

Internal Granulation or External Compression

Running powder: _____________+______________

External disintegrant + lubricant

tablet disinetegrant : 5-20%

starch

1. ___________ (Natural Clay) 2. __________ (Synthetic clay)

clays bentonite veegum

Ion-exchange resin

Polacrillin K

Other disientegrants

Na CMC Cellulose Alginates Polyvinyl pyrrolidone Gums (Acacia, Tragacanth)

Effective at lower levels Hygroscopic

SUPERDISINTEGRANTS

Cross-linked cellulose derivatives

Crosscarmellose Na (Ac Disol)

Cross-linked polyvinylpyrrolidone

Crospovidone (Kollidon)

Cross-linked starch polymer aka ______________

Na Starch Glycolate (Explotab, Primojel) Na carboxymethylstarch

Agent that acts between surfaces in relative motion to prevent friction and wear Facilitates ejection from the die

Lubricant

Material that improves the flow characteristics of granules by aiding in the flow of materials through smaller apertures in the tablet press to the die

Glidant

Agent that prevents granules from picking to the faces of the punches and sticking to die walls

anti-adherent

LUBRICANT, GLIDANT, ANTI-ADHERENT

Stearates (Mg, Na, Ca)

LUBRICANT, ANTI-ADHERENT

Purified Talc

GLIDANTS

Colloidal Talc Colloidal SiO2 (Cab-O-Sil)

Added to promote adhesion among the particles of the formulation

Binders/Adhesives

ADHESIVE ACTIVITY

GLUCOSE > ACACIA > GELATIN > SIMPLE SYRUP > STARCH

Protein Substance

Gelatin

Gums

Acacia, Tragacanth

Cellulose Derivatives

Na CMC Methylcellulose HPMC

Binder of Choice for chewable tablet

PVP (Polyvinylpyrrolidone)

Adsorb fluids and moisture, keep products dry ex ___________________

Adsorbents * Magnesium oxide * Magnesium carbonate * Bentonite * Silicon dioxide - dessicants

Examples of Products that undergo direct compression

KCl (Kalium) Ascorbic Acid

Examples of Products that undergo dry granulation

aspirin

Examples of Products that undergo wet granulation

acetaminophen standard

Steps in wet granulation

Milling → Mixing → Add liquid binder → Wet screening → Drying → Dry screening → Add running powder → Compression → Coating

Steps in Dry granulation

Milling → Mixing → Slugging (or roller compaction) → Dry screening → Add running powder → Compression → Coating

Steps in Direct Compression

Milling → Mixing → Compression → Coating

part of a tablet press used for Storing of materials for compression

Hopper

part of a tablet press used for Distribution of materials into the die

Feed Shoe

part of a a tablet press used for compaction and determines the hardness of tablet

Punch

part of atablet press used to determine the size and and shape

die

part of a tablet press used for guiding the movement of the punches

Camtrack/ die table

removal of top and bottom crown of the tablets

capping

separation of two or more layers

lamination

due to raid expansion of tablets when deep concave punches are used

cracking

removal of small porion of granules or edge of tablets

Chipping

adherence to die wall; punch face

sticking

adherence to punch; punch tip

picking

due to free rotation of the punches and dies which have some engraving on the punch faces

double impression

uneven colored material due to excipients and process

mottling

method of tablet coating that is most widely used

pan coating

method of tablet coating characterized by increased in efficiency

pan spraying

method of tablet coating used for viscous solutions

pan pouring

Steps in Sugar coating: To protect tablet core from water ex _______________

Sealing/Waterproofing 10-30% alcoholic Shellac solution

Steps in Sugar coating: MOST CRITICAL STEP → MOST INCREASE IN WT. To round-off the contour, rapid-build up of size ex _______________________

Subcoating 70% Gelatin-acacia solution

To finalize the rounding off of tablet and smooth out the subcoated surfaces

smoothing/syruping/final rounding

1. ________: develop color, color base 2. _________: builds up color 3. __________: final color

Coloring Grossing Heavy Syruping Regular Syruping

Employs “jogging” Quick on-off process to attain final smoothness

Finishing

For sheen or gloss ex_______________

Polishing Beeswax

smooth thin films ex _____________

Film Formers Shellac, MC, Methacrylate, PVA, PVP

Provides water-solubility ex________________________

Alloying sub PEG

Imparts flexibility, elasticity ex ___________________

Plasticizer Castor oil/Glycerin

Enhances spreadability of films ex_________________________

Surfactants Tweens/Polysorbates

Provide luster ex ___________________

Glossant Beeswax

Vehicle to spread other components ex______________________

Volatile solvent ROH + Acetone

Enhance appearance ex_____________________

Opaquant/Colorant TiO2, FD&C

Palatability ex ________________

Sweetener Saccharin Flavorant, Aromatic Vanillin

Often associated with exposure of the tablet cores to the coating process condition rather than a direct effect of applied coating

Delayed Dissolution of IR

Partially spray dried materials accumulate within the logo, causing an unclear logo design

Logo Infilling

When the coating itself fills in the letters or logo of the tablet

Logo Bridging

Thermal Expansion of tablet cores caused by overdrying

Type 1 Cracking (HOT)

Core Swelling caused by excessive moisture uptake

Type 2 Cracking (COLD)

Partial spray drying or of overwetting causing the soft coating to rub

Rough coating

Tablets stick to each other ex ______________

Tablet Twinning Caplets

Removal of Coating from the tablet surface due to friction among themselves

Tablet Core Erosion

Tablets break during pan loading or unloading or while tumbling in the pan

Tablet Breakage

Film becomes chipped and dented, usually at the edges

Edge Chipping

Uneven color distribution

Mottling

marking are obscured

Bridging

Presence of an oily film on the coat of surface to the migration of additives to the surface

sweating

Craters appear exposing the tablet surface due to coating solution penetrating parts of the surface where it is more porous

cratering

Detachment of the film due to the entrapment of gas

Blistering

Manufacture of Select Solution (Aromatic Waters) a. by distillation _____________, _______________, __________

Strong Rose H20, Orange Flower H20, Hammamelis H20

Manufacture of Select Solution (Aromatic Waters) a. Simple solution _____________, _______________, __________

Camphor H2O, Chloroform H2O, Concentrated Peppermint H2O

Manufacture of Select Solution (Aromatic Waters) a. alternate solution by intervention _____________, _______________, __________

Cinnamon H2O

method used to manufacture select solutions specifically syrup which is faster risk __________________

solution by heat caramelization

Manufacture of Select Solution (syrup) a. percolation _____________, _______________, __________

column, ipecac syrup, simple syrup

Manufacture of Select Solution (syrups) a. reconstitution _____________

senna syrup

Manufacture of Select Solution (tinctures) a. simple solution _________, _____________

I2 tincture, Thimerosal

Manufacture of Select Solution (tincture) a. percolation __________, ____________

belladonna tincture, vanilla tincture

Manufacture of Select Solution (tincture) a. maceration _________, _________, _______

soaking, sweet orange peel, compound benzoin tincture

Manufacture of Select Solution (spirit) a. simple solution ___________________

Aromatic NH3 spirit

Manufacture of Select Solution (spirit) a. solution w/ maceration __________________

peppermint spirit

Manufacture of Select Solution (spirit) a. chemical reaction _______________________

ethylnitrite

Manufacture of Select Solution (spirit) a. distillation _________, ___________

brandy, whisky

General Manufacture of solution: Preparation of formulation, materials, and equipment

Dispensing

General Manufacture of solution: * Charge the solute to the solvent * Agitate with the use of mixers until solution is homogenous * Heat may be employed to increase solubility * Solutes in small conc. (ex. Dyes) must be pre-dissolved prior to mixing with the whole batch

COMPOUNDING/MIXING

Mixing Tanks: Most widely used stainless steel ___% Cr ___% Ni

SS304 18% 8%

Mixing Tanks: Most inert esp. for chlorinated solutions ___% Cr ___% Ni ___% Mo

SS316 16% 10% 2%

* Aim for 3-5 microns * Filter media: (1) ________; (2) ________; (3) _________; (4) _______

FILTRATION/CLARIFICATION cellulose nitrate polyamde polyvinylidene chloride nylon

Types of filtration that contains 1 filter and is faster

Parallel

Type of filtration that contains more than 1 filter and is more efficient

series

type of filter used for slow, difficult filtration (ex ______)

gravity magma

types of filter used for large quantities

vacuum (pull)

type of filter that is fast and achieves a highly polished product

pressure (push)

The use of a clarifying agent (________) to allow complete blending of all the components and enhance the odor and flavor.

ageing/clarification bentonite

Should be carefully monitored and allow constant mixing

Filling and Packing

Weighing according to weight For large containers, highly viscous liquids, mobile and frothy solutions

Gravimetric

Positive displacement of piston action or by the pumping of a liquid at a constant pressure and gives constant volume

Volumetric

uses the container as the means for controlling the fill. Adjusted by height.

Constant-Level

Viscosity-increasing agents used to reduce sedimentation rate of particles in a vehicle

SUSPENDING AGENTS

example of clays as suspending agent

Veegum, bentonite, kaolin

example of hydrocolloids as supending agent

acacia, tragacanth, cellulose derivatives

other suspending agents

Agar, Gelatin, Pectin, Gelatinized starch

Displaces air from the crevices of drug particles to allow penetration of water ex______________

Wetting Agents Glycerin, sorbitol solution, syrup

Decreases zeta potential of the suspended charged particles that cause aggregation. ex__________

Flocculating agents Electrolytes (NaCl, KCl, AlCl3)

method of suspension wherein Finely divided solid drug is wetted first before dispersion in the liquid vehicle

Dispersion

method of suspension wherein Finely divided solid drug is reacted with another substance ex ___________________

Precipitation Milk of Magnesia

Acts as a bridge between two immiscible phases Stabilizer of the internal phase Retards coalescence of the globules

EMULSIFYING AGENTS

a natural emulsifier that forms hydrophilic colloids ex _____________

carbohydrates acacia, tragacanth, pectin, cellulose derivatives

a natural emulsifier that produces o/w emulsions but can become too fluid upon standing ex _______________

proteins agg yolk, gelatin, asein

Form o/w emulsions when the insoluble material is added to the aq. Phase if there is a greater volume of the aqueous phase than of the oleaginous phase ex _____________

Finely Divided Solids bentonite magma, veegum

Thickening agents and stabilizers for o/w emulsions of certain topical preparations ex ______________________

High Molecular weight alcohols stearyl/cetyl alcohol, glyceryl monostearate (o/w), cholesterol derivatives (w/)

emulsifier that contains both hydrophilic and lipophilic groups

synthetic wetting agents

a type of synthetic wetting agents that is negative, effective at basic ph ex __________________

anionic SLS, soap, sarcosinates

a type of synthetic wetting agent that is positive, effective at acidic ph ex _________________

cationic benzalkonium cl, cetylpyridinium cl

a type of synthetic wetting agent not affected by ph ex ___________________

nonionic sorbitan esters/SPANS, Polysorbates/TWEENS

a type of synthetic wetting agent that is both cationic and anionic ex ___________

amphoteric lecithin, betaine

a method of ointment preparation by mixing components to achieve a uniform preparation via levigation or geometric dilution equipment __________________

incorporation ointment roller mills, unguator

a method of ointment preparation : Components are combined by melting together (70-75C) and cooled with constant stirring until congealed equipment ___________________

Fusion stem-jacketed kettle

Molding of suppository by using fingers

Hand rolling

a method of sppository by using a mold

compression

Should be carried out in clean areas, entry to which should be thru airlocks for personnel, equipment and materials This is why we use HEPA: _____________

Sterile Dosage Forms High Efficiency Particulate Air

An area with defined environmental control of particulate and microbical contamination, constructed and used in such a way as to reduce the introduction, generation, and retention of contaminants within the area. measure by : ______________________

Clean Area number of particles > or = 0.5 micron in 1 cubic foot of sampled air

An enclosed space with 2 or more doors, which is interposed between two or more rooms

airlock

Step 1 in Cleaning Areas

Cleaning

Step 2 in Cleaning Areas

Compounding

Step 3 in Cleaning Areas

Filtering

Step 4 in Cleaning Areas

Filling

Step 5 in Cleaning Areas 1. ______________: made by melting the tip of the neck of an ampule to form a bead; not efficient, slower 2. ______________ made by heating the neck of a rotating ampule below the tip and pulling the glass away; more efficient

Sealing Tip seal (bead seal) Pull seal

Step 6 in Cleaning Areas

Sterilization and Quality Control

Step 7 in Cleaning Areas

Packaging